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Sample records for b-cell lymphoma correlation

  1. p53 and bcl-2 expression in high-grade B-cell lymphomas: correlation with survival time.

    PubMed Central

    Piris, M. A.; Pezzella, F.; Martinez-Montero, J. C.; Orradre, J. L.; Villuendas, R.; Sanchez-Beato, M.; Cuena, R.; Cruz, M. A.; Martinez, B.; Pezella F [corrected to Pezzella, F. ].

    1994-01-01

    B-cell high-grade lymphomas are heterogeneous in terms of histology, clinical presentation, treatment response and prognosis. As bcl-2 and p53 gene deregulations are frequently involved in several types of lymphoid malignancies, we aimed our investigation at the study of the relation between bcl-2 and p53 expression and survival probability in a group of 119 patients with B-cell high-grade lymphoma. These were obtained from the Virgen de la Salud Hospital, Toledo, Spain (73 cases), John Radcliffe Hospital, Oxford, UK (31 cases), and the Istituto Nazionale dei Tumori, Milan, Italy (15 cases). The relation between bcl-2 protein expression and survival was small, depending on the primary localisation of the tumour (in lymph node of mucosae), and lacked a significant correlation with overall survival. In contrast with this, p53 expression was related to survival probability in our series, this relation being both significant and independent of histological diagnosis. p53-positive patients showed a sudden decrease in life expectancy in the first months after diagnosis. Multivariant regression analysis confirmed that the only parameters significantly related with survival were extranodal origin, which is associated with a better prognosis, and p53 expression, which indicates a poor prognosis. Simultaneous expression of bcl-2 and p53 was associated with a poorer prognosis than p53 alone. This is particularly significant for large B-cell lymphomas presenting in lymph nodes. The cumulative poor effect of both p53 and bcl-2 in large B-cell lymphomas, which is more significant in nodal tumours, could confirm the existence of a multistep genetic deregulation in non-Hodgkin's lymphoma. This indicates that the genetic mechanisms controlling apoptosis and their disregulation are critical steps in the progression of lymphomas. PMID:8297731

  2. High concordance of gene expression profiling-correlated immunohistochemistry algorithms in diffuse large B-cell lymphoma, not otherwise specified.

    PubMed

    Hwang, Hee Sang; Park, Chan-Sik; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung

    2014-08-01

    Diffuse large B-cell lymphoma (DLBCL) is classified into prognostically distinct germinal center B-cell (GCB) and activated B-cell subtypes by gene expression profiling (GEP). Recent reports suggest the role of GEP subtypes in targeted therapy. Immunohistochemistry (IHC) algorithms have been proposed as surrogates of GEP, but their utility remains controversial. Using microarray, we examined the concordance of 4 GEP-correlated and 2 non-GEP-correlated IHC algorithms in 381 DLBCLs, not otherwise specified. Subtypes and variants of DLBCL were excluded to minimize the possible confounding effect on prognosis and phenotype. Survival was analyzed in 138 cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)-treated and 147 rituximab plus CHOP (R-CHOP)-treated patients. Of the GEP-correlated algorithms, high concordance was observed among Hans, Choi, and Visco-Young algorithms (total concordance, 87.1%; κ score: 0.726 to 0.889), whereas Tally algorithm exhibited slightly lower concordance (total concordance 77.4%; κ score: 0.502 to 0.643). Two non-GEP-correlated algorithms (Muris and Nyman) exhibited poor concordance. Compared with the Western data, incidence of the non-GCB subtype was higher in all algorithms. Univariate analysis showed prognostic significance for Hans, Choi, and Visco-Young algorithms and BCL6, GCET1, LMO2, and BCL2 in CHOP-treated patients. On multivariate analysis, Hans algorithm retained its prognostic significance. By contrast, neither the algorithms nor individual antigens predicted survival in R-CHOP treatment. The high concordance among GEP-correlated algorithms suggests their usefulness as reliable discriminators of molecular subtype in DLBCL, not otherwise specified. Our study also indicates that prognostic significance of IHC algorithms may be limited in R-CHOP-treated Asian patients because of the predominance of the non-GCB type. PMID:24705314

  3. High concordance of gene expression profiling-correlated immunohistochemistry algorithms in diffuse large B-cell lymphoma, not otherwise specified.

    PubMed

    Hwang, Hee Sang; Park, Chan-Sik; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung

    2014-08-01

    Diffuse large B-cell lymphoma (DLBCL) is classified into prognostically distinct germinal center B-cell (GCB) and activated B-cell subtypes by gene expression profiling (GEP). Recent reports suggest the role of GEP subtypes in targeted therapy. Immunohistochemistry (IHC) algorithms have been proposed as surrogates of GEP, but their utility remains controversial. Using microarray, we examined the concordance of 4 GEP-correlated and 2 non-GEP-correlated IHC algorithms in 381 DLBCLs, not otherwise specified. Subtypes and variants of DLBCL were excluded to minimize the possible confounding effect on prognosis and phenotype. Survival was analyzed in 138 cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)-treated and 147 rituximab plus CHOP (R-CHOP)-treated patients. Of the GEP-correlated algorithms, high concordance was observed among Hans, Choi, and Visco-Young algorithms (total concordance, 87.1%; κ score: 0.726 to 0.889), whereas Tally algorithm exhibited slightly lower concordance (total concordance 77.4%; κ score: 0.502 to 0.643). Two non-GEP-correlated algorithms (Muris and Nyman) exhibited poor concordance. Compared with the Western data, incidence of the non-GCB subtype was higher in all algorithms. Univariate analysis showed prognostic significance for Hans, Choi, and Visco-Young algorithms and BCL6, GCET1, LMO2, and BCL2 in CHOP-treated patients. On multivariate analysis, Hans algorithm retained its prognostic significance. By contrast, neither the algorithms nor individual antigens predicted survival in R-CHOP treatment. The high concordance among GEP-correlated algorithms suggests their usefulness as reliable discriminators of molecular subtype in DLBCL, not otherwise specified. Our study also indicates that prognostic significance of IHC algorithms may be limited in R-CHOP-treated Asian patients because of the predominance of the non-GCB type.

  4. Primary cutaneous B-cell lymphoma.

    PubMed

    Bogle, Melissa A; Riddle, Christy C; Triana, Emily M; Jones, Dan; Duvic, Madeleine

    2005-09-01

    Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.

  5. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-04-26

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma,; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  6. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

    PubMed Central

    Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas

    2015-01-01

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell–like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  7. B Cell Lymphoma mimicking Rheumatoid Arthritis.

    PubMed

    Cosatti, M A; Pisoni, C N; Altuve, J L; Lorente, C

    2016-01-01

    Non Hodking´s lymphoma (NHL) may involve bones but synovial involvement is uncommon. We describe a patient who presented with polyarthritis, sicca symptoms and rash suggestive of rheumatoid arthritis. An atypical skin rash prompted skin and synovial biopsies. A diagnosis of synovial and skin malignant large B-cell lymphoma anaplastic subtype was performed. Chemotherapy with dexamethasone, vincristine and rituximab was started. Following treatment the patient had complete resolution of cutaneous and articular lymphoma manifestations. PMID:27419896

  8. Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies: A Case Report.

    PubMed

    Kim, Yeong-Jin; Kim, Hee Kyung; Yang, Deok-Hwan; Jung, Shin; Noh, Myung-Giun; Lee, Jae-Hyuk; Lee, Kyung-Hwa; Moon, Kyung-Sub

    2016-02-01

    This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma.A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma.

  9. Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies

    PubMed Central

    Kim, Yeong-Jin; Kim, Hee Kyung; Yang, Deok-Hwan; Jung, Shin; Noh, Myung-Giun; Lee, Jae-Hyuk; Lee, Kyung-Hwa; Moon, Kyung-Sub

    2016-01-01

    Abstract This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma. A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL. Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma. PMID:26937937

  10. Epigenetics and B-cell Lymphoma

    PubMed Central

    Shaknovich, Rita; Melnick, Ari

    2011-01-01

    STRUCTURED ABSTRACT Purpose of review It has only recently become apparent that mutations in epigenetic mechanisms and perturbation of epigenomic patterning are frequent events in B-cell lymphomas. The purpose of this review is to highlight these new findings and provide a conceptual framework for understanding how epigenetic modifications might contribute to lymphomagenesis. Recent findings Somatic mutations affecting histone methyltransferases such as EZH2 and MLL2, histone demethylases including UTX and JMJD2C and histone acetyltransferases including CBP and p300 are recurrent and common in lymphomas. These mutations result in disruption of chromatin structure and functions of other proteins, ultimately causing aberrant transcriptional programming affecting multiple gene networks. Widespread perturbation of cytosine methylation patterning now appears to be a hallmark of B-cell lymphomas and occurs in specific patterns that can distinguish disease subtypes. Therapeutic targeting strategies can overcome abnormal epigenetic mechanisms and potently kill lymphoma cells. Summary Newly discovered epigenetic lesions may provide critical insights into the genesis of B-cell lymphomas but further studies are required to understand how they affect biological mechanism. Epigenetic lesions offer tremendous opportunities for the development of improved biomarkers and treatments. PMID:21577103

  11. Primary Mediastinal B-Cell Lymphoma

    PubMed Central

    Pileri, Stefano A.; Gaidano, Gianluca; Zinzani, Pier Luigi; Falini, Brunangelo; Gaulard, Philippe; Zucca, Emanuele; Pieri, Federica; Berra, Eva; Sabattini, Elena; Ascani, Stefano; Piccioli, Milena; Johnson, Peter W. M.; Giardini, Roberto; Pescarmona, Edoardo; Novero, Domenico; Piccaluga, Pier Paolo; Marafioti, Teresa; Alonso, Miguel A.; Cavalli, Franco

    2003-01-01

    Although primary mediastinal (thymic) large B-cell lymphoma has been primarily studied, its precise phenotype, molecular characteristics, and histogenesis are still a matter of debate. The International Extranodal Lymphoma Study Group collected 137 such cases for extensive pathological review. Histologically, the lymphomatous growth was predominantly diffuse with fibrosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. On immunohistochemistry, the following phenotype was observed: CD45+, CD20+, CD79a+, PAX5/BSAP+, BOB.1+, Oct-2+, PU.1+, Bcl-2+, CD30+, HLA-DR+, MAL protein+/−, Bcl-6+/−, MUM1/IRF4+/−, CD10−/+, CD21−, CD15−, CD138−, CD68−, and CD3−. Immunoglobulins were negative both at immunohistochemistry and in situ hybridization. Molecular analysis, performed in 45 cases, showed novel findings. More than half of the cases displayed BCL-6 gene mutations, which usually occurred along with functioning somatic IgVH gene mutations and Bcl-6 and/or MUM1/IRF4 expression. The present study supports the concept that a sizable fraction of cases of this lymphoma are from activated germinal center or postgerminal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective immunoglobulin production despite the expression of OCT-2, BOB.1, and PU.1 transcription factors and the lack of IgVH gene crippling mutations. PMID:12507907

  12. AT13387 in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2016-10-06

    Anaplastic Large Cell Lymphoma, ALK-Positive; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma

  13. Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type.

    PubMed

    Senff, Nancy J; Zoutman, Willem H; Vermeer, Maarten H; Assaf, Chalid; Berti, Emilio; Cerroni, Lorenzo; Espinet, Blanca; de Misa Cabrera, Ricardo Fernandez; Geerts, Marie-Louise; Kempf, Werner; Mitchell, Tracey J; Paulli, Marco; Petrella, Tony; Pimpinelli, Nicola; Santucci, Marco; Whittaker, Sean J; Willemze, Rein; Tensen, Cornelis P

    2009-05-01

    Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) is the most aggressive type of primary cutaneous B-cell lymphoma. In a recent study on 12 patients it was found that inactivation of CDKN2A by either deletion of 9p21.3 or promoter hypermethylation is correlated with a worse prognosis. In the present EORTC multicenter study, skin biopsies of 64 PCLBCL, LT patients were analyzed by multiplex ligation-dependent probe amplification to validate these previous results and to fine-map the losses in this region. Although no minimal common region of loss could be identified, most homozygous loss was observed in the CDKN2A gene (43 of 64; 67%) encoding p16 and p14ARF. Promoter hypermethylation of p16 and p14ARF was found in six and zero cases, respectively. Survival was markedly different between patients with versus without aberrations in the CDKN2A gene (5-year disease-specific survival 43 versus 70%; P=0.06). In conclusion, our results confirm that deletion of chromosome 9p21.3 is found in a considerable proportion of PCLBCL, LT patients and that inactivation of the CDKN2A gene is associated with an unfavorable prognosis. In most patients the deletion involves a large area of at least several kilobase pairs instead of a small minimal common region.

  14. [Primary mediastinal B-cell lymphoma].

    PubMed

    Coso, D; Rey, J; Bouabdallah, R

    2010-02-01

    Primary mediastinal B-cell lymphoma (PMBL) is a clinicopathological entity among the world health organization classification of lymphoid neoplasms. PMBL often concerns young adults, and the disease remains a localized disease in the majority of cases. The outcome of patients with PMBL is variable and unlike diffuse large cell lymphomas, the international prognostic index seems to be less applicable to such disease. The combination of rituximab and chemotherapy is the gold standard treatment of patients with good prognosis features and allows high cure rates. However, high-dose chemotherapy supported by peripheral blood stem cell support is often warranted in poor-prognosis patients. The use of positrons emission tomography examination is more and more used in such situations to select the best therapeutic strategy. PMID:20207294

  15. Primary B-cell lymphoblastic lymphoma of the testis.

    PubMed

    Tombolini, Flavia; Lacetera, Vito; Gini, Guido; Capelli, Debora; Leoni, Pietro; Montironi, Rodolfo; Galosi, Andrea Benedetto; Muzzonigro, Giovanni

    2014-12-01

    We present a rare case of primary lymphoblastic B-cell lymphoma of the testis focusing on ultrasonographic and pathological features and clinical implications. Pathological examination revealed primary testicular lymphoblastic B-cell lymphoma which was treated with adjuvant chemotherapy, including rachicentesis with administration of chemotherapy and with radiotherapy of contralateral testis. Primary testicular lymphoblastic B cell lymphoma is an aggressive disease and it is necessary a multimodal therapy (surgery, chemotherapy and radiotherapy) to prevent metastasis. PMID:25641484

  16. B-cell markers in malignant B-cell lymphoma with scleroderma-like manifestation.

    PubMed

    Van Joost, T; Stolz, E; Blog, F B; Van der Kwast, T H; Vuzevski, V D; Van Dongen, J M

    1984-12-01

    A case is described of malignant B-cell lymphoma with scleroderma-like manifestation. Using different monoclonals as B-cell markers the tumor appeared to be positive for surface immunoglobulins (SmIg) and for B2-antigen, but negative for intracytoplasmic immunoglobulin (CIg), BA2- and FMC7-antigens. Therefore, the tumor could be determined as a highly differentiated Sm-positive early B-cell type of B-cell lymphoma. In this clinically rare manifestation of cutaneous B-cell lymphoma aspects of the cell morphology and of cellular mediated immunity are briefly discussed.

  17. Relation of CD30 expression to survival and morphology in large cell B cell lymphomas.

    PubMed Central

    Noorduyn, L A; de Bruin, P C; van Heerde, P; van de Sandt, M M; Ossenkoppele, G J; Meijer, C J

    1994-01-01

    AIMS--To investigate whether CD30 expression is correlated with anaplastic morphology, and whether this correlated with a better survival in large cell B cell lymphomas, as has been described for T cell lymphomas. METHODS--CD30 expression was investigated using frozen sections in a series of 146 large cell B cell lymphomas. Clinical data and follow up information were collected from 25 lymphomas with strong CD30 expression, 30 lymphomas with partial CD30 expression, and a control group of 25 lymphomas which did not express CD30. RESULTS--Morphological distinction between anaplastic and non-anaplastic tumours was difficult. Of the cases with an anaplastic morphology, 50% were CD30 positive, as were 24% of the polymorphic centroblastic B cell lymphomas. Only 65% of the morphologically non-anaplastic tumours were completely CD30 negative. There was no difference in survival among patients with lymphomas expressing CD30 and those that did not. Patients with morphologically anaplastic B cell lymphomas did not differ in their survivals from those with other high grade B cell lymphomas. Clinical stage at presentation was the only variable that was significantly associated with survival. CONCLUSIONS--CD30 expression occurs frequently in large cell B cell lymphomas and is poorly related to anaplastic morphology. Morphological distinction between anaplastic and non-anaplastic tumours is difficult. In contrast to T cell lymphomas, CD30 positive B cell lymphomas do not show a relatively favourable clinical course. The results presented here raise serious doubts as to whether large cell B cell lymphoma, based on the expression of CD30 or anaplastic morphology, can really be termed a separate entity. Images PMID:8132806

  18. CD3+/CD16+CD56+ cell numbers in peripheral blood are correlated with higher tumor burden in patients with diffuse large B-cell lymphoma.

    PubMed

    Hus, Iwona; Starosławska, Elżbieta; Bojarska-Junak, Agnieszka; Dobrzyńska-Rutkowska, Aneta; Surdacka, Agata; Wdowiak, Paulina; Wasiak, Magdalena; Kusz, Maria; Twardosz, Anna; Dmoszyńska, Anna; Roliński, Jacek

    2011-01-01

    Diffuse large B-cell lymphoma is the commonest histological type of malignant lymphoma, and remains incurable in many cases. Developing more efficient immunotherapy strategies will require better understanding of the disorders of immune responses in cancer patients. NKT (natural killer-like T) cells were originally described as a unique population of T cells with the co-expression of NK cell markers. Apart from their role in protecting against microbial pathogens and controlling autoimmune diseases, NKT cells have been recently revealed as one of the key players in the immune responses against tumors. The objective of this study was to evaluate the frequency of CD3(+)/CD16(+)CD56(+) cells in the peripheral blood of 28 diffuse large B-cell lymphoma (DLBCL) patients in correlation with clinical and laboratory parameters. Median percentages of CD3(+)/CD16(+)CD56(+) were significantly lower in patients with DLBCL compared to healthy donors (7.37% vs. 9.01%, p = 0.01; 4.60% vs. 5.81%, p = 0.03), although there were no differences in absolute counts. The frequency and the absolute numbers of CD3(+)/CD16(+)CD56(+) cells were lower in advanced clinical stages than in earlier ones. The median percentage of CD3(+)/CD16(+)CD56(+) cells in patients in Ann Arbor stages 1-2 was 5.55% vs. 3.15% in stages 3-4 (p = 0.02), with median absolute counts respectively 0.26 G/L vs. 0.41 G/L (p = = 0.02). The percentage and absolute numbers of CD3(+)/CD16(+)CD56(+) cells were significantly higher in DL -BCL patients without B-symptoms compared to the patients with B-symptoms, (5.51% vs. 2.46%, p = 0.04; 0.21 G/L vs. 0.44 G/L, p = 0.04). The percentage of CD3(+)/CD16(+)CD56(+) cells correlated adversely with serum lactate dehydrogenase (R= -445; p 〈 0.05) which might influence NKT count. These figures suggest a relationship between higher tumor burden and more aggressive disease and decreased NKT numbers. But it remains to be explained whether low NKT cell counts in the peripheral blood

  19. The molecular biology of diffuse large B-cell lymphoma.

    PubMed

    Frick, Mareike; Dörken, Bernd; Lenz, Georg

    2011-12-01

    Diffuse large B-cell lymphoma (DLBCL) represents the most common type of malignant lymphoma. In the last few years, significant progress has been achieved in the understanding of the molecular pathogenesis of this entity. Gene expression profiling has identified three molecular DLBCL subtypes, termed germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). In this review, we summarize our current understanding of the biology of these DLBCL subtypes with a special emphasis on novel diagnostic and therapeutic approaches. PMID:23556103

  20. Novel Therapies for Aggressive B-Cell Lymphoma

    PubMed Central

    Foon, Kenneth A.; Takeshita, Kenichi; Zinzani, Pier L.

    2012-01-01

    Aggressive B-cell lymphoma (BCL) comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and mantle cell lymphoma (MCL). DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper. PMID:22536253

  1. Study of BKM120 & Rituximab in Patients With Relapsed or Refractory Indolent B-Cell Lymphoma

    ClinicalTrials.gov

    2016-10-18

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  2. Cyclin Dl expression in B-cell non Hodgkin lymphoma.

    PubMed

    Aref, Salah; Mossad, Y; El-Khodary, T; Awad, M; El-Shahat, E

    2006-10-01

    Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL). In this study, we investigated the expression of cyclin Dl in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin Dl protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin Dl over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin Dl over expression and that with normal cyclin Dl expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin D1 over expression is associated with poor outcome of NHL patients. Cyclin Dl over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin Dl over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL. PMID:17607588

  3. Alisertib and Romidepsin in Treating Patients With Relapsed or Refractory B-Cell or T-Cell Lymphomas

    ClinicalTrials.gov

    2016-10-25

    Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Hodgkin Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma

  4. BCL2 Antibodies Targeted At Different Epitopes Detect Varying Levels of Protein Expression and Correlate with Frequent Gene Amplification in Diffuse Large B Cell Lymphoma

    PubMed Central

    Kendrick, Samantha L.; Redd, Lucas; Muranyi, Andrea; Henricksen, Leigh A.; Stanislaw, Stacey; Smith, Lynette M.; Perry, Anamarija M.; Fu, Kai; Weisenburger, Dennis D.; Rosenwald, Andreas; Ott, German; Gascoyne, Randy D.; Jaffe, Elaine S.; Campo, Elías; Delabie, Jan; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Staudt, Louis M.; Chan, Wing Chung; Steidl, Christian; Grogan, Thomas M.; Rimsza, Lisa M.

    2014-01-01

    Summary Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare two alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in two independent DLBCL cohorts E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse OS. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in-situ hybridization (Dual ISH) as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence ISH for translocation but a higher amplification frequency, indicating that BCL2 amplification may be under-reported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false-negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies. PMID:25090918

  5. Cutaneous primary B-cell lymphomas: from diagnosis to treatment*

    PubMed Central

    Lima, Margarida

    2015-01-01

    Primary cutaneous B-cell lymphomas are a heterogeneous group of mature B-cells neoplasms with tropism for the skin, whose biology and clinical course differ significantly from the equivalent nodal lymphomas. The most indolent forms comprise the primary cutaneous marginal zone and follicle center B-cell lymphomas that despite the excellent prognosis have cutaneous recurrences very commonly. The most aggressive forms include the primary cutaneous large B-cell lymphomas, consisting in two major groups: the leg type, with poor prognosis, and others, the latter representing a heterogeneous group of lymphomas from which specific entities are supposed to be individualized over time, such as intravascular large B-cell lymphomas. Treatment may include surgical excision, radiotherapy, antibiotics, corticosteroids, interferon, monoclonal antibodies and chemotherapy, depending on the type of lymphoma and on the type and location of the skin lesions. In subtypes with good prognosis is contraindicated overtreatment and in those associated with a worse prognosis the recommended therapy relies on CHOP-like regimens associated with rituximab, assisted or not with local radiotherapy. We review the primary cutaneous B-cell lymphomas, remembering the diagnostic criteria, differential diagnosis, classification, and prognostic factors and presenting the available therapies. PMID:26560215

  6. Tetraspanin CD37 protects against the development of B cell lymphoma.

    PubMed

    de Winde, Charlotte M; Veenbergen, Sharon; Young, Ken H; Xu-Monette, Zijun Y; Wang, Xiao-Xiao; Xia, Yi; Jabbar, Kausar J; van den Brand, Michiel; van der Schaaf, Alie; Elfrink, Suraya; van Houdt, Inge S; Gijbels, Marion J; van de Loo, Fons A J; Bennink, Miranda B; Hebeda, Konnie M; Groenen, Patricia J T A; van Krieken, J Han; Figdor, Carl G; van Spriel, Annemiek B

    2016-02-01

    Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention. PMID:26784544

  7. Tetraspanin CD37 protects against the development of B cell lymphoma

    PubMed Central

    de Winde, Charlotte M.; Veenbergen, Sharon; Young, Ken H.; Xu-Monette, Zijun Y.; Wang, Xiao-xiao; Xia, Yi; Jabbar, Kausar J.; van den Brand, Michiel; van der Schaaf, Alie; Elfrink, Suraya; van Houdt, Inge S.; Gijbels, Marion J.; van de Loo, Fons A.J.; Bennink, Miranda B.; Hebeda, Konnie M.; Groenen, Patricia J.T.A.; van Krieken, J. Han; Figdor, Carl G.; van Spriel, Annemiek B.

    2016-01-01

    Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center–derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37– B cell malignancies as a possible therapeutic intervention. PMID:26784544

  8. Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2016-10-27

    Activated B-Cell-Like Diffuse Large B-Cell Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  9. Diffuse Large B-Cell Lymphoma Version 1.2016.

    PubMed

    Zelenetz, Andrew D; Gordon, Leo I; Wierda, William G; Abramson, Jeremy S; Advani, Ranjana H; Andreadis, C Babis; Bartlett, Nancy; Byrd, John C; Fayad, Luis E; Fisher, Richard I; Glenn, Martha J; Habermann, Thomas M; Lee Harris, Nancy; Hernandez-Ilizaliturri, Francisco; Hoppe, Richard T; Horwitz, Steven M; Kaminski, Mark S; Kelsey, Christopher R; Kim, Youn H; Krivacic, Susan; LaCasce, Ann S; Lunning, Matthew; Nademanee, Auayporn; Porcu, Pierluigi; Press, Oliver; Rabinovitch, Rachel; Reddy, Nishitha; Reid, Erin; Roberts, Kenneth; Saad, Ayman A; Sokol, Lubomir; Swinnen, Lode J; Vose, Julie M; Yahalom, Joachim; Zafar, Nadeem; Dwyer, Mary; Sundar, Hema

    2016-02-01

    Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes. PMID:26850490

  10. Rituximab and Interleukin-12 in Treating Patients With B-Cell Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2013-08-23

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma

  11. Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma?

    PubMed

    Dunleavy, Kieron; Grant, Cliona; Eberle, Franziska C; Pittaluga, Stefania; Jaffe, Elaine S; Wilson, Wyndham H

    2012-09-01

    Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma." Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called "anaplastic large-cell lymphoma Hodgkin-like," and their outcome with standard approaches was poor, with short overall survivals. In this review-following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS-we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically. PMID:22833351

  12. R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-10-13

    Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  13. Biological correlation between glucose transporters, Ki-67 and 2-deoxy-2-[18F]-fluoro-D-glucose uptake in diffuse large B-cell lymphoma and natural killer/T-cell lymphoma.

    PubMed

    Liu, Y M; Zhai, X M; Wu, Y W

    2016-01-01

    The purpose of this study was to investigate the association between cellular 2-deoxy-2-[18F]-fluoro-D-glucose ((18)F-FDG) uptake and the expression of several subtypes of glucose transporters (GLUT) and Ki-67 in diffuse large B-cell lymphoma (DLBCL) and natural killer (NK)/T-cell lymphoma (NKTCL). Cell lines were histologically determined to be DLBCL (Raji cells) and NKTCL (Daudi cells), and uptake after pretreatment with (18)F-FDG was determined. Real-time polymerase chain reaction was performed to detect the expression levels of GLUTs 1, 2, 3, 4, and 7 and Ki-67, and to evaluate their association with (18)F-FDG uptake in DLBCL and NKTCL cells. The uptake rates of (18)F-FDG ranged from 18 to 46% (average 30 ± 10.20%) in Raji cells and 25 to 48% (average 35.6 ± 7.57%) in Daudi cells. In DLBCL cells, the expression levels of GLUTs 1, 3, and 7 were significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rank correlation coefficient of 0.667, 0.516, and 0.468, respectively; P < 0.05). In NKTCL cells, the expression levels of GLUTs 1 and 3 were observed to be significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rho of 0.756 and 0.498, respectively; P < 0.05). Ki-67 played no role in (18)F-FDG uptake in Raji or Daudi cells. In conclusion, the data acquired through this preliminary study indicate that GLUT 1 and GLUT 3 contribute to 18F-FDG uptake in DLBCL and NKTCL. PMID:27173341

  14. The spectrum of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases.

    PubMed

    Gualco, Gabriela; Natkunam, Yasodha; Bacchi, Carlos E

    2012-05-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, is a diagnostic provisional category in the World Health Organization (WHO) 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this study, we present 10 cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma and have organized the criteria described by the WHO into four patterns along with detailed clinical, morphological and immunophenotypic characterization and outcome data. Our findings show a male preponderance, median age of 37 years and a mediastinal presentation in 80% of cases. All cases expressed at least two markers associated with B-cell lineage and good response to combination chemotherapy currently employed for non-Hodgkin lymphomas.

  15. B-cell leukemia/lymphoma panel

    MedlinePlus

    ... Elsevier Saunders; 2016:chap 183. Bierman PJ, Armitage JO. Non-Hodgkin lymphomas. In: Goldman L, Schafer AI, ... cytometry in oncologic diagnosis. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff's ...

  16. Alisertib With and Without Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-07-15

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  17. Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)

    ClinicalTrials.gov

    2016-07-04

    Non-Hodgkin Lymphoma; Burkitt's Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Lymphoma, Marginal Zone; Waldenstrom Macroglobulinemia

  18. Fusion Protein Cytokine Therapy After Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-06-03

    Anaplastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  19. Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo.

    PubMed

    Kasama, Yuri; Sekiguchi, Satoshi; Saito, Makoto; Tanaka, Kousuke; Satoh, Masaaki; Kuwahara, Kazuhiko; Sakaguchi, Nobuo; Takeya, Motohiro; Hiasa, Yoichi; Kohara, Michinori; Tsukiyama-Kohara, Kyoko

    2010-12-01

    Extrahepatic manifestations of hepatitis C virus (HCV) infection occur in 40%-70% of HCV-infected patients. B-cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with HCV infection. The mechanism by which HCV infection of B cells leads to lymphoma remains unclear. Here we established HCV transgenic mice that express the full HCV genome in B cells (RzCD19Cre mice) and observed a 25.0% incidence of diffuse large B-cell non-Hodgkin lymphomas (22.2% in males and 29.6% in females) within 600 days after birth. Expression levels of aspartate aminotransferase and alanine aminotransferase, as well as 32 different cytokines, chemokines and growth factors, were examined. The incidence of B-cell lymphoma was significantly correlated with only the level of soluble interleukin-2 receptor α subunit (sIL-2Rα) in RzCD19Cre mouse serum. All RzCD19Cre mice with substantially elevated serum sIL-2Rα levels (> 1000 pg/mL) developed B-cell lymphomas. Moreover, compared with tissues from control animals, the B-cell lymphoma tissues of RzCD19Cre mice expressed significantly higher levels of IL-2Rα. We show that the expression of HCV in B cells promotes non-Hodgkin-type diffuse B-cell lymphoma, and therefore, the RzCD19Cre mouse is a powerful model to study the mechanisms related to the development of HCV-associated B-cell lymphoma.

  20. Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2014-08-04

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  1. MicroRNA signatures in B-cell lymphomas

    PubMed Central

    Di Lisio, L; Sánchez-Beato, M; Gómez-López, G; Rodríguez, M E; Montes-Moreno, S; Mollejo, M; Menárguez, J; Martínez, M A; Alves, F J; Pisano, D G; Piris, M A; Martínez, N

    2012-01-01

    Accurate lymphoma diagnosis, prognosis and therapy still require additional markers. We explore the potential relevance of microRNA (miRNA) expression in a large series that included all major B-cell non-Hodgkin lymphoma (NHL) types. The data generated were also used to identify miRNAs differentially expressed in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) samples. A series of 147 NHL samples and 15 controls were hybridized on a human miRNA one-color platform containing probes for 470 human miRNAs. Each lymphoma type was compared against the entire set of NHLs. BL was also directly compared with DLBCL, and 43 preselected miRNAs were analyzed in a new series of routinely processed samples of 28 BLs and 43 DLBCLs using quantitative reverse transcription-polymerase chain reaction. A signature of 128 miRNAs enabled the characterization of lymphoma neoplasms, reflecting the lymphoma type, cell of origin and/or discrete oncogene alterations. Comparative analysis of BL and DLBCL yielded 19 differentially expressed miRNAs, which were confirmed in a second confirmation series of 71 paraffin-embedded samples. The set of differentially expressed miRNAs found here expands the range of potential diagnostic markers for lymphoma diagnosis, especially when differential diagnosis of BL and DLBCL is required. PMID:22829247

  2. Are T cells at the origin of B cell lymphomas?

    PubMed

    Meyer-Hermann, Michael E

    2007-02-21

    Lymphoma pathogenesis is at least in some cases related to transformed B cells (BCs) arising from germinal centre reactions (GCRs). In this article possible deregulations of GCRs are investigated using in silico simulations. It is found that the final differentiation of BCs as regulated by helper T cells (TCs) is the best candidate mechanism for such a deregulation. This shifts the paradigm of BC lymphoma pathogenesis from BC transformations to an emphasized role of TC-BC interactions. PMID:17070849

  3. JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-09-06

    Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma

  4. High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

    ClinicalTrials.gov

    2016-07-08

    Post-Transplant Lymphoproliferative Disorder; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  5. B-Cell Lymphoma of the Mandible: A Case Report

    PubMed Central

    Adouani, Ali; Bouguila, Jed; Jeblaoui, Yassine; Ben Aicha, Mehdi; Abdelali, Mouhamed Ali; Hellali, Mouna; Zitouni, Karima; Amani, Landolsi; Issam, Zairi

    2008-01-01

    Summary Introduction The mandible is an infrequent localisation of primary osseous non-Hodgkin’s lymphomas. Few cases of mandibular non-Hodgkin’s lymphomas (NHL) have been reported. Case report A rare condition of primary malignant non-Hodgkin’s lymphoma of the mandible in 53-year-old man, was reported at the Department of Maxillofacial and Plastic Surgery in Charles Nicolle Hospital (Tunis, Tunisia). Histologic and Immunohistochemical (IHC) examination Confirmed a B-Cell lymphoma. Discussion The purpose of this report is to describe this rare case of NHL of the mandible, explore the diagnosis and workup, and discuss treatment strategies. In this localisation, neither the clinical features nor the radiologic appearances are often pathognomonic. Conclusion Particular care must be taken to consider lymphoma in the differential diagnosis because this uncommon lesion can pose significant diagnostic problems and is frequently misdiagnosed. PMID:21892315

  6. Clonal relationships in recurrent B-cell lymphomas.

    PubMed

    Lee, Seung Eun; Kang, So Young; Yoo, Hae Yong; Kim, Seok Jin; Kim, Won Seog; Ko, Young Hyeh

    2016-03-15

    Immunoglobulin (Ig) gene rearrangements remain largely unmodified during the clonal expansion of neoplastic cells. We investigated the clonal relationships between lymphoma components at diagnosis and at relapse by analyzing Ig gene rearrangements. A BIOMED-2 multiplex polymerase chain reaction (PCR) assay was performed in 27 patients using formalin-fixed paraffin embedded tissues, with subsequent cloning and sequencing of the amplified Ig genes in 17 patients. All 27 cases of primary and corresponding relapsed tumors showed monoclonal rearrangements of the Ig genes by BIOMED-2 PCR. Whereas IgVH or IgVK fragment lengths were identical in 8/27 pairs (30%), fragment lengths differed in 19/27 pairs (70%). In 17 cases analyzed by sequencing, an identical VDJ gene rearrangement was confirmed in 4/4 pairs (100%) with the same fragment lengths and in 10/13 pairs (77%) with different fragment lengths. Four of 17 primary lymphomas had multiple VDJ rearrangements, and three of them showed an unrelated relapse. Unrelated relapse was observed in 1/8 mantle cell lymphomas, 1/5 diffuse large B-cell lymphomas, and a large B cell lymphoma developed in a patient with a small lymphocytic lymphoma. Unrelated relapses developed after a longer disease-free interval and tended to show poorer outcome compared with related relapse. In summary, relapse of a lymphoma from an unrelated clone is uncommon, but can occur in B-cell lymphomas. Clonal relationships should be determined by sequencing of the Ig genes, and not just by comparing the PCR product size. PMID:26848863

  7. The Histological Classification of Diffuse Large B-cell Lymphomas

    PubMed Central

    Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S.

    2015-01-01

    Diffuse large B cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic and pathologic diversity, in part reflecting the functional diversity of the B-cell system and multiple pathways of transformation. In recent years, the advent of new high-throughput genomic technologies has provided new insights into the biology of DLBCL, leading to the identification of distinct molecular identities and novel pathogenetic pathways. This increasing complexity had led to an expanding number of entities in the WHO classification. Using a multi-modality approach, the updated 2008 classification delineated some new subgroups, including DLBCLs associated with particular age groups or specific anatomic sites, as well as two borderline categories: tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL as well as between Burkitt Lymphoma (BL) and DLBCL. This article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes included in the 2008 classification, with emphasis on some of the new entities as well as areas of diagnostic challenge. PMID:25805585

  8. Diffuse Large B Cell Lymphoma Mimicking Granulomatosis with Polyangiitis

    PubMed Central

    Horowitz, Netanel; Ben-Itzhak, Ofer; Braun-Moscovici, Yolanda

    2016-01-01

    In a patient with systemic multiorgan disease with overlapping features, the differential diagnosis included infectious diseases, malignancies, and systemic autoimmune or inflammatory diseases. We present an unusual case of a young male with B cell lymphoma who presented with symptoms mimicking systemic vasculitis and review the existing literature. PMID:27293945

  9. Diffuse large B cell lymphoma with chronic granulomatous inflammation.

    PubMed

    Nyunt, W W T; Wong, Y P; Wan Jamaludin, W F; Abdul Wahid, S F S

    2016-04-01

    Non-necrotic epithelioid granulomas have been reported in association with neoplasms including Hodgkin and non-Hodgkin lymphoma. We report a case of diffuse large B cell lymphoma with chronic granulomatous inflammation to highlight awareness of obscure tumour cells within the granuloma, to avoid delay in diagnosis and management of lymphoma. A 39-year-old Malay lady with no past medical history, presented with a 2-month history of progressive worsening of difficulty in breathing, cough, low-grade fever, loss of weight and loss of appetite. Chest X-ray showed an anterior mediastinal mass and computed tomography (CT)-guided biopsy was reported as chronic granulomatous inflammation suggestive of tuberculosis. After 2 months of anti-TB treatment, her symptoms were not relieved. The patient underwent another CT-guided biopsy of the anterior mediastinal mass in another hospital and the histopathology revealed diffuse large B cell lymphoma. The patient was referred for treatment. On histopathological review, the first sample showed noncaseating granulomas engulfing tumour cells and large abnormal lymphoid cells which were CD20 positive and with high Ki-67 proliferative index. The patient was diagnosed with diffuse large B cell lymphoma stage IV B IPSS score 3. She underwent chemotherapy (R-EPOCH) and responded well to treatment. PMID:27126666

  10. [EXPRESSION OF THE LIGHT CHAINS OF IMMUNOGLOBULINS IN NORMAL B-CELLS AND SOME B-CELL LYMPHOMAS].

    PubMed

    Khudoleeva, O A; Vorobjev, I A

    2015-01-01

    The quantitative method of determining the level of expression of immunoglobulin light chains on uncompensated data was suggested and used to examine disorders in light chain expression in various B-cell tumors. The average level of expression of the lambda isotype was 4 times higher than the level of expression of kappa isotype. The level of surface and cytoplasmic expression of LC IG varied within wide limits for different people, but there was a high degree of correlation between the levels of expression of kappa and lambda isotypes LC IG as well as between expression of the surface and cytoplasmic forms of each in isotype the same individual. In the majority of B-cell non-Hodgkin's lymphomas correlation between the expression of LC IG on the surface and in the cytoplasm of the cells was diminished. Expression of LC IG in CLL was significantly reduced on the surface of the cells and to a lesser extent--in the cytoplasm. In the case of marginal zone cell lymphoma, LC IG expression level was reduced on the surface of circulating cells and to a lesser extent--in the cytoplasm. In the case of mantle cell lymphoma and DLBCL, expression level of LC IG on the cell surface and in the cytoplasm was the same as in normal B-cells. However, in some cases DLBCL, no LC IG was expressed both on the surface and in the cytoplasm. PMID:26863766

  11. Epiglottic diffuse B-cell malignant lymphoma: A case report

    PubMed Central

    CHANG, HUNG-MIN; LI, CHIUNG-CHON; TSAI, STELLA CHIN-SHAW; TSAO, TANG-YI

    2016-01-01

    A 55-year-old male patient was admitted to our department with complaints of dysphagia and throat soreness for 2 months. A tumor of the left epiglottis, with an irregular surface, was identified by video laryngoscopy. The diagnosis of malignant lymphoma was confirmed by biopsy during laryngomicrosurgery. The atypical diffuse lymphocytic lymphoma was positive for CD20 and Bcl-2, and negative for CD3, CD10 and Bcl-1. The diagnosis was diffuse large B-cell malignant lymphoma. The patient was treated with eight cycles of rituximab with cyclophosphamide + doxorubicin + vincristine + prednisolone (R-CHOP regimen). This is a rare case of extranodal non-Hodgkin lymphoma occurring in the epiglottis. PMID:26870358

  12. Genetic lesions in diffuse large B-cell lymphomas

    PubMed Central

    Testoni, M.; Zucca, E.; Young, K. H.; Bertoni, F.

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%–40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL. PMID:25605746

  13. Primary Malignant B-cell Lymphoma of the Epididymis

    PubMed Central

    Suh, Jungyo; Jeong, Hyeon; Kim, Young A.

    2015-01-01

    Primary epididymal lymphomas are very rare condition, only 6 case report was published. In 4 of them, initial presentation was non-tender, continuous growth of testis. It can be misdiagnosed with epididymitis, 5 of them was treated by antibiotics before surgery. One patients treated by surgery another 5 makes neoadjuvant therapy, 2 of radiotherapy 3 of chemotherapy. Only one man died after treatment. This case is about 54-year male patients, diagnosed by diffuse large B-cell lymphoma, who treated by surgery and neoadjuvant chemotherapy combined with radiotherapy. PMID:26793572

  14. Bilateral conjunctival extranodal marginal zone B-cell lymphoma.

    PubMed

    Kram, David E; Brathwaite, Carole D; Khatib, Ziad A

    2010-12-15

    Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation. PMID:20981695

  15. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Burkitt's lymphoma: A case report and review

    PubMed Central

    Chettiankandy, Tabita Joy; Tupkari, Jagdish Vishnu; Kumar, Keshav; Ahire, Manisha Sandeep

    2016-01-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Burkitt's lymphoma (BL), is a diagnostic provisional category in the World Health Organization 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between DLBCL and classical BL or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this article, we present a “classical unclassifiable lymphoma with features intermediate between DLBCL and BL” in a young male patient and review of literature. PMID:27601842

  16. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Burkitt's lymphoma: A case report and review

    PubMed Central

    Chettiankandy, Tabita Joy; Tupkari, Jagdish Vishnu; Kumar, Keshav; Ahire, Manisha Sandeep

    2016-01-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Burkitt's lymphoma (BL), is a diagnostic provisional category in the World Health Organization 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between DLBCL and classical BL or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this article, we present a “classical unclassifiable lymphoma with features intermediate between DLBCL and BL” in a young male patient and review of literature.

  17. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Burkitt's lymphoma: A case report and review.

    PubMed

    Chettiankandy, Tabita Joy; Tupkari, Jagdish Vishnu; Kumar, Keshav; Ahire, Manisha Sandeep

    2016-01-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Burkitt's lymphoma (BL), is a diagnostic provisional category in the World Health Organization 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between DLBCL and classical BL or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this article, we present a "classical unclassifiable lymphoma with features intermediate between DLBCL and BL" in a young male patient and review of literature. PMID:27601842

  18. T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma.

    PubMed

    Advani, Pooja; Starr, Jason; Swaika, Abhisek; Jiang, Liuyan; Qiu, Yushi; Li, Zhimin; Tun, Han W

    2015-12-29

    Primary central nervous system (PCNSL) lymphoma is an aggressive extranodal non-Hodgkin lymphoma, and most cases are classified as diffuse large B-cell lymphoma (DLBCL) by histology. T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) represents a distinct subtype of diffuse large B-cell lymphoma and is characterized by the presence of scattered large neoplastic B-cells in a background of abundant T-cells and histiocytes. This is in contrast to the dense perivascular cuffing of neoplastic B-cells in classic DLBCL. T-cell/histiocyte-rich large B-cell lymphoma should be considered in PCNSL cases in which neoplastic B-cells are sparse and scattered. Immunohistochemistry will help identify the B-cells and surrounding infiltrate rich in Tlymphocytes and histiocytes. Future studies exploring the biology of TCRLBCL and the crosstalk between the neoplastic cells and the surrounding inflammatory infiltrate may provide exciting prospects for future therapies for TCRLBCL. PMID:26788280

  19. CPI-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-08-12

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  20. CCI-779 in Treating Patients With Recurrent or Refractory B-Cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2014-05-07

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Malignant Neoplasm; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  1. Clinical Significance of sIL-2R Levels in B-Cell Lymphomas

    PubMed Central

    Yoshida, Noriaki; Oda, Miyo; Kuroda, Yoshiaki; Katayama, Yuta; Okikawa, Yoshiko; Masunari, Taro; Fujiwara, Megumu; Nishisaka, Takashi; Sasaki, Naomi; Sadahira, Yoshito; Mihara, Keichiro; Asaoku, Hideki; Matsui, Hirotaka; Seto, Masao; Kimura, Akiro; Arihiro, Koji; Sakai, Akira

    2013-01-01

    Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas. PMID:24236041

  2. Hepatitis C virus - associated B cell non-Hodgkin's lymphoma

    PubMed Central

    Mihăilă, Romeo-Gabriel

    2016-01-01

    The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin’s lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin’s lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they

  3. Hepatitis C virus - associated B cell non-Hodgkin's lymphoma.

    PubMed

    Mihăilă, Romeo-Gabriel

    2016-07-21

    The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin's lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin's lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they seem to

  4. Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers.

    PubMed

    Hopp, Lydia; Nersisyan, Lilit; Löffler-Wirth, Henry; Arakelyan, Arsen; Binder, Hans

    2015-01-01

    We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt's lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation. PMID:26506391

  5. Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers

    PubMed Central

    Hopp, Lydia; Nersisyan, Lilit; Löffler-Wirth, Henry; Arakelyan, Arsen; Binder, Hans

    2015-01-01

    We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt’s lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation. PMID:26506391

  6. Vaccine Therapy With or Without Cryosurgery in Treating Patients With Residual, Relapsed, or Refractory B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-04-19

    Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Adult Diffuse Mixed Cell Lymphoma; Adult Diffuse Small Cleaved Cell Lymphoma; Adult Grade III Lymphomatoid Granulomatosis; Adult Immunoblastic Large Cell Lymphoma; Adult Lymphoblastic Lymphoma; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3 Follicular Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia With Nodal Disease

  7. Diffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse

    PubMed Central

    Malkan, Umit Yavuz; Gunes, Gursel; Yayar, Okan; Demiroglu, Haluk

    2015-01-01

    Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation. PMID:26457084

  8. Dominant neurologic symptomatology in intravascular large B-cell lymphoma.

    PubMed

    Kubisova, K; Martanovic, P; Sisovsky, V; Tomleinova, Z; Steno, A; Janega, P; Rychly, B; Babal, P

    2016-01-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal large B-cell lymphoma and it is characterized by selective intravascular proliferation of malignant cells. Typical features of the disease include aggressive behavior, rapid and frequently fatal course. Clinical picture is non-specific and heterogeneous, depending on the affected organ. It is not uncommon that this unique type of lymphoma is diagnosed post mortem. Herein, we report two cases of IVLBCL with neurologic symptomatology. In our clinical study patient 1 was an 80-year-old male with mixed paraparesis of lower extremities and difficulties with sphincter control. Patient 2 (56-year-old male) had vision malfunction, mental status changes and defect in phatic and motor functions. In both cases definite diagnosis was established by histological examination of necroptic material. We propose to include IVLBCL in differential diagnostic considerations in patients presenting with gradually impairing neurological status and spinal cord damage of unknown etiology (Fig. 2, Ref. 9). PMID:27546361

  9. Large anaplastic spinal B-cell lymphoma in a cat.

    PubMed

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

  10. Large anaplastic spinal B-cell lymphoma in a cat.

    PubMed

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown. PMID:19055573

  11. Cerebral toxoplasmosis in a diffuse large B cell lymphoma patient

    PubMed Central

    Savsek, Lina; Opaskar, Tanja Ros

    2016-01-01

    Background Toxoplasmosis is an opportunistic protozoal infection that has, until now, probably been an underestimated cause of encephalitis in patients with hematological malignancies, independent of stem cell or bone marrow transplant. T and B cell depleting regimens are probably an important risk factor for reactivation of a latent toxoplasma infection in these patients. Case report We describe a 62-year-old HIV-negative right-handed Caucasian female with systemic diffuse large B cell lymphoma who presented with sudden onset of high fever, headache, altered mental status, ataxia and findings of pancytopenia, a few days after receiving her final, 8th cycle of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (R-CHOP) chemotherapy regimen. A progression of lymphoma to the central nervous system was suspected. MRI of the head revealed multiple on T2 and fluid attenuated inversion recovery (FLAIR) hyperintense parenchymal lesions with mild surrounding edema, located in both cerebral and cerebellar hemispheres that demonstrated moderate gadolinium enhancement. The polymerase chain reaction on cerebrospinal fluid (CSF PCR) was positive for Toxoplasma gondii. The patient was diagnosed with toxoplasmic encephalitis and successfully treated with sulfadiazine, pyrimethamine and folic acid. Due to the need for maintenance therapy with rituximab for lymphoma remission, the patient now continues with secondary prophylaxis of toxoplasmosis. Conclusions With this case report, we wish to emphasize the need to consider cerebral toxoplasmosis in patients with hematological malignancies on immunosuppressive therapy when presenting with new neurologic deficits. In such patients, there are numerous differential diagnoses for cerebral toxoplasmosis, and the CNS lymphoma is the most difficult among all to distinguish it from. If left untreated, cerebral toxoplasmosis has a high mortality rate; therefore early recognition and treatment are of essential importance. PMID

  12. Pathobiology of primary mediastinal B-cell lymphoma.

    PubMed

    Pileri, Stefano A; Zinzani, Pier L; Gaidano, Gianluca; Falini, Brunangelo; Gaulard, Philippe; Zucca, Emanuele; Sabattini, Elena; Ascani, Stefano; Rossi, Maura; Cavalli, Franco

    2003-01-01

    Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It

  13. Molecular characterization of primary mediastinal B cell lymphoma.

    PubMed

    Tsang, P; Cesarman, E; Chadburn, A; Liu, Y F; Knowles, D M

    1996-06-01

    Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of its distinctive clinical and morphological features and putative unique cellular origin, PMBL is generally considered a distinct clinicopathological entity. Little is known, however, about the molecular characteristics of PMBL. Therefore, we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6, c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection, which are commonly involved in lymphoid neoplasia. Employing a combination of Southern blotting and/or polymerase chain reaction and single-strand conformation polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs. Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the 5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%), although c-myc gene rearrangements were not seen by Southern blotting. Missense point mutations of the p53 gene were identified in 3 additional PMBLs (19%). Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus infection were not observed. In conclusion, a variety of molecular lesions occur in PMBLs and may be involved in their pathogenesis. This molecular genetic pattern bears little resemblance to that known for other B cell malignancies, including DLCL. In particular, the infrequent occurrence of bcl-6 gene rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin, suggesting that PMBLs do not represent a distinct subtype of DLCL. PMID:8669486

  14. Molecular characterization of primary mediastinal B cell lymphoma.

    PubMed Central

    Tsang, P.; Cesarman, E.; Chadburn, A.; Liu, Y. F.; Knowles, D. M.

    1996-01-01

    Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of its distinctive clinical and morphological features and putative unique cellular origin, PMBL is generally considered a distinct clinicopathological entity. Little is known, however, about the molecular characteristics of PMBL. Therefore, we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6, c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection, which are commonly involved in lymphoid neoplasia. Employing a combination of Southern blotting and/or polymerase chain reaction and single-strand conformation polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs. Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the 5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%), although c-myc gene rearrangements were not seen by Southern blotting. Missense point mutations of the p53 gene were identified in 3 additional PMBLs (19%). Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus infection were not observed. In conclusion, a variety of molecular lesions occur in PMBLs and may be involved in their pathogenesis. This molecular genetic pattern bears little resemblance to that known for other B cell malignancies, including DLCL. In particular, the infrequent occurrence of bcl-6 gene rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin, suggesting that PMBLs do not represent a distinct subtype of DLCL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8669486

  15. T-cell leukemia 1 expression in nodal Epstein-Barr virus-negative diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma.

    PubMed

    Gualco, Gabriela; Weiss, Lawrence M; Barber, Glen N; Bacchi, Carlos E

    2010-09-01

    The physiologic expression of the product of the proto-oncogene TCL1 (T-cell leukemia 1) is primarily restricted to early embryonic cells. In nonneoplastic B cells, the expression of TCL1 is determined by the differentiation step with silencing at the germinal center stage. TCL1 protein is overexpressed in a wide variety of human diseases. It has been shown that TCL1 is a powerful B-cell oncogene, which has been implicated in the pathogenesis of various types of mature B-cell lymphomas. There is no comparative information in the literature addressing the expression of TCL1 in pediatric and adult nodal diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma. We studied 55 cases of adult and pediatric diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma to analyze the phenotypic profile of these lymphomas, including TCL1 expression, and its relationship with clinical outcome in different age groups. The cases were analyzed by immunohistochemistry for the expression of TCL1, CD10, BCL-2, BCL-6, and MUM1. We also evaluated c-MYC translocation by fluorescence in situ hybridization. TCL1 was observed in 11 cases, 5 pediatric and 6 adult cases, all but one diffuse large B-cell lymphoma. Pediatric cases showed a significant association between TCL1 expression, high proliferative index, and presence of c-MYC translocation. TCL1 positivity was predominantly found in germinal center phenotype diffuse large B-cell lymphoma. Overall survival was worse in adult TCL1-positive cases than pediatric ones. Primary mediastinal large B-cell lymphomas infrequently expressed TCL1 in both age groups.

  16. Clinicopathological features of aggressive B-cell lymphomas including B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and Burkitt lymphomas: a study of 44 patients from Argentina.

    PubMed

    Bürgesser, María Virginia; Gualco, Gabriela; Diller, Ana; Natkunam, Yasodha; Bacchi, Carlos E

    2013-06-01

    Aggressive B-cell lymphomas incorporate a wide spectrum of lymphomas that pose challenges in diagnosis as well as treatment. We evaluated the clinicopathological features of 44 patients with aggressive B-cell lymphomas which were classified into 3 groups based on the World Health Organization 2008 classification as follows: including 30 cases of diffuse large B-cell lymphoma (DLBCL), 8 cases of Burkitt lymphoma (BL) and 6 cases of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (BCLU). Male predominance was observed in BL and BCLU groups and the mean age varied from 29 years in BL, 61 years in DLBCL and 70 years in BCLU. Patients with BCLU presented at more advanced stages and had a higher international prognostic index. By immunohistochemistry, they shared characteristics of both BL (including more frequent expression of SOX11) and DLBCL. FISH analyses showed three cases with more than one rearrangement: one MYC/BCL2 and two BCL2/BCL6, in addition to which one case with BCL2/IGH translocation and another with MYC rearrangement were also detected. The mean follow-up survival time of BCLU was 6.6 months, which was significantly shorter in comparison to DLBCL (31 months) and BL (30 months), respectively. The importance of recognizing this BCLU group relies on its different clinical course, poor prognosis and shorter survival than DLBCL and BL. An accurate diagnosis is critical for risk stratification and to improve therapeutic approaches and outcomes.

  17. Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

    ClinicalTrials.gov

    2015-11-23

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  18. Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    ClinicalTrials.gov

    2016-07-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

  19. G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas.

    PubMed

    Duquette, Michelle L; Huber, Michael D; Maizels, Nancy

    2007-03-15

    Diffuse large B-cell lymphoma is the most common lymphoid malignancy in adults. It is a heterogeneous disease with variability in outcome. Genomic instability of a subset of proto-oncogenes, including c-MYC, BCL6, RhoH, PIM1, and PAX5, can contribute to initial tumor development and has been correlated with poor prognosis and aggressive tumor growth. Lymphomas in which these proto-oncogenes are unstable derive from germinal center B cells that express activation-induced deaminase (AID), the B-cell-specific factor that deaminates DNA to initiate immunoglobulin gene diversification. Proto-oncogene instability is evident as both aberrant hypermutation and translocation, paralleling programmed instability which diversifies the immunoglobulin loci. We have asked if genomic sequence correlates with instability in AID-positive B-cell lymphomas. We show that instability does not correlate with enrichment of the WRC sequence motif that is the consensus for deamination by AID. Instability does correlate with G-richness, evident as multiple runs of the base guanine on the nontemplate DNA strand. Extending previous analysis of c-MYC, we show experimentally that transcription of BCL6 and RhoH induces formation of structures, G-loops, which contain single-stranded regions targeted by AID. We further show that G-richness does not characterize translocation breakpoints in AID-negative B- and T-cell malignancies. These results identify G-richness as one feature of genomic structure that can contribute to genomic instability in AID-positive B-cell malignancies.

  20. MicroRNAs in diffuse large B-cell lymphoma

    PubMed Central

    NI, HUIYUN; TONG, RONG; ZOU, LINQING; SONG, GUOQI; CHO, WILLIAM C.

    2016-01-01

    The aberrant expression of microRNAs (miRs) has a significant impact on the biological characteristics of lymphocytes, and is important in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). It has been demonstrated, using miR profiling and detecting distinct miR signatures, that certain miRs may accurately distinguish different subtypes and prognostic classifications of DLBCL, as well as distinguish DLBCL from other more indolent lymphomas, including follicular lymphoma. miRs are excellent biomarkers for cancer diagnosis and prognosis. In DLBCL, specific miR expression profiles in the tissues of patients are associated with prognosis and clinical outcome. Over the past decade, there has been substantial investigation concerning the pathogenetic, diagnostic and prognostic roles of miRs in DLBCL. The aim of the present review is to describe the aberrant expression of miRs in DLBCL, and the functions, potential clinical use and possible therapeutic targets of miRs in this disease. PMID:26893730

  1. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    ClinicalTrials.gov

    2016-08-31

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  2. Rituximab, Romidepsin, and Lenalidomide in Treating Patients With Recurrent or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-08-09

    B-cell Adult Acute Lymphoblastic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  3. B Cell Lymphoma, Unclassifiable, Transformed from Follicular Lymphoma: A Rare Presentation with Review of the Literature

    PubMed Central

    Kanna, Anila; Agrawal, Swati; Jayant, Kumar; Kumar Pala, Varun; Altujjar, Mohammad; Hadid, Tarik; Khurram, Muhammad

    2015-01-01

    B cell lymphoma, unclassifiable, with features of diffuse large B cell lymphoma and classical Hodgkin's lymphoma (BCLu-DLBCL/CHL) is more commonly known as gray zone lymphoma. These cases more often present with mediastinal disease. In this report, we present a very rare case of BCLu-DLBCL/CHL without mediastinal involvement, transformed from follicular lymphoma (FL) to BCLu-DLBCL/CHL. This patient initially presented with a mass in the right neck; biopsy of the lymph node showed predominantly nodular, follicular pattern. Immunohistochemical (IHC) staining of tumor cells expressed positivity for mature B cell markers CD20, CD19, CD10, CD23, CD45, and CD38 but negative for CD5,11c. Hence, diagnosed with FL, he was given rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) regimen, followed by maintenance rituximab. He showed good response. After 2 years, he presented again with a mass in the right side of the neck. Although the needle core biopsy of this mass was suggestive of B cell lymphoma, excisional biopsy showed morphological features of DLBCL as well as foci of histological pattern of CHL. IHC staining expressed positivity for CD20, CD79a, PAX5, and CD15 and CD30 consistent with DLBCL and CHL. He was diagnosed with BCLu-DLBCL/CHL. The patient received “ACVBP” (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) followed by radiation. BCLu-DLBCL/CHL is clinically an aggressive tumor with poorer outcomes, but our case showed complete response to ACVBP regimen with tumor regression. PMID:26380128

  4. Diffuse large B-cell lymphoma in patient after treatment of angioimmunoblastic T-cell lymphoma.

    PubMed

    Skugor, Nives Dzeko; Perić, Zinaida; Vrhovac, Radovan; Radić-Kristo, Delfa; Kardum-Skelin, Ika; Jaksić, Branimir

    2010-03-01

    Relatively few cases of Epstein-Barr (EBV)-positive B-cell lymphomas arising in patients with angioimmunoblastic T-cell lymphoma (AITL) have been reported. We report a case of AITL in which diffuse large B-cell lymphoma arose 13 months after the initial diagnosis of AITL. In a 36-year-old female patient, evaluated for moderate leukocytosis, peripheral and abdominal lymphadenopathy AITL was diagnosed in March 2008, based on results of fine-needle aspiration cytology (FNAC) of the enlarged cervical and supraclavicular lymph nodes. The diagnosis was also confirmed by immunophenotyping and histopathology of the cervical lymph nodes. The patient initially recieved FED chemotherapy (fludarabine, cyclophosphamide, dexamethasone) followed by elective autologous hematopoietic stem cell transplantation. In April 2009 the patient was hospitalized because of fever, pancytopenia, hyperbilirubinemia and peripheral lymphadenopathy. The FNAC of the enlarged cervical lymph nodes was performed again, but this time the smears were composed of polymorphous population of lymphocytes with the predomination of large cells, CD20+ on immunocytochemical stains. The immunophenotyping confirmed a predomination of monoclonal mature B-cells. Patient had high number of EBV DNA copies in plasma and serologic testing revealed increased titers of EBV VCA IgG and EBV EBNA IgG. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in good partial response of the disease. Reduced intensity allogeneic stem cell transplantation performed thereafter, resulted in complete remission of the disease. AITL is a rare lymphoproliferative disorder in which the neoplastic T-cells represent the minority of the lymph node cell population and almost all cases harbor EBV-infected B-cells. Various authors postulated that immunodeficiency in AITL patients together with immunosuppressive effects of cytotoxic drugs, may be responsible for EBV

  5. Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

    ClinicalTrials.gov

    2016-08-24

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic

  6. Rituximab in the treatment of primary cutaneous B-cell lymphoma: a review.

    PubMed

    Fernández-Guarino, M; Ortiz-Romero, P L; Fernández-Misa, R; Montalbán, C

    2014-06-01

    Rituximab is a chimeric mouse-human antibody that targets the CD20 antigen, which is found in both normal and neoplastic B cells. In recent years, it has been increasingly used to treat cutaneous B-cell lymphoma and is now considered an alternative to classic treatment (radiotherapy and surgery) of 2 types of indolent lymphoma, namely, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma. Rituximab is also administered as an alternative to polychemotherapy in the treatment of primary cutaneous large B-cell lymphoma, leg type. Its use as an alternative drug led to it being administered intralesionally, with beneficial effects. In the present article, we review the literature published on the use of rituximab to treat primary cutaneous B-cell lymphoma.

  7. Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge.

    PubMed

    Khan, Maria S; McCubbin, Mark; Nand, Sucha

    2014-01-01

    Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT) 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT) 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH) 1231 IU/L. Except for a positive DNA test for Epstein-Barr virus (EBV) infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL) is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH, and about 65% are

  8. Angiomirs expression profiling in diffuse large B-Cell lymphoma

    PubMed Central

    Borges, Natália M.; do Vale Elias, Marcela; Fook-Alves, Veruska L.; Andrade, Tathiana A.; de Conti, Marina Lourenço; Macedo, Mariana Petaccia; Begnami, Maria Dirlei; Campos, Antônio Hugo J. F. M.; Etto, Leina Yukari; Bortoluzzo, Adriana Bruscato; Alves, Antonio C.; Young, Ken H.; Colleoni, Gisele W. B.

    2016-01-01

    Despite advances in treatment, 30% of diffuse large B-cell lymphoma (DLBCL) cases are refractory or relapse after chemoimmunotherapy. Currently, the relationship between angiogenesis and angiomiRs in DLBCL is unknown. We classified 84 DLBCL cases according to stromal signatures and evaluated the expression of pro- and antiangiomiRs in paraffin embedded tissues of DLBCL and correlated them with microvascular density (MVD). 40% of cases were classified as stromal-1, 50% as stromal-2 and 10% were not classified. We observed increased expression of proangiomiRs Let-7f, miR-17, miR-18a, miR-19b, miR-126, miR-130a, miR-210, miR-296 and miR-378 in 14%, 57%, 30%, 45%, 12%, 12%, 56%, 58% and 48% of the cases, respectively. Among antiangiomiRs we found decreased expression of miR-16, miR-20b, miR-92a, miR-221 and miR-328 in, respectively, 27%, 71%, 2%, 44% and 11%. We found association between increased expression of proangiomiRs miR-126 and miR-130a and antiangiomiR miR-328 and the subtype non-GCB. We found higher levels of the antiangiomiRs miR-16, miR-221 and miR-328 in patients with low MVD and stromal-1 signature. IPI and CD34 confirmed independent impact on survival of the study group. None of the above angiomiRs showed significance as biomarker in an independent serum samples cohort of patients and controls. In conclusion, we confirmed association between antiangiomiRs miR-16, miR-221 and miR-328 and stromal-1 signature. Four angiomiRs emerged as potential therapeutic targets: proangiomiRs miR-17, miR-210 and miR-296 and antiangiomiR miR-20b. Although the four microRNAs seem to be important in DLBCL pathogenesis, they were not predictive of DLBCL onset or relapse in the serum independent cohort. PMID:26683099

  9. B-cell monoclonality, Epstein Barr virus, and t(14;18) in myoepithelial sialadenitis and low-grade B-cell MALT lymphoma of the parotid gland.

    PubMed

    Diss, T C; Wotherspoon, A C; Speight, P; Pan, L; Isaacson, P G

    1995-05-01

    Low-grade mucosa-associated lymphoid tissue (MALT) type B-cell lymphomas of the salivary gland arise in a background of myoepithelial sialadenitis (MESA), usually in association with Sjögren's syndrome. The distinction between benign MESA and early lymphoma has proved difficult using histological criteria alone and the significance of B-cell monoclonality in this respect is controversial. We have used immunohistochemistry and polymerase chain reaction (PCR) amplification of immunoglobulin heavy-chain VDJ regions to assess clonality in biopsies from 45 patients with lymphoid infiltration of the parotid. Sequential biopsies spanning 3-18 years were available from seven patients, three of whom had developed disseminated nodal B-cell lymphoma. In light of previous studies, each biopsy was additionally analyzed for the presence of t(14;18) and Epstein Barr Virus (EBV) DNA using PCR. Monoclonality was detected in 34/45 cases. Comparison of histology with clonality confirmed earlier suggestions that the emergence of an identifiable population of centrocyte-like B cells around ducts or epithelial islands correlated with monoclonality. In six of seven patients with sequential biopsies PCR fragments of identical size were amplified from each biopsy, suggesting that demonstrable monoclonality in "lymphoepithelial" lymphoproliferative lesions of the salivary gland is indicative of lymphoma. No t(14;18) chromosome translocations were identified; EBV sequences were detected in three of 45 cases.

  10. Primary splenic B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: A case report

    PubMed Central

    Shi, Feng; Zhou, Quan; Gao, Ying; Cui, Xiang-Qing; Chang, Hong

    2016-01-01

    B-cell lymphoma (BCL), unclassifiable, with features intermediate between diffuse large BCL (DLBCL) and classical Hodgkin's lymphoma (CHL), is a novel entity to the World Health Organization classification system. These tumors are rare aggressive lymphomas that have a poor prognosis. The present study reports the case of a patient with one such lymphoma that occurred in the spleen, which expressed cluster of differentiation (CD)20, CD79α, melanoma associated antigen (mutated) 1, BCL6, CD15 and CD30. Polymerase chain reaction analysis demonstrated a clonal rearrangement of the genes coding for immunoglobulin heavy chains. The tumor cells demonstrated a negative reaction in the Epstein-Barr virus-encoded small RNA assay. Following the diagnosis of unclassifiable BCL, with intermediate features between DLBCL and CHL, the patient received 7 cycles of the CHOP regimen, and so far, has been in good general condition and tumor-free for 17 months. PMID:27602118

  11. Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.

    PubMed

    Aukema, Sietse M; Kreuz, Markus; Kohler, Christian W; Rosolowski, Maciej; Hasenclever, Dirk; Hummel, Michael; Küppers, Ralf; Lenze, Dido; Ott, German; Pott, Christiane; Richter, Julia; Rosenwald, Andreas; Szczepanowski, Monika; Schwaenen, Carsten; Stein, Harald; Trautmann, Heiko; Wessendorf, Swen; Trümper, Lorenz; Loeffler, Markus; Spang, Rainer; Kluin, Philip M; Klapper, Wolfram; Siebert, Reiner

    2014-04-01

    Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

  12. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    ClinicalTrials.gov

    2016-10-25

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  13. The Genetic Basis of Diffuse Large B Cell Lymphoma

    PubMed Central

    Pasqualucci, Laura

    2014-01-01

    Purpose of review Diffuse large B cell lymphoma (DLBCL) is an aggressive disease featuring heterogeneous genetic, phenotypic and clinical characteristics. Understanding the basis for this heterogeneity represents a critical step toward further progress in the management of this disease, which remains a clinical challenge in approximately one third of patients. This review summarizes current knowledge about the molecular pathogenesis of DLBCL, and describes how recent advances in the genomic characterization of this cancer have provided new insights into its biology, revealing several potential targets for improved diagnosis and therapy. Recent findings In the past few years, the development of high-resolution technologies has provided significant help in identifying genetic lesions and/or disrupted signaling pathways that are required for DLBCL initiation and progression. These studies uncovered the involvement of cellular programs that had not been previously appreciated, including histone/chromatin remodeling and immune recognition. Alterations in these pathways could favor epigenetic reprogramming and escape from cellular immunity. Summary The identification of genetic alterations that contribute to the malignant transformation of a B cell into a DLBCL is helping to better understand the biology of this disease and to identify critical nodes driving tumor progression or resistance to therapy. The rapid pace at which these discoveries are taking place is poised to have significant impact for patients stratification based on molecular predictors and for the development of rational targeted therapies. PMID:23673341

  14. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma | Office of Cancer Genomics

    Cancer.gov

    Abstract: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in non-Hodgkin lymphoma patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines.

  15. Plasmodium Infection Promotes Genomic Instability and AID Dependent B Cell Lymphoma

    PubMed Central

    Robbiani, Davide F.; Deroubaix, Stephanie; Feldhahn, Niklas; Oliveira, Thiago Y.; Callen, Elsa; Wang, Qiao; Jankovic, Mila; Silva, Israel T.; Rommel, Philipp C.; Bosque, David; Eisenreich, Tom; Nussenzweig, André; Nussenzweig, Michel C.

    2015-01-01

    Summary Chronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt’s lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by what mechanism remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments where B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells. PMID:26276629

  16. Mangiferin inhibition of proliferation and induction of apoptosis in human prostate cancer cells is correlated with downregulation of B-cell lymphoma-2 and upregulation of microRNA-182

    PubMed Central

    LI, MINGLIN; MA, HUILI; YANG, LIXIN; LI, PENG

    2016-01-01

    Mangiferin, a flavonoid extracted from the mango tree, possesses anti-inflammatory, antibacterial, anti-herpes simplex and antitumor activity, and is able to affect immune function. The present study investigated the anticancer effects of mangiferin treatment on PC3 human prostate cancer cells, and the potential underlying mechanisms. In the present study, an MTT assay was used to analyze the proliferation of PC3 cells. Subsequently, flow cytometry and colorimetric assay kits were utilized to measure the PC3 cell apoptotic rate. The expression levels of B-cell lymphoma-2 (Bcl-2) and microRNA-182 (miR-182) were detected using western blot analysis and quantitative reverse transcription-polymerase chain reaction, respectively. Finally, miR-182 and anti-miR-182 were transfected into PC3 cells, which were used to investigate the effects of mangiferin. Mangiferin treatment reduced the proliferation of PC3 human prostate cancer cells in a concentration- and time-dependent manner. In addition, mangiferin was able to promote apoptosis and induce the caspase-3 activity of PC3 human prostate cancer cells. Mangiferin treatment was also able to significantly reduce Bcl-2 expression levels and enhance miR-182 expression in PC3 cells. Finally, it was observed that mangiferin inhibited proliferation and induced apoptosis in PC3 human prostate cancer cells, and this effect was correlated with downregulation of Bcl-2 and upregulation of miR-182. PMID:26870290

  17. Identification of Highly Methylated Genes across Various Types of B-Cell Non-Hodgkin Lymphoma

    PubMed Central

    Bethge, Nicole; Honne, Hilde; Hilden, Vera; Trøen, Gunhild; Eknæs, Mette; Liestøl, Knut; Holte, Harald; Delabie, Jan; Smeland, Erlend B.; Lind, Guro E.

    2013-01-01

    Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480) when compared to normal B cells (n = 5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n = 25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients. PMID:24260260

  18. Cavitary pulmonary involvement of diffuse large B-cell lymphoma transformed from extra nodal marginal zone B-cell lymphoma MALT type.

    PubMed

    Yamane, Hiromichi; Ohsawa, Masahiro; Shiote, Yasuhiro; Umemura, Shigeki; Suwaki, Toshimitsu; Shirakawa, Atsuko; Kamei, Haruhito; Takigawa, Nagio; Kiura, Katsuyuki

    2011-12-01

    We describe a case of pulmonary diffuse large B-cell lymphoma (DLBCL), which was thought to arise from extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). A 68-year-old woman presented with a 2-month history of cough and bloody sputum. The chest X-ray and computed tomography revealed a mass with cavitation in the right lower lobe. Transbronchial biopsy specimens revealed a granulomatous infiltration without malignant cells. However, diagnosis of MALT lymphoma was established from gastric biopsy specimen. Subsequently, a right lower lobectomy was performed because of hemoptysis. Examination of the resected specimen revealed a diffuse large B-cell lymphoma, which was considered to have transformed from MALT lymphoma, because both lung and stomach lesions had the chromosomal translocation t(11;18)(q21;q21) in common. In addition, there were no nodules, masses, alveolar or interstitial infiltrates in the lung fields, which are usually observed in the case of marginal zone B-cell lymphoma of bronchial mucosa-associated lymphoid tissue. These findings indicate that involvement of DLBCL have to be considered in patients with MALT lymphoma and cavitary lesion of the lung. PMID:26189744

  19. Assessment of carbonic anhydrase IX expression and extracellular pH in B-cell lymphoma cell line models

    PubMed Central

    Chen, Liu Qi; Howison, Christine M.; Spier, Catherine; Stopeck, Alison T.; Malm, Scott W.; Pagel, Mark D.; Baker, Amanda F.

    2015-01-01

    The expression of carbonic anhydrase (CA IX) and it’s relation to acidosis in lymphomas has not been widely studied. We investigated the protein expression of CA IX in a human B-cell lymphoma tissue microarray, and in Raji, Ramos, and Granta 519 lymphoma cell lines and tumor models, while also investigating the relation with hypoxia. An imaging method, acidoCEST MRI, was used to estimate lymphoma xenograft extracellular pH (pHe). Our results showed that clinical lymphoma tissues and cell line models in vitro and in vivo had moderate CA IX expression. Although in vitro studies showed that CA IX expression was induced by hypoxia, in vivo studies did not show this correlation. Untreated lymphoma xenograft tumor pHe had acidic fractions, and an Acidity Score was qualitatively correlated with CA IX expression. Therefore, CA IX is expressed in B-cell lymphomas and is qualitatively correlated with extracellular acidosis in xenograft tumor models. PMID:25130478

  20. My Treatment Approach to Patients With Diffuse Large B-Cell Lymphoma

    PubMed Central

    Armitage, James O.

    2012-01-01

    My favored treatment approach for patients with diffuse large B-cell lymphoma continues to evolve. Diffuse large B-cell lymphoma can now be cured in more than 50% of patients. This is a result of improved definitions of the disease, improved diagnostic capabilities, better staging and restaging techniques, a useful prognostic index to guide therapeutic decisions, and the development of increasingly effective therapies. Positron emission tomographic scans have improved the accuracy of both staging and restaging. Findings on a positron emission tomographic scan at the end of therapy are the best predictors of a good treatment outcome. Numerous subtypes of diffuse large B-cell lymphoma have been identified that require specific treatment approaches. For example, plasmablastic lymphoma typically lacks CD20 and does not benefit from treatment with rituximab. Diffuse large B-cell lymphoma originating in specific extranodal sites such as the central nervous system, testes, and skin presents special problems and requires specific treatment approaches. A subgroup of diffuse large B-cell lymphoma with a very high proliferative rate seems to have a poor outcome when treated with CHOP-R and does better with regimens used for patients with Burkitt lymphoma. New insights into the biology of these disorders are likely to further change treatment approaches. Recognition that diffuse large B-cell lymphoma is not one disease, but a variety of clinicopathologic syndromes provides the opportunity to further improve our ability to benefit patients. PMID:22305028

  1. My treatment approach to patients with diffuse large B-cell lymphoma.

    PubMed

    Armitage, James O

    2012-02-01

    My favored treatment approach for patients with diffuse large B-cell lymphoma continues to evolve. Diffuse large B-cell lymphoma can now be cured in more than 50% of patients. This is a result of improved definitions of the disease, improved diagnostic capabilities, better staging and restaging techniques, a useful prognostic index to guide therapeutic decisions, and the development of increasingly effective therapies. Positron emission tomographic scans have improved the accuracy of both staging and restaging. Findings on a positron emission tomographic scan at the end of therapy are the best predictors of a good treatment outcome. Numerous subtypes of diffuse large B-cell lymphoma have been identified that require specific treatment approaches. For example, plasmablastic lymphoma typically lacks CD20 and does not benefit from treatment with rituximab. Diffuse large B-cell lymphoma originating in specific extranodal sites such as the central nervous system, testes, and skin presents special problems and requires specific treatment approaches. A subgroup of diffuse large B-cell lymphoma with a very high proliferative rate seems to have a poor outcome when treated with CHOP-R and does better with regimens used for patients with Burkitt lymphoma. New insights into the biology of these disorders are likely to further change treatment approaches. Recognition that diffuse large B-cell lymphoma is not one disease, but a variety of clinicopathologic syndromes provides the opportunity to further improve our ability to benefit patients. PMID:22305028

  2. An Unusual Presentation of B-Cell Lymphoma as a Large Isolated Epiglottic Mass: Case Report and Literature Review

    PubMed Central

    Liu, Changxing; Brown, Tamara N.

    2016-01-01

    Extranodal presentation of B-cell lymphoma is uncommon. Isolated primary epiglottic B-cell lymphoma is even rarer. To our knowledge, there has been only one description of isolated B-cell lymphoma presenting as a large epiglottic mass. We report an unusual type of B-cell lymphoma of the epiglottis, as it could not be subtyped based on routine staining and hybridization. The lymphoma presented as a large isolated globular mass pedicled to the epiglottis, occupying most of the oropharynx, but did not have any ball-valving effect or increased respiratory efforts. Initial radiographic findings were nonspecific. The diagnosis of B-cell lymphoma was determined by transoral incisional biopsy under local anesthesia. The condition was treated successfully with chemoradiation. The current standard of treatment for high grade B-cell lymphoma is concurrent chemoradiotherapy, with excellent prognosis. Although rare, B-cell lymphoma should be considered when investigating pedunculated hypopharyngeal masses. PMID:27213065

  3. Patients With Celiac Disease and B-Cell Lymphoma Have a Better Prognosis Than Those With T-Cell Lymphoma

    PubMed Central

    Halfdanarson, Thorvardur R.; Rubio–Tapia, Alberto; Ristow, Kay M.; Habermann, Thomas M.; Murray, Joseph A.; Inwards, David J.

    2013-01-01

    Background & Aims Celiac disease (CD) is associated with an increased risk of lymphoma. However, relatively few studies have assessed the outcome of patients diagnosed with both CD and lymphoma. We evaluated the temporal association between lymphoma and CD, along with clinical presentation, response to therapy, and prognosis. Methods Patients diagnosed with both CD and lymphoma were identified retrospectively in a tertiary referral center. Clinical characteristics and survival were analyzed. Results Sixty-three patients (36 men) were identified who had been diagnosed with lymphoma and CD. Thirty-six (57%) were diagnosed with CD before they were diagnosed with lymphoma. The most common histologic entity was diffuse, large, B-cell lymphoma, which affected 18 (29%) patients. Complete information for staging was available in 59 patients; 24 (38%) had stage IV disease. Only chemotherapy or only radiation therapy was used for 43 (68%) and 11 (17%) patients, respectively. The 5- and 10-year cumulative survival rates for the entire cohort were 58% and 39%, respectively. Survival of patients with T-cell lymphoma was shorter than for all other lymphomas (119.4 vs 22.8 mo; P = .02). Conclusions CD is associated with B- and T-cell lymphomas. Patients with B-cell lymphomas had a better prognosis than those with T-cell lymphoma. Therapy is unsatisfactory for enteropathy-type T-cell lymphoma. PMID:20851210

  4. The Genetic Landscape of Diffuse Large B Cell Lymphoma

    PubMed Central

    Pasqualucci, Laura; Dalla-Favera, Riccardo

    2015-01-01

    Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in the western world, is an aggressive disease that remains incurable in approximately 30% of patients. Over the past decade, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic and transcriptional changes has revolutionized our understanding of the genetic basis of DLBCL by providing a comprehensive and unbiased view of the genes/pathways that are disrupted by genetic alterations in this disease, and may contribute to tumor initiation and expansion. These studies uncovered the existence of several previously unappreciated alterations in key cellular pathways that may also influence treatment outcome. Indeed, a number of newly identified genetic lesions are currently being explored as markers for improved diagnosis and risk stratification, or are entering clinical trials as promising therapeutic targets. This review focuses on recent advances in the genomic characterization of DLBCL and discusses how information gained from these efforts has provided new insights into its biology, uncovering potential targets of prognostic and therapeutic relevance. PMID:25805586

  5. Epigenomic evolution in diffuse large B-cell lymphomas

    PubMed Central

    Pan, Heng; Jiang, Yanwen; Boi, Michela; Tabbò, Fabrizio; Redmond, David; Nie, Kui; Ladetto, Marco; Chiappella, Annalisa; Cerchietti, Leandro; Shaknovich, Rita; Melnick, Ari M.; Inghirami, Giorgio G.; Tam, Wayne; Elemento, Olivier

    2015-01-01

    The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis–relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. PMID:25891015

  6. Cerebral infratentorial large B-cell lymphoma presenting as Parkinsonism.

    PubMed

    Lin, Chih-Ming; Hong, Kelvin

    2010-03-01

    Though rare, primary intracranial tumors can present with Parkinsonian symptoms, and diagnosis can be delayed unless there is a high index of suspicion. We herein present an 81-year-old man who was seen in our neurology clinic due to acute onset of unsteady gait and altered consciousness. Parkinsonism was initially diagnosed because of the typical manifestations. Levodopa was prescribed; however, there was a limited effect on his symptoms. Upon detail history and neurological examination, left sided hemiparesis was disclosed. Cerebral imaging studies revealed a solid mass over the right infratentorial para-midbrain area leading to reactive obstructive hydrocephalus. Work-up including chest and abdominal CT scanning, upper and lower GI endoscopy, and tumor marker studies failed to uncover any abnormalities. A neurosurgeon was consulted and a shunt procedure and biopsy of the infratentorial mass were performed. Histopathological examination of the biopsy tissue revealed tumor diffusely intermixed with large cells consistent with large B-cell lymphoma. The patient and his family declined further treatment. Though rare, cerebral tumors can present with Parkinsonian features and represent a diagnostic challenge. Clinicians should be aware of the possibility of cerebral neoplasms causing Parkinsonism, and include them in the differential diagnosis, especially for patients presenting with atypical Parkinsonian features, or those not responsive to initial therapy.

  7. Diffuse Large B-Cell Lymphoma Mimicking Schwannoma of Lumbar Spine

    PubMed Central

    Kim, Seung-Kook; Lee, Sun-Ho; Kim, Eun-Sang

    2016-01-01

    A rare case of solitary diffuse large B-cell lymphoma arising from the lumbar spinal nerve root is reported. A 37-year-old man presented with a 3-month history of progressive numbness and paraparesis in both legs. The initial diagnosis was benign primary intradural extramedullary tumor including schwannoma and meningioma. Histopathological examination revealed diffuse large B-cell lymphoma. While a well-defined T1 isointense mass is common in primary spinal schwannoma, the present case was atypical and had a yellowish neural component. The pathogenesis and radiological findings of spinal diffuse large B-cell lymphoma are discussed and related literature is reviewed. PMID:27437017

  8. Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

    ClinicalTrials.gov

    2015-08-18

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  9. An Open-Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas

    ClinicalTrials.gov

    2016-09-01

    B-cell Lymphomas (Phase 1); Advanced Solid Tumors (Phase 1); Diffuse Large B-cell Lymphoma (Phase 2); Follicular Lymphoma (Phase 2); Transformed Follicular Lymphoma; Primary Mediastinal Large B-Cell Lymphoma

  10. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach?

    PubMed Central

    Dunleavy, Kieron

    2015-01-01

    Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that is putatively derived from a thymic B cell. Accounting for up to 10% of cases of DLBCL, this subtype predominantly affects women in the third and fourth decades of life. Its clinical and molecular characteristics are distinct from other subtypes of DLBCL and, in fact, closely resemble those of nodular sclerosing Hodgkin lymphoma (NSHL). Recently, mediastinal lymphomas with features intermediate between PMBL and NSHL, called mediastinal gray-zone lymphomas, have been described. The optimal management of PMBL is controversial, and most standard approaches include a combination of immunochemotherapy and mediastinal radiation. Recently, the recognition that mediastinal radiation is associated with significant long-term toxicities has led to the development of novel approaches for PMBL that have shown excellent efficacy and challenge the need for routine mediastinal radiation. PMID:25499450

  11. The unexpected evolution of a case of diffuse large B-cell non-Hodgkin lymphoma.

    PubMed

    Găman, Amelia; Bold, Adriana; Găman, G

    2011-01-01

    The diffuse large B-cell lymphoma (DLBCL) represents the most common type of aggressive non-Hodgkin's lymphoma with a heterogeneous morphology, biology and clinical presentation. Gene expression profiling studies identified three distinct molecular subtypes of DLCBL arisen from B-cells at different stages of differentiation: germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, primary mediastinal B-cell lymphoma (PMBL). The most relevant oncogenic pathways in diffuse large B-cell lymphoma are: deregulated B-cell receptor/proliferation signaling, BCL6 and NF-kB constitutive expression, defects in apoptosis and neoangiogenesis. The treatment of DLBCL has been completely modified in the last ten years by combination of anti-CD20 monoclonal antibody (rituximab) and CHOP chemotherapy, which is now the first line therapy. In the last years, there have been reported several cases of progressive multifocal leukoencephalopathy (PML) at patients with rheumatoid arthritis treated with rituximab. Progressive multifocal leukoencephalopathy is possible as an adverse reaction to rituximab at patients treated with R-CHOP for diffuse large B-cell lymphoma. PMID:21655667

  12. MLL2 protein is a prognostic marker for gastrointestinal diffuse large B-cell lymphoma

    PubMed Central

    Ye, Haige; Lu, Lu; Ge, Bei; Gao, Shenmeng; Ma, Yongyong; Liang, Bin; Yu, Kang; Yang, Kaiyan

    2015-01-01

    Mixed linage leukemia gene 2 (MLL2) is identified as a novel mutation gene in diffuse large B cell lymphoma (DLBCL). However, the significance of MLL2 protein expression for the prognosis of DLBCL is unclear. In this study, we detected MLL2 protein expression in primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) samples by using tissue microarray immunohistochemistry, and analyzed the correlation between MLL2 protein expression and tumor proliferation activity. In addition, we investigated clinical significance of MLL2 protein expression for PGI-DLBCL prognosis. We found that there was significant difference in MLL2 protein expression between PGI-DLBCL and reactive hyperplasia of lymph node. High expression of MLL2 protein indicated higher clinical stage. In older patients (>60 years) with PGI-DLBCL, MLL2 protein expression was positively correlated with Ki-67 expression and negatively correlated with patient survival. Our data suggest that MLL2 protein is overexpressed in PGI-DLBCL and appears as a prognostic factor for patients of PGI-DLBCL, especially for those older than 60 years old. PMID:26722499

  13. MLL2 protein is a prognostic marker for gastrointestinal diffuse large B-cell lymphoma.

    PubMed

    Ye, Haige; Lu, Lu; Ge, Bei; Gao, Shenmeng; Ma, Yongyong; Liang, Bin; Yu, Kang; Yang, Kaiyan

    2015-01-01

    Mixed linage leukemia gene 2 (MLL2) is identified as a novel mutation gene in diffuse large B cell lymphoma (DLBCL). However, the significance of MLL2 protein expression for the prognosis of DLBCL is unclear. In this study, we detected MLL2 protein expression in primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) samples by using tissue microarray immunohistochemistry, and analyzed the correlation between MLL2 protein expression and tumor proliferation activity. In addition, we investigated clinical significance of MLL2 protein expression for PGI-DLBCL prognosis. We found that there was significant difference in MLL2 protein expression between PGI-DLBCL and reactive hyperplasia of lymph node. High expression of MLL2 protein indicated higher clinical stage. In older patients (>60 years) with PGI-DLBCL, MLL2 protein expression was positively correlated with Ki-67 expression and negatively correlated with patient survival. Our data suggest that MLL2 protein is overexpressed in PGI-DLBCL and appears as a prognostic factor for patients of PGI-DLBCL, especially for those older than 60 years old. PMID:26722499

  14. Lenalidomide And Rituximab as Maintenance Therapy in Treating Patients With B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-11-25

    Adult Non-Hodgkin Lymphoma; Adult Grade III Lymphomatoid Granulomatosis; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent

  15. T-cell/histiocyte-rich large B-cell lymphoma of stomach.

    PubMed

    Barut, Figen; Kandemir, Nilufer Onak; Gun, Banu Dogan; Ozdamar, Sukru Oguz

    2016-07-01

    T-cell/histiocyte-rich large B-cell lymphoma is an unusually encountered lymphoid neoplasm of stomach with aggressive course, and is an uncommon morphologic variant of diffuse large B-cell lymphoma. An ulcerated mass, 7x5x1 cm in size was observed within the gastrectomy specimen of a 76-year-old female patient. In cross sections, besides mature lymphoid cells displaying T-cell phenotype, a neoplastic formation composed of large, pleomorphic atypical lymphoid cells with, prominent nucleoli, vesicular nuclei and abundant eosinophilic cytoplasm displaying B-cell phenotype were observed. Meanwhile, histiocyte-like mononuclear cells and Reed-Sternberg-like multinuclear cells expressing CD68 and Mac387 were also observed. The diagnosis of the case was T cell/histiocyte-rich large B-cell lymphoma. This rarely encountered neoplasm should be kept in mind in the differential diagnosis of primary gastric lymphomas. PMID:27427148

  16. Antigen selection in B-cell lymphomas--tracing the evidence.

    PubMed

    Sutton, Lesley-Ann; Agathangelidis, Andreas; Belessi, Chrysoula; Darzentas, Nikos; Davi, Frederic; Ghia, Paolo; Rosenquist, Richard; Stamatopoulos, Kostas

    2013-12-01

    While signaling through the B cell receptor (BcR) facilitates B cell development and maintenance, it also carries intertwined risks for the development of lymphomas since malignant B cells can exploit these pathways in order to trigger and fuel clonal expansion. This corruption of the normal B cell response to antigens, leading to sustained BcR signaling, has given great impulse to investigate in detail the role of antigen in lymphomas. Suffice it to conclude from such studies, largely immunogenetics based, that the evidence implicating antigens (exogenous or self) in lymphoma development is substantial and that lymphomagenesis is functionally driven and dynamic, rather than a simple stochastic process. As the paradigm of antigen-driven lymphoma evolves, further investigation will be paramount to the identification of the inciting agent(s) that may be responsible for immunoproliferative neoplasms and also for the development of therapeutic agents targeting effectors of the BcR signaling pathway.

  17. A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency.

    PubMed

    Neven, Bénédicte; Mamessier, Emilie; Bruneau, Julie; Kaltenbach, Sophie; Kotlarz, Daniel; Suarez, Felipe; Masliah-Planchon, Julien; Billot, Katy; Canioni, Danielle; Frange, Pierre; Radford-Weiss, Isabelle; Asnafi, Vahid; Murugan, Dhaarini; Bole, Christine; Nitschke, Patrick; Goulet, Olivier; Casanova, Jean-Laurent; Blanche, Stéphane; Picard, Capucine; Hermine, Olivier; Rieux-Laucat, Frederic; Brousse, Nicole; Davi, Frederic; Baud, Véronique; Klein, Christoph; Nadel, Bertrand; Ruemmele, Frank; Fischer, Alain

    2013-11-28

    Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis. PMID:24089328

  18. TLR9 Agonist SD-101, Ipilimumab, and Radiation Therapy in Treating Patients With Low-Grade Recurrent B-cell Lymphoma

    ClinicalTrials.gov

    2016-04-23

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma

  19. Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

    PubMed Central

    Gouveia, Gisele Rodrigues; Siqueira, Sheila Aparecida Coelho; Pereira, Juliana

    2012-01-01

    Diffuse large B-Cell lymphoma is the most common subtype of non-Hodgkin lymphoma in the West. In Brazil, it is the fifth cause of cancer, with more than 55,000 cases and 26,000 deaths per year. At Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, diffuse large B-Cell lymphoma represents 49.7% of all non-Hodgkin lymphoma cases. Initially, the classification of non-Hodgkin lymphoma was based on morphology, but advances in immunology and molecular medicine allowed the introduction of a biological classification for these diseases. As for other cancers, non-Hodgkin lymphoma involves patterns of multifactorial pathogenesis with environmental factors, as well as genetic, occupational and dietary factors, contributing to its development. Multiple lesions involving molecular pathways of B-cell proliferation and differentiation may result in the activation of oncogenes such as the BCL2, BCL6, and MYC genes and the inactivation of tumor suppressor genes such as p53 and INK4, as well as other important transcription factors such as OCT-1 and OCT-2. A dramatic improvement in survival was seen after the recent introduction of the anti-CD20 monoclonal antibody. The association of this antibody to the cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) regimen has increased overall survival of diffuse large B-Cell lymphoma and follicular lymphoma patients by 20%. However, 50% of all diffuse large B-Cell lymphoma patients remain incurable, creating a demand for more research with new advances in treatment. Thus, it is important to know and understand the key factors and molecular pathways involved in the pathogenesis of diffuse large B-Cell lymphoma. PMID:23323070

  20. KLF4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classic Hodgkin lymphoma.

    PubMed

    Guan, Hanfeng; Xie, Linka; Leithäuser, Frank; Flossbach, Lucia; Möller, Peter; Wirth, Thomas; Ushmorov, Alexey

    2010-09-01

    The transcription factor KLF4 may act both as an oncogene and a tumor suppressor in a tissue-depending manner. In T- and pre-B-cell lymphoma, KLF4 was found to act as tumor suppressor. We found the KLF4 promoter methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas, namely, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, and in classic Hodgkin lymphoma (cHL) cases. Promoter hypermethylation was associated with silencing of KLF4 expression. Conditional overexpression of KLF4 in Burkitt lymphoma cell lines moderately retarded proliferation, via cell-cycle arrest in G(0)/G(1). In the cHL cell lines, KLF4 induced massive cell death that could partially be inhibited with Z-VAD.fmk. A quantitative reverse-transcribed polymerase chain reaction array revealed KLF4 target genes, including the proapoptotic gene BAK1. Using an shRNA-mediated knock-down approach, we found that BAK1 is largely responsible for KLF4-induced apoptosis. In addition, we found that KLF4 negatively regulates CXCL10, CD86, and MSC/ABF-1 genes. These genes are specifically up-regulated in HRS cells of cHL and known to be involved in establishing the cHL phenotype. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may favor lymphoma survival by loosening cell-cycle control and protecting from apoptosis. PMID:20519630

  1. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma

    PubMed Central

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies. PMID:27630997

  2. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma.

    PubMed

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies. PMID:27630997

  3. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma

    PubMed Central

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies.

  4. EBV+ diffuse large B-cell lymphoma arising within atrial myxoma in Chinese immunocompetent patient

    PubMed Central

    Liu, Xiaoyan; Liu, Pu; Li, Jun

    2015-01-01

    The incidence rate of Primary cardiac lymphoma is very low. Primary cardiac lymphoma within myxoma is extremely rare disease. So far, these cases have been reported only eight in the world, which has not reported in Chinese so far. Hence, we reported the unique Chinese case of 52-year-old immunocompetent male with primary Epstein-Barr virus positive diffuse large B-cell lymphoma arising within atrial myxoma, and had no evidence of systemic lymphoma. The patient presented right sided body numbness, arm weakness no incentive and mouth twitch. A transthoracic echocardiogram revealed a large intraatrial mass, attached to the left atrial wall. The mass was removed by open thoracic surgery and subsequently diagnosed as malignant diffuse large B-cell lymphoma with myxoma by histopathology. This was the fourth case of discovered Epstein-Barr virus positive diffuse large B-cell lymphoma in a cardiac myxoma reported so far. The patient has been well by followed up for 5 months without chemotherapy. Now we discuss the importance of histodiagnosis and the proper treatment. Epstein-Barr virus positive diffuse large B-cell lymphoma arising within atrial myxoma is an extraordinary lymphoma for better prognosis, avoiding excessive treatment. PMID:25973119

  5. Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma.

    PubMed

    Witkowska, Magdalena; Smolewski, Piotr

    2015-01-01

    During the last decade, significant prolonged survival in diffusive large B-cell lymphoma (DLBCL) has been observed. The efficacy of initial treatment improved mostly due to addition of a chimeric anti-CD20 monoclonal antibody (rituximab) to standard chemotherapeutic regimens. Moreover, accurate understanding of DLBCL pathogenesis and remarkable progress in gene expression profiling have led to the development of a variety of tumor-specific regimens. Novel agents target directly the pathways involved in signal transduction, lead to apoptosis and cancer cells differentiation. In this article, we mainly focus on new treatment options, such as monoclonal antibodies, tyrosine kinase inhibitors and immunomodulatory drugs, currently investigated in aggressive B-cell lymphoma with particular attention to DLBCL type.

  6. The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification

    PubMed Central

    Menon, Madhu P.; Pittaluga, Stefania; Jaffe, Elaine S.

    2012-01-01

    Diffuse large B cell lymphomas (DLBCL) are aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been towards incorporation of clinical features, morphology, immunohistochemistry and ever evolving genetic data into the classification scheme. The 2008 WHO classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling (GEP) heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age, and include EBV-positive large B-cell lymphoma of the elderly. HHV-8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a “solid variant.” Two borderline categories were created; one deals with tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL. The second confronts the interface between Burkitt Lymphoma (BL) and DLBCL, so called “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma” in the 2008 classification. Most cases harbor both MYC and BCL2 translocations, and are highly aggressive. Another interesting entity is ALK+ DLBCL, which renders itself potentially targetable by ALK inhibitors. Ongoing investigations at the genomic level, with both exome and whole genome sequencing, are sure to reveal new pathways of transformation in the future. PMID:23006945

  7. Diffuse large B-cell lymphoma of the cauda equina

    PubMed Central

    Broen, Martijn; Draak, Tim; Riedl, Robert G; Weber, Wim E J

    2014-01-01

    Primary central nervous system (CNS) lymphoma is a rare form of non-Hodgkin's lymphoma. The clinical presentation is variable, depending on its localisation within the nervous system. Only 1% of primary CNS lymphoma emerges in the spinal cord, and the prevalence of primary lymphoma of the cauda equina is unknown, but probably even rarer. Diagnosing primary lymphoma of the cauda equina is difficult, since it can mimic other more common disorders such as a herniated disc, especially in its early stages. Here we present two cases of primary cauda equina lymphoma in which diagnostic work up took a long time, as the final diagnosis was only reached after a nerve root biopsy. PMID:25368124

  8. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.

    PubMed

    Yamamoto, K; Lee, B J; Li, C; Dubois, R L; Hobeika, E; Bhagat, G; Zha, S

    2015-06-01

    Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL. PMID:25676421

  9. Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma.

    PubMed

    Pellicelli, Adriano M; D'Ambrosio, Cecilia; Dessanti, Maria L; Villani, Roberto; Fondacaro, Lucia; Miglioresi, Lucia; Grillo, Lucia R; Andreoli, Arnaldo

    2015-01-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.

  10. Undertreatment of patients with localized extranodal compared with nodal diffuse large B-cell lymphoma.

    PubMed

    Kuper-Hommel, Marion J J; van de Schans, Saskia A M; Vreugdenhil, Gerard; van Krieken, J Han; Coebergh, Jan-Willem W

    2013-08-01

    Population-based studies analyzing clinical implications of nodal versus extranodal (EN) presentation of diffuse large B-cell lymphoma (DLBCL) are scarce. We studied clinical differences and trends in incidence, treatment and survival of nodal and EN DLBCL in a population-based cohort. All patients newly diagnosed with localized (Ann Arbor stage [AAS] I and II) nodal (n = 5124) and EN (n = 4776) DLBCL, and primary mediastinal B-cell lymphoma (PMBL; n = 88), diagnosed between 1989 and 2010, were selected from the Netherlands Cancer Registry. Primary EN disease was correlated with older age and more favorable clinical stage (AAS I). The age standardized incidence rates for men with localized EN DLBCL, and for men and women with localized PMBL, increased significantly, whereas the age standardized incidence rates of all other subgroups remained stable. The stomach was the most common EN localization. Patients with EN disease received less chemotherapy and targeted therapy than their nodal counterparts, irrespective of age and period of diagnosis. Their 5-year overall survival (OS) was 48% vs. 54% in the nodal group, but in multivariate analysis primary extranodal presentation was not independently associated with inferior survival. This population-based study shows clinically relevant differences between localized nodal and EN DLBCL and PMBL. Since patients with EN were significantly less often optimally treated, we advocate better interaction between medical disciplines. PMID:23190406

  11. FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.

    PubMed

    Xie, Linka; Ritz, Olga; Leithäuser, Frank; Guan, Hanfeng; Färbinger, Johanna; Weitzer, Clarissa D; Gehringer, Franziska; Bruederlein, Silke; Holzmann, Karlheinz; Vogel, Marion J; Möller, Peter; Wirth, Thomas; Ushmorov, Alexey

    2014-07-30

    Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative Med-B1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL. PMID:24977668

  12. FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma

    PubMed Central

    Leithäuser, Frank; Guan, Hanfeng; Färbinger, Johanna; Weitzer, Clarissa D.; Gehringer, Franziska; Brüderlein, Silke; Holzmann, Karlheinz; Vogel, Marion J.; Möller, Peter; Wirth, Thomas; Ushmorov, Alexey

    2014-01-01

    Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative MedB-1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL. PMID:24977668

  13. Pediatric B-Cell Lymphoma With Lymphoblastic Morphology, TdT Expression, MYC Rearrangement, and Features Overlapping With Burkitt Lymphoma.

    PubMed

    Meznarich, Jessica; Miles, Rodney; Paxton, Christian N; Afify, Zeinab

    2016-05-01

    Burkitt lymphoma (BL) and B-lymphoblastic lymphoma are subtypes of pediatric non-Hodgkin lymphoma with different presenting features, treatment, and outcomes. This case report documents a 5-year-old female who presented with B-cell lymphoma with lymphoblastic morphology, terminal deoxynucleotidyl transferase expression, MYC rearrangement, and features overlapping with BL. Genomic microarray analysis identified a gain on the long arm of chromosome 1 without other definitive changes. She was treated according to a BL protocol and remains in remission 16-months after initial diagnosis. PMID:26785246

  14. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.

    PubMed

    Lenz, Georg; Nagel, Inga; Siebert, Reiner; Roschke, Anna V; Sanger, Warren; Wright, George W; Dave, Sandeep S; Tan, Bruce; Zhao, Hong; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Campo, Elias; Jaffe, Elaine S; Smeland, Erlend B; Fisher, Richard I; Kuehl, W Michael; Chan, Wing C; Staudt, Louis M

    2007-03-19

    To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB. PMID:17353367

  15. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder

    PubMed Central

    Jones, Carol

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms. PMID:27648316

  16. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder

    PubMed Central

    Jones, Carol

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms.

  17. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder.

    PubMed

    Deel, Chelsey D; Jones, Carol; Scordino, Teresa

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms. PMID:27648316

  18. The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

    PubMed Central

    Vardhana, Santosha; Younes, Anas

    2016-01-01

    Classical Hodgkin lymphoma is curable in the majority of cases with chemotherapy and/or radiation. However, 15–20% of patients ultimately relapse and succumb to their disease. Pathologically, classical Hodgkin lymphoma is characterized by rare tumor-initiating Reed-Sternberg cells surrounded by a dense immune microenvironment. However, the role of the immune microenvironment, particularly T and B cells, in either promoting or restricting Classical Hodgkin lymphoma growth remains undefined. Recent dramatic clinical responses seen using monoclonal antibodies against PD-1, a cell surface receptor whose primary function is to restrict T cell activation, have reignited questions regarding the function of the adaptive immune system in classical Hodgkin lymphoma. This review summarizes what is known regarding T cells, B cells, and immune checkpoints in classical Hodgkin lymphoma. PMID:27365459

  19. Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma

    PubMed Central

    Merli, Michele; Carli, Giuseppe; Arcaini, Luca; Visco, Carlo

    2016-01-01

    The association of hepatitis C virus (HCV) and B-cell non-Hodgkin lymphomas (NHL) has been highlighted by several epidemiological and biological insights; however the most convincing evidence is represented by interventional studies demonstrating the capability of antiviral treatment (AT) with interferon (IFN) with or without ribavirin to induce the regression of indolent lymphomas, especially of marginal-zone origin. In the largest published retrospective study (100 patients) the overall response rate (ORR) after first-line IFN-based AT was 77% (44% complete responses) and responses were sustainable (median duration of response 33 mo). These results were confirmed by a recent meta-analysis on 254 patients, demonstrating an ORR of 73%. Moreover this analysis confirmed the highly significant correlation between the achievement of viral eradication sustained virological response (SVR) and hematological responses. Two large prospective studies demonstrated that AT is associated with improved survival and argue in favor of current guidelines’ recommendation of AT as preferential first-line option in asymptomatic patients with HCV-associated indolent NHL. The recently approved direct-acting antiviral agents (DAAs) revolutionized the treatment of HCV infection, leading to SVR approaching 100% in all genotypes. Very preliminary data of IFN-free DAAs therapy in indolent HCV-positive NHL seem to confirm their activity in inducing lymphoma regression. PMID:27784957

  20. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

    PubMed Central

    Dubanet, Lydie; Bentayeb, Hafidha; Petit, Barbara; Olivrie, Agnès; Saada, Sofiane; de la Cruz-Morcillo, Miguel A; Lalloué, Fabrice; Gourin, Marie-Pierre; Bordessoule, Dominique; Faumont, Nathalie; Delage-Corre, Manuela; Fauchais, Anne-Laure; Jauberteau, Marie-Odile; Troutaud, Danielle

    2015-01-01

    Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines. Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies. Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model. Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups. PMID:26284337

  1. Diffuse large B cell lymphoma of the spermatic cord: a case report and literature review.

    PubMed

    Joshi, Shivam; Mansour, Ahmed M; Eldefrawy, Ahmed; Soloway, Mark S

    2012-12-01

    Primary lymphoma of the spermatic cord is rare. We report a case of primary lymphoma of the spermatic cord and review the literature. A 77-year-old man presented with a 5 month history of an enlarging right inguino-scrotal mass. On physical exam, the mass involved the spermatic cord. Computerized tomography and magnetic resonance imaging revealed a 10 cm x 4 cm inguinoscrotal mass related to the spermatic cord. A right inguinal orchidectomy with wide local excision was performed. Pathological and immunohistochemical evaluation identified the tumor as a diffuse large B cell lymphoma of the spermatic cord. Postoperatively, patient began a chemoradiotherapy regimen consistent with metastatic lymphoma.

  2. Development of a Malignancy-Associated Proteomic Signature for Diffuse Large B-Cell Lymphoma

    PubMed Central

    Romesser, Paul B.; Perlman, David H.; Faller, Douglas V.; Costello, Catherine E.; McComb, Mark E.; Denis, Gerald V.

    2009-01-01

    The extreme pathological diversity of non-Hodgkin’s lymphomas has made their accurate histological assessment difficult. New diagnostics and treatment modalities are urgently needed for these lymphomas, particularly in drug development for cancer-specific targets. Previously, we showed that a subset of B cell lymphoma, diffuse large B cell lymphoma, may be characterized by two major, orthogonal axes of gene expression: one set of transcripts that is differentially expressed between resting and proliferating, nonmalignant cells (ie, a “proliferative signature”) and another set that is expressed only in proliferating malignant cells (ie, a “cancer signature”). A differential proteomic analysis of B cell proliferative states, similar to previous transcriptional profiling analyses, holds great promise either to reveal novel factors that participate in lymphomagenesis or to define biomarkers of onset or progression. Here, we use a murine model of diffuse large B cell lymphoma to conduct unbiased two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomic analyses of malignant proliferating B cells and tissue-matched, normal resting, or normal proliferating cells. We show that the expression patterns of particular proteins or isoforms across these states fall into eight specific trends that provide a framework to identify malignancy-associated biomarkers and potential drug targets, a signature proteome. Our results support the central hypothesis that clusters of proteins of known function represent a panel of expression markers uniquely associated with malignancy and not normal proliferation. PMID:19498000

  3. A case of diffuse large B-cell lymphoma misdiagnosed as an erysipelas of the face.

    PubMed

    Teresiak-Mikołajczak, Ewa; Szymańska, Magdalena; Czarnecka-Operacz, Magdalena

    2013-08-01

    We report a case of a woman with diffuse large B-cell lymphoma (DLBCL). Primary cutaneous lymphomas (PCLs) represent distinct clinical and histopathologic subtypes of extranodal T- and B-cell lymphomas. Cutaneous B-cell lymphomas comprise 20-25% of all primary cutaneous lymphomas. The patient presented an erythematous tumour mass of the left nasolabial fold, nose and left cheek as well as disseminated infiltrative plagues on the trunk, arms and left lower leg. Skin biopsy revealed a diffuse infiltrate of lymphocytes around hair follicles and blood vessels within dermis and subcutaneous tissue. An immunohistochemistry showed a diffuse infiltrate of large non-cleaved B-cells, with a high proportion of centroblast-like cells within dermis. Tumor cells expressed CD20, bcl-2 protein and did not express CD10. The patient was misdiagnosed as the erysipelas of the face and unsuccessfully treated with long-term antibiotic therapy by a laryngologist and a dermatologist. The correct diagnosis was delayed and established after 6 months' history of DLBCL lesions. Therefore, we would like to strongly stress the importance of considering diagnosis of cutaneous lymphomas in chronic skin lesions non-responsive to adequate therapies.

  4. B-cell non-Hodgkin lymphoma linked to Coxiella burnetii.

    PubMed

    Melenotte, Cléa; Million, Matthieu; Audoly, Gilles; Gorse, Audrey; Dutronc, Hervé; Roland, Gauthier; Dekel, Michal; Moreno, Asuncion; Cammilleri, Serge; Carrieri, Maria Patrizia; Protopopescu, Camelia; Ruminy, Philippe; Lepidi, Hubert; Nadel, Bertrand; Mege, Jean-Louis; Xerri, Luc; Raoult, Didier

    2016-01-01

    Bacteria can induce human lymphomas, whereas lymphoproliferative disorders have been described in patients with Q fever. We observed a lymphoma in a patient with Q fever that prompted us to investigate the association between the 2 diseases. We screened 1468 consecutive patients of the 2004 to 2014 French National Referral Center for Q fever database. The standardized incidence ratios (SIRs) of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were calculated comparatively to the 2012 Francim Registry. The presence of Coxiella burnetii was tested using immunofluorescence and fluorescence in situ hybridization using a specific 16S ribosomal RNA probe and genomic DNA probe. Seven patients (0.48%) presented mature B-cell lymphoma consisting of 6 DLBCL and 1 FL. An excess risk of DLBCL and FL was found in Q fever patients compared with the general population (SIR [95% confidence interval], 25.4 [11.4-56.4] and 6.7 [0.9-47.9], respectively). C burnetii was detected in CD68(+) macrophages within both lymphoma and lymphadenitis tissues but localization in CD123(+) plasmacytoid dendritic cells (pDCs) was found only in lymphoma tissues. Q fever patients with persistent focalized infection were found more at risk of lymphoma (hazard ratio, 9.35 [1.10-79.4]). Interleukin-10 (IL10) overproduction (P = .0003) was found in patients developing lymphoma. These results suggest that C burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma, possibly by the infection of pDCs and IL10 overproduction. Screening for early lymphoma diagnosis should be considered in the management of patients with Q fever, especially those with persistent focalized infections. PMID:26463422

  5. Diagnostic value of immunoglobulin κ light chain gene rearrangement analysis in B-cell lymphomas

    PubMed Central

    KOKOVIC, IRA; NOVAKOVIC, BARBARA JEZERSEK; NOVAKOVIC, SRDJAN

    2015-01-01

    Analysis of the immunoglobulin κ light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis. PMID:25501347

  6. Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

    ClinicalTrials.gov

    2016-10-24

    Childhood B Acute Lymphoblastic Leukemia; Childhood Burkitt Leukemia; Childhood Diffuse Large Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma

  7. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells.

    PubMed

    Polo, Jose M; Dell'Oso, Tania; Ranuncolo, Stella Maris; Cerchietti, Leandro; Beck, David; Da Silva, Gustavo F; Prive, Gilbert G; Licht, Jonathan D; Melnick, Ari

    2004-12-01

    The BTB/POZ transcriptional repressor and candidate oncogene BCL6 is frequently misregulated in B-cell lymphomas. The interface through which the BCL6 BTB domain mediates recruitment of the SMRT, NCoR and BCoR corepressors was recently identified. To determine the contribution of this interface to BCL6 transcriptional and biological properties, we generated a peptide that specifically binds BCL6 and blocks corepressor recruitment in vivo. This inhibitor disrupts BCL6-mediated repression and establishment of silenced chromatin, reactivates natural BCL6 target genes, and abrogates BCL6 biological function in B cells. In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest. BTB domain peptide inhibitors may constitute a novel therapeutic agent for B-cell lymphomas. PMID:15531890

  8. Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

    PubMed Central

    Frank, Matthew J.; Dawson, David W.; Bensinger, Steven J.; Hong, Jason S.; Knosp, Wendy M.; Xu, Lizhong; Balatoni, Cynthia E.; Allen, Eric L.; Shen, Rhine R.; Bar-Sagi, Dafna; Martin, Gail R.

    2009-01-01

    B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling. PMID:19147787

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

    PubMed Central

    Deng, Lijuan; Wang, Xiaoxiao; Manyam, Ganiraju C.; Visco, Carlo; Montes-Moreno, Santiago; Zhang, Li; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W.L.; van Krieken, J. Han; Huh, Jooryung; Ponzoni, Maurilio; Ferreri, Andrés J.M.; Parsons, Ben M.; Møller, Michael B.; Piris, Miguel A.; Winter, Jane N.; Medeiros, L. Jeffrey; Hu, Shimin; Young, Ken H.

    2016-01-01

    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. PMID:26573234

  10. Imbalanced MHC class II molecule expression at surface of murine B cell lymphomas

    PubMed Central

    1986-01-01

    To study the role of class II MHC expression in mouse lymphomagenesis, we examined the cell surface expression of I-A/E antigens on 24 spontaneous or murine leukemia virus (MuLV)-induced mouse B10.A (I-Ak, I-Ek) B cell lymphomas. Two primary B10.A B cell lymphomas were observed with strong I-Ek expression but with only minimal cell surface I-Ak expression. Both tumors are readily transplantable in syngeneic mice, with maintenance of their I-A-, I-E+ phenotype. Strikingly, one I- A-, I-E+ B cell lymphoma contains a (11; 17) translocation with a breakpoint on chromosome 17 that is localized within or very close to the H-2 complex. DNA of both tumors contains normal restriction enzyme fragments of the A alpha and A beta genes. Northern blot analyses indicated that one I-A-, I-E+ tumor strongly expressed A alpha, E alpha, and E beta mRNAs but possessed only a weak expression of A beta mRNA. The other B cell lymphoma showed A beta, E alpha, and E beta mRNA expression but only minimal A alpha mRNA expression. In 11 primary B10.A B cell lymphomas with a normal I-A+, I-E+ phenotype, no imbalances in A alpha/A beta mRNA levels were observed. The implications of these findings for the role of class II MHC expression in mouse B cell lymphoma-genesis are discussed. PMID:3486245

  11. Primary bilateral adrenal B-cell lymphoma associated with EBV and JCV infection

    PubMed Central

    Barzon, Luisa; Trevisan, Marta; Marino, Filippo; Guzzardo, Vincenza; Palù, Giorgio

    2009-01-01

    Primary lymphoma of the adrenal gland is a rare and highly aggressive disease, with only a few reports in the literature. The pathogenesis is unknown, but detection of Epstein Barr virus (EBV) genome sequences and gene expression in some cases of primary adrenal lymphomas suggested the virus might be a causative agent of the malignancy. While investigating the presence of genome sequences of oncogenic viruses in a large series of adrenal tumors, both EBV and JC polyomavirus (JCV) DNA sequences were detected in a diffuse large primary bilateral B-cell non-Hodgkin lymphoma of the adrenal gland, which was diagnosed only at postmortem examination in a 77 year-old woman with incidentally discovered adrenal masses and primary adrenal insufficiency. The presence of both EBV and JCV genome sequences suggests the relevance of EBV and JCV coinfection in the pathogenesis of this rare form of B-cell lymphoma. PMID:19146683

  12. Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment

    PubMed Central

    2013-01-01

    Background Toll-like receptor (TLR) agonists have important properties that can be exploited for immunotherapy against tumors. Locally injected immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG-ODNs), which are TLR9 agonists, have shown promise in cancer models. Several studies have demonstrated that these motifs have immunologic effects similar to those of bacterial DNA and can stimulate monocytes, macrophages, dendritic, and B cells, which then produce several proinflammatory cytokines. However, these CpG-ODNs appear to produce opposite effects on tumor B cells. Methods In this study, we investigated the direct effects of a murine class B CpG (1826) ODNs on lymphoma B cells in vitro and in vivo, using mouse models of non-Hodgkin B lymphomas developing in immunoprivileged sites, specifically the brain and the eye, and in subcutaneous sites. Results In vitro, CpG-ODNs produced antiproliferative and proapoptotic effects on lymphoma B cells. In vivo, it had an antitumor effect when injected into tumors in murine models of subcutaneous lymphoma (SCL) and primary cerebral lymphoma (PCL). However, its intravitreal administration into a primary intraocular lymphoma (PIOL) mouse model did not produce an antitumor effect. In vitro experiments using supernatant from mouse PIOL samples demonstrated that the PIOL molecular microenvironment inhibits the antiproliferative effect of CpG-ODNs on lymphoma B-cells. Conclusions Responsiveness to CpG stimulation differs in subcutaneous, cerebral, and ocular tumors, according to the tumoral and molecular microenvironment, and this should be considered for further therapeutic approaches. PMID:23561041

  13. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma.

    PubMed

    Ritz, Olga; Guiter, Chrystelle; Castellano, Flavia; Dorsch, Karola; Melzner, Julia; Jais, Jean-Philippe; Dubois, Gwendoline; Gaulard, Philippe; Möller, Peter; Leroy, Karen

    2009-08-01

    Primary mediastinal B-cell lymphoma (PMBL) is a separate entity of aggressive B-cell lymphoma, characterized by a constitutive activation of janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, also observed in Hodgkin lymphoma. Although many cancers exhibit constitutive JAK-STAT pathway activation, mutations of STAT genes have not been reported in neoplasms. Here, we show that MedB-1 PMBL-derived and L1236 Hodgkin-derived cell lines and 20 of 55 (36%) PMBL cases harbor heterozygous missense mutations in STAT6 DNA binding domain, whereas no mutation was found in 25 diffuse large B-cell lymphoma samples. In 3 cases, somatic origin was indicated by the absence of the mutations in the nontumoral tissue. The pattern of STAT6 mutations was different from the classical features of somatic hypermutations. The mutant STAT6 proteins showed a decreased DNA binding ability in transfected HEK cells, but no decrease in expression of STAT6 canonical target genes was observed in PMBL cases with a mutated STAT6 gene. Although the oncogenic properties of STAT6 mutant proteins remain to be determined, their recurrent selection in PMBL strongly argues for their involvement in the pathogenesis of this aggressive B-cell lymphoma. PMID:19423726

  14. DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma

    SciTech Connect

    Wang, Lei; Nishihara, Hiroshi; Kimura, Taichi; Kato, Yasutaka; Tanino, Mishie; Nishio, Mitsufumi; Obara, Masato; Endo, Tomoyuki; Koike, Takao; Tanaka, Shinya

    2010-04-23

    DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression. Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy.

  15. Diffuse large B-cell lymphoma involving the central nervous system.

    PubMed

    Gualco, Gabriela; Weiss, Lawrence M; Barber, Glen N; Bacchi, Carlos E

    2011-02-01

    Lymphomas involving the central nervous system are recognized increasingly in immunocompetent as well as immunosuppressed individuals, and the majority of the cases are diffuse large B-cell lymphoma (DLBCL). The aim of this study was to compare the immunophenotype, clinicopathological features, and association with Epstein-Barr virus (EBV) of DLBCL of the central nervous system (CNS) in 3 different clinical situations: primary, in immunocompetent patients; "primary," in immunosuppressed patients; and in patients with secondary involvement by systemic lymphoma. The authors reviewed the clinicopathological features, morphology, immunophenotype (according to germinal-center B-cell-like and nongerminal B-cell-like subtypes), and association with EBV in 36 cases of DLBCL of the CNS, including 25 primary cases, 5 associated with immunosuppression, and 6 cases with secondary involvement. Survival was evaluated in 15 cases of primary CNS lymphomas. Of the 36 patients, 19 were male and 18 female. Only 2 cases of lymphomas were EBV-positive; both occurred in immunosuppressed patients. Separation into germinal-center and non-germinal center subtypes by an immunohistochemistry panel showed that 68% of primary, 80% of secondary, and 83% of the cases associated with immunosuppression were of non-germinal-center subtype, respectively. Patients with non-germinal-center immunophenotype showed significantly worse survival than those with CNS lymphomas of the germinal-center subtype.

  16. B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

    PubMed Central

    Vaqué, José P.; Martínez, Nerea; Batlle-López, Ana; Pérez, Cristina; Montes-Moreno, Santiago; Sánchez-Beato, Margarita; Piris, Miguel A.

    2014-01-01

    B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities. PMID:24497559

  17. Pathological features of lymphoid proliferations of the salivary glands: lymphoepithelial sialadenitis versus low-grade B-cell lymphoma of the malt type.

    PubMed

    Carbone, A; Gloghini, A; Ferlito, A

    2000-12-01

    Lymphoid proliferations of the salivary glands can be either reactive or neoplastic. Reactive lesions include the lymphoepithelial sialadenitis (LESA; also known as myoepithelial sialadenitis [MESA]) of Sjogren's syndrome. Lymphomas of the salivary glands are predominantly B-cell type and include extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. The spectrum of histopathologic features of LESA/MESA includes 1) "fully benign lymphoid infiltrate," with or without an associated lymphoid follicular structure, without immunoglobulin (Ig) light chain restriction in B-cells, and without any features of aggressive behavior, and 2) "lymphoproliferative lesions," with or without areas of Ig light chain restriction in B-cells, with the usual presence of centrocyte-like cells. A more or less pronounced lymphoepithelial aggressiveness may be present without definite evidence of malignancy. B-cell clones are detected in over 50% of cases of LESA/MESA by molecular genetic methods, but this does not correlate with morphological or clinical evidence of overt lymphoma. On the other hand, "marginal zone B-cell lymphoma of the MALT type" of the salivary glands produces a dense lymphoid infiltrate diffusely involving the gland, with obliteration of acini. The centrocyte-like cells form broad "halos" around the epithelial cell nests and broad strands between lymphoepithelial lesions, often linking together several lymphoepithelial lesions. Further, lymphoma cells express monotypic surface Ig, and in the majority of the cases, the plasma cells are also monoclonal. In conclusion, the diagnosis of LESA/MESA versus marginal zone B-cell lymphoma of the MALT type still relies on the evaluation of morphological features. It seems that molecular genetic analysis has little or no practical role in the clinical diagnosis of salivary gland lymphoma in a setting of LESA/MESA and Sjögren's syndrome.

  18. Primary bilateral adrenal intravascular large B-cell lymphoma associated with adrenal failure.

    PubMed

    Fukushima, Ayumi; Okada, Yosuke; Tanikawa, Takahisa; Onaka, Takashi; Tanaka, Aya; Higashi, Takehiro; Tsukada, Junichi; Tanaka, Yoshiya

    2003-07-01

    We report a rare case of bilateral primary adrenal non-Hodgkin's lymphoma with adrenal failure. A 66-year-old woman developed symptoms of adrenal failure. The cause of adrenal failure was suspected to be malignant lymphoma based on the high levels of serum soluble interleukin-2 receptor and LDH. Bilateral adrenalectomy was performed and pathological examination showed intravascular large B-cell lymphoma (IVL). Although complete remission was achieved, recurrence occurred three months later with brain metastases. IVL should be suspected in patients with bilateral adrenal tumors who present with rapidly progressive adrenal failure.

  19. Diffuse Large B-Cell Lymphoma Presenting with Bilateral Renal Masses and Hematuria: A Case Report.

    PubMed

    Erdoğmuş, Şiyar; Aktürk, Serkan; Kendi Çelebi, Zeynep; Kiremitçi, Saba; Kaygusuz, Gülşah; Altınbaş, Namık Kemal; Üstüner, Evren; Keven, Kenan

    2016-06-01

    Renal involvement is most often seen in conjunction with multisystemic, disseminated lymphoma either by direct extension from a retroperitoneal mass or via hematogenous spread. Primary lymphoma of the kidney is not a common entity and it is a controversial issue on account of the absence of lymphatic tissues in the normal kidney. In this case report, we describe a 19-year-old male with hematuria, acute kidney injury, and bilateral renal masses due to massive lymphomatous infiltration of the kidneys, which was diagnosed as diffuse large B-cell non-Hodgkin lymphoma by Tru-Cut biopsy. PMID:27095511

  20. Rare clinical presentation of diffuse large B-cell lymphoma as otitis media and facial palsy.

    PubMed

    Siddiahgari, Sirisha Rani; Yerukula, Pallavi; Lingappa, Lokesh; Moodahadu, Latha S

    2016-01-01

    Extra nodal presentation of Non Hodgkins Lymphoma (NHL) is a rare entity, and data available about the NHL that primarily involves of middle ear and mastoid is limited. We report a case of diffuse large B cell lymphoma (DLBCL), in a 2 year 8 month old boy, who developed otalgia and facial palsy. Computed tomography revealed a mass in the left mastoid. Mastoid exploration and histopathological examination revealed DLBCL. This case highlights the importance of considering malignant lymphoma as one of the differential diagnosis in persistent otitis media and/facial palsy.

  1. [Diffuse large B-cell lymphoma of the testis relapsed 16 years after achieving complete response].

    PubMed

    Nagasaka, Isao; Mitsui, Takeki; Ishizaki, Takuma; Koiso, Hiromi; Yokohama, Akihiko; Saitoh, Takayuki; Hirato, Junko; Igarashi, Tadahiko; Kojima, Masaru; Tsukamoto, Norifumi; Nojima, Yoshihisa; Murakami, Hirokazu; Handa, Hiroshi

    2015-12-01

    Testicular lymphoma is a rare disease, accounting for 1-2% of non-Hodgkin lymphoma and 5-9% of all testicular tumors, and has a high relapse rate with a poor prognosis. We report a patient with testicular diffuse large B-cell lymphoma (DLBCL) who relapsed after being in remission for 16 years. He had undergone orchiectomy of the right testis and was diagnosed as having DLBCL (stage IAE) at 49 years of age. After 3 cycles of CHOP, he achieved a complete remission. Orchiectomy was performed because of a left testicular tumor, and he was again diagnosed with DLBCL at the age of 65. VH3-21 was detected in lymphoma cells at the times of both the first diagnosis and the relapse based on analysis of the variable region of the immunoglobulin heavy chain. Accordingly, the lymphoma cells at relapse were confirmed to be the same clone as that which had been documented at the first diagnosis.

  2. [Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

    PubMed

    Sancho, Juan-Manuel; Ribera, Josep-Maria

    2016-01-15

    Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary.

  3. [Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

    PubMed

    Sancho, Juan-Manuel; Ribera, Josep-Maria

    2016-01-15

    Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary. PMID:25817451

  4. Human lymphoma-lymphoma hybrids and lymphoma-leukemia hybrids. I. Isolation, characterization, cell surface markers, and B-cell markers.

    PubMed

    Zeuthen, J; Klein, G; Ber, R; Masucci, G; Bisballe, S; Povey, S; Terasaki, P; Ralph, P

    1982-02-01

    Four new somatic cell hybrids were obtained by fusion of various Burkitt's lymphoma (BL)-derived cell lines that had different selective markers: Raji-P3HR-1, Daudi-Raji, and a P3HR-1-P3HR-1 "autohybrid" derived from two P3HR-1 sublines. In addition, a hybrid was obtained between the Daudi (BL) line and the human leukemia cell line K562. The hybrids were extensively characterized by means of chromosome, isozyme, and HLA surface markers. The phenotypic differences between the parent cell lines allowed some conclusions with respect to the expression of latent Epstein-Barr virus (EBV) genomes, C3 and EBV receptors, and of immunoglobulin and beta 2-microglobulin-HLA expression as well as the influence of the leukemia cell (K562) genome on B-cell properties in the Daudi-K562 hybrid. B-cell and differentiated markers of these hybrids were characterized. High-level expression dominated for the marker C3 and EBV receptors, which showed a good correlation coefficient of 0.84, as was true for Fc receptors and surface immunoglobulin. The Daudi-K562 hybrid showed loss of all B-cell markers but retention of the leukemia cell markers (e.g., hemoglobin synthesis).

  5. Bromodomain inhibition in diffuse large B-cell lymphoma--giving MYC a brake.

    PubMed

    Mottok, Anja; Gascoyne, Randy D

    2015-01-01

    Bromodomains are conserved protein regions that function as epigenetic readers by recognizing specific histone modifications. The common association of bromodomains with enhancer and super-enhancer regions in diffuse large B-cell lymphoma contributes to its pathogenesis. Bromodomain inhibition reduces tumor growth largely through the disruption of transcriptional networks driven by oncogenic MYC. PMID:25165099

  6. B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

    PubMed Central

    Irish, Jonathan M.; Myklebust, June H.; Alizadeh, Ash A.; Houot, Roch; Sharman, Jeff P.; Czerwinski, Debra K.; Nolan, Garry P.; Levy, Ronald

    2010-01-01

    Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient's disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell–cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma. PMID:20543139

  7. Cutaneous B-Cell Lymphoma in a Perdido Key Beach Mouse (Peromyscus poliontus trissyllepsis)

    PubMed Central

    Aitken-Palmer, Copper; Kiupel, Matti; Russell, Kathy; Hayes, Linda; Heard, Darryl

    2012-01-01

    The Perdido Key beach mouse (Peromyscus poliontus trissyllepsis) is an endangered mammal indigenous to the panhandle beaches of Northwest Florida. A captive 3.5-y-old female mouse was evaluated because of severe pruritus, diffuse alopecia, skin reddening, and ulcerations over the dorsum of her body. Initial skin biopsy of the affected area suggested bacterial dermatitis but was inconclusive. Despite empiric antibiotic, anthelmintic, and antihistamine treatments, she continued to decline and developed severe ulcerations over the majority of her body. Postmortem histopathologic evaluation led to a tentative diagnosis of epitheliotropic lymphoma, suggestive of a mycosis fungoides T-cell–type cutaneous lymphoma. However, immunohistochemistry results challenged this diagnosis, indicating that the lesion was actually an epidermotropic B-cell lymphoma. Spontaneous cutaneous B-cell lymphomas are rare in rodents and had not previously been reported to occur in Perdido Key beach mice. This case report provides initial evidence that the Perdido Key beach mouse is susceptible to cutaneous B-cell lymphoma. PMID:22546914

  8. Clonal rearrangements of immunoglobulin genes and progression to B cell lymphoma in cutaneous lymphoid hyperplasia.

    PubMed

    Wood, G S; Ngan, B Y; Tung, R; Hoffman, T E; Abel, E A; Hoppe, R T; Warnke, R A; Cleary, M L; Sklar, J

    1989-07-01

    Cutaneous lymphoid hyperplasia (CLH) is a disorder characterized by the development of one or more skin lesions containing dense lymphoid infiltrates that exhibit the histopathologic features of a benign, reactive process. Nevertheless, some cases have been associated with the subsequent development of clinically overt lymphomas. This suggests that monoclonal populations may exist in some cases of CLH and that these cases may represent a subset more likely to evolve into lymphoma. To determine if such a subset of CLH can be distinguished, Southern blot analysis of DNA was used to study the immunogenotypic features of lesions from 14 patients with clinical, histopathologic, and immunopathologic findings characteristic of CLH. Five cases exhibited detectable clonal rearrangements of immunoglobulin genes. Furthermore, one of these five cases evolved into overt diffuse large cell lymphoma of B cell lineage during a 2-year follow-up of recurrent disease at the original cutaneous site. The immunoglobulin gene rearrangements of this lymphoma were identical to those of the prior CLH lesion. There was no evidence of detectable t(14;18) chromosomal translocations or clonal rearrangements of the beta gene of the T cell receptor in any case. It was concluded that CLH can be divided into two subsets based on the presence or absence of a clonal B cell population, and that overt lymphoma can arise from the former subset and contain the same B cell clone identified in the pre-existent CLH lesion.

  9. Using biologic predictive factors to direct therapy of diffuse large B-cell lymphoma

    PubMed Central

    Grant, Cliona; Wilson, Wyndham H.

    2013-01-01

    While diffuse large B-cell lymphoma (DLBCL) was once considered to be a single disease entity, recent biological insights have demonstrated that it can be divided up into at least three molecular subtypes. Gene expression profiling has revealed that DLBCL consists of a germinal center B-cell like subtype (GCB), an activated B-cell like subtype (ABC) and a primary mediastinal B-cell lymphoma subtype (PMBL). These three entities arise from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. In GCB DLBCL, the BCL6 transcription factor may play an important role in tumor survival and treatment resistance and strategies that target this are under investigation. ABC DLBCL is characterized by high expression of target genes of the nuclear factor kappa B (NF-κB)/Rel family of transcription factors and strategies that target NF-κB are in clinical trials. PMBL is a distinct clinicopathologic entity that shares many molecular features with nodular sclerosis Hodgkin lymphoma (HL) and may benefit from dose intensity approaches and inhibition of the Janus kinases. Other biologic predictive factors such as MYC and BCL2 may be overexpressed in both the GCB and ABC subtypes and strategies that target these complexes are also being tested. PMID:23610613

  10. Using biologic predictive factors to direct therapy of diffuse large B-cell lymphoma.

    PubMed

    Dunleavy, Kieron; Grant, Cliona; Wilson, Wyndham H

    2013-02-01

    While diffuse large B-cell lymphoma (DLBCL) was once considered to be a single disease entity, recent biological insights have demonstrated that it can be divided up into at least three molecular subtypes. Gene expression profiling has revealed that DLBCL consists of a germinal center B-cell like subtype (GCB), an activated B-cell like subtype (ABC) and a primary mediastinal B-cell lymphoma subtype (PMBL). These three entities arise from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. In GCB DLBCL, the BCL6 transcription factor may play an important role in tumor survival and treatment resistance and strategies that target this are under investigation. ABC DLBCL is characterized by high expression of target genes of the nuclear factor kappa B (NF-κB)/Rel family of transcription factors and strategies that target NF-κB are in clinical trials. PMBL is a distinct clinicopathologic entity that shares many molecular features with nodular sclerosis Hodgkin lymphoma (HL) and may benefit from dose intensity approaches and inhibition of the Janus kinases. Other biologic predictive factors such as MYC and BCL2 may be overexpressed in both the GCB and ABC subtypes and strategies that target these complexes are also being tested. PMID:23610613

  11. Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy

    PubMed Central

    Galati, Giovanni; Rampa, Lorenzo; Vespasiani-Gentilucci, Umberto; Marino, Mirella; Pisani, Francesco; Cota, Carlo; Guidi, Alessandro; Picardi, Antonio

    2016-01-01

    B cells lymphoma is one of the most challenging extra-hepatic manifestations of hepatitis C virus (HCV). Recently, a new kind of B-cell lymphoma, named double-hit B (DHL), was characterized with an aggressive clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents (DAAs) against HCV are effective and curative in the majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully treated by new DAAs. According to our experience, a DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management because a worse prognosis might be expected. A possible effect of DAAs on DHL regression should be investigated, but eradicating HCV would avoid life-threatening reactivation of viral hepatitis during pharmacological immunosuppression in onco-haematological diseases. PMID:27803769

  12. Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

    PubMed Central

    Yang, Yibin; Shaffer, Arthur L.; Emre, N.C. Tolga; Ceribelli, Michele; Zhang, Meili; Wright, George; Xiao, Wenming; Powell, John; Platig, John; Kohlhammer, Holger; Young, Ryan M.; Zhao, Hong; Yang, Yandan; Xu, Weihong; Buggy, Joseph J.; Balasubramanian, Sriram; Mathews, Lesley A.; Shinn, Paul; Guha, Rajarshi; Ferrer, Marc; Thomas, Craig; Waldmann, Thomas A.; Staudt, Louis M.

    2014-01-01

    Summary Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and also amplify pro-survival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor (BCR) signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies. PMID:22698399

  13. Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model

    PubMed Central

    2013-01-01

    Background B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. However, previous idiotype vaccines mostly lacked efficiency due to a low immunogenicity of the idiotype. The objective of the present study was the determination of the feasibility, safety and immunogenicity of a novel chemically linked phage idiotype vaccine. Methods In the murine B cell lymphoma 1 model, tumor idiotypes were chemically linked to phage particles used as immunological carriers. For comparison, the idiotype was genetically expressed on the major phage coat protein g8 or linked to keyhole limpet hemocynanin. After intradermal immunizations with idiotype vaccines, tolerability and humoral immune responses were assessed. Results Feasibility and tolerability of the chemically linked phage idiotype vaccine was demonstrated. Vaccination with B cell lymphoma 1 idiotype expressing phage resulted in a significant survival benefit in the murine B cell lymphoma 1 protection model (60.2 ± 23.8 days vs. 41.8 ± 1.6 days and 39.8 ± 3.8 days after vaccination with wild type phage or phosphate buffered saline, respectively). Superior immunogenicity of the chemically linked phage idiotype vaccine compared to the genetically engineered phage idiotype and keyhole limpet hemocynanin-coupled idiotype vaccine was demonstrated by significantly higher B cell lymphoma 1 idiotype-specific IgG levels after vaccination with chemically linked phage idiotype. Conclusion We present a novel, simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible therapy and may produce a superior immune response compared to previously employed idiotype vaccination strategies. PMID:24152874

  14. Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do?

    PubMed

    Grant, Cliona; Dunleavy, Kieron; Eberle, Franziska C; Pittaluga, Stefania; Wilson, Wyndham H; Jaffe, Elaine S

    2011-09-01

    In recent years, an overlap in biologic and clinical features has been identified between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). Further strengthening this relationship is the identification of lymphomas with clinical and morphologic features transitional between the two, known as gray zone lymphomas (GZL). However, this diagnostic gray zone is not just of theoretical interest: it presents a practical problem, as the treatment approaches for CHL traditionally differ from those for aggressive B-cell lymphomas. This article reviews the treatment approach for mediastinal lymphomas, including CHL of the nodular sclerosis subtype (CHL-NS), PMBL, and mediastinal GZL. Though several trials have evaluated different regimens with or without radiation in PMBL and CHL-NS, there is a lack of prospective experience in treating GZL because of the rarity of these tumors. Historical data indicate that they have done poorly with traditional approaches developed for the treatment of either CHL or diffuse large B-cell lymphoma. PMID:21590365

  15. A Gene Panel, Including LRP12, Is Frequently Hypermethylated in Major Types of B-Cell Lymphoma

    PubMed Central

    Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera; Trøen, Gunhild; Liestøl, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E.; Smeland, Erlend B.

    2014-01-01

    Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma. PMID:25226156

  16. A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma.

    PubMed

    Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera; Trøen, Gunhild; Liestøl, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E; Smeland, Erlend B

    2014-01-01

    Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma. PMID:25226156

  17. Mycosis Fungoides Associated with Kaposi's Sarcoma, T-cell Rich B-cell Lymphoma, and T-cell Lymphoma with Angioimmunoblastic Features.

    PubMed

    Samuelov, Liat; Gat, Andrea; Bergman, Reuven; Sprecher, Eli; Goldberg, Ilan

    2016-08-01

    A patient with mycosis fungoides (MF), Kaposi's sarcoma, T-cell rich B-cell lymphoma, and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell rich B-cell lymphoma which he underwent. PMID:27663924

  18. Intravascular large B-cell lymphoma with hemophagocytic syndrome (Asian variant) in a Caucasian patient.

    PubMed

    Fung, Kar-Ming; Chakrabarty, Jennifer H; Kern, William F; Magharyous, Hany; Gehrs, Bradley C; Li, Shibo

    2012-01-01

    Intravascular lymphoma is an aggressive and extremely rare extranodal lymphoma with neoplastic lymphoid cells confined exclusively within intravascular spaces. The histopathologic findings are subtle due to the rarity of the neoplastic cells in blood vessels. Clinical presentations are non-specific and focal space-occupying lesions or lymphoadenopathy are always lacking. It is a diagnostic challenge. Secondary hemophagocytic syndrome is uncommon and is typically associated with infection, malignancy, and suppressed immune states. Intravascular lymphoma has a strong association with hemophagocytic syndrome in Asian patients, the so-called "Asian variant", but not in Western patients. We report a case of intravascular B-cell lymphoma in a Caucasian patient associated with secondary hemophagocytic syndrome. The patient was diagnosed by core liver biopsy and successfully treated. This case demonstrates the importance of high index of suspicion and astute histopathologic examination in recognition of this unusual clinical and pathologic combination.

  19. Extranodal Marginal Zone Lymphoma (MALT) – Like Presentations of Angioimmunoblastic T-cell lymphoma: A T-cell lymphoma masquerading as a B-cell lymphoproliferative disorder

    PubMed Central

    Kaffenberger, Ben; Haverkos, Brad; Tyler, Kelly; Wong, Henry; Porcu, Pierluigi; Gru, Alejandro Ariel

    2014-01-01

    Angioimmunoblastic T-cell lymphoma (AITL) is the second most common type of peripheral T-cell lymphoma (PTCL) worldwide, and in some countries the most common form. Clinically, AITL usually presents with systemic symptoms, diffuse lymphadenopathy, hepatosplenomegaly and common laboratory abnormalities such as hypergammaglobulinemia. Skin rashes are seen in 50–80% of patients. AITL derives follicular T-helper cells (TFH), that express germinal center markes and produces hyperactivation of B-cell seen in AITL. Although the histologic features of AITL in the skin could be similar to pathologic findings present in lymph node biopsies, we present herein 2 cases of AITL with histologic and immunophenotypic features that were somewhat suggestive of extranodal marginal zone lymphoma (MALT).Caution is urged to exclude the possibility of a systemic T-cell lymphoma such as AITL in cutaneous and lymph node B-cell proliferations. PMID:25839892

  20. Current trends in the treatment of primary mediastinal large B-cell lymphoma – an overview

    PubMed Central

    2015-01-01

    Primary mediastinal large B-cell lymphoma has been recognised as a distinct entity with unique clinical, pathologic, and genetic features. According to WHO 2008 classification it is marked as a variant of diffuse large B-cell lymphoma but shares characteristics with classic Hodgkin lymphoma. Genetic analysis has shown that amplification of the 9p24.1 region is the disease's specific structural alteration. Aggressive behaviour and a tendency to invade surrounding tissues of the thoracic cavity, often causing superior vena cava syndrome, or pleural or pericardial effusions, are the clinical hallmarks of this disease. For a long period of time it has been considered as a disease with poor prognosis, which responds poorly to the conventional treatment created for diffuse large B-cell lymphoma. An elective treatment has not yet been established, but recently the situation has became much more favourable. After the introduction of rituximab the cure rates have risen to over 80%, and the most recent results have demonstrated a new insight with dose-adjusted intensified continuous treatments, in which the cure rates have exceeded 90%. Current trends have led to the introduction of dose-adjusted intensified protocols becoming a standard of care, whereas the use of radiotherapy remains controversial because of the questionable predictive value of post-treatment PET/CT validity. The relapse rate is very low after two years of sustained complete remission. If the disease relapses or is resistant the outcome is very poor regardless of the applied treatment modality. PMID:26843837

  1. Anti-cancer activity of withaferin A in B-cell lymphoma.

    PubMed

    McKenna, M K; Gachuki, B W; Alhakeem, S S; Oben, K N; Rangnekar, V M; Gupta, R C; Bondada, S

    2015-01-01

    Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-κB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90. PMID:26020511

  2. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma

    PubMed Central

    Arora, Mili; Gowda, Sonia; Tuscano, Joseph

    2016-01-01

    Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID:27493711

  3. Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas.

    PubMed

    Wu, Rui; Nijland, Marcel; Rutgers, Bea; Veenstra, Rianne; Langendonk, Myra; van der Meeren, Lotte E; Kluin, Philip M; Li, Guanwu; Diepstra, Arjan; Chiu, Jen-Fu; van den Berg, Anke; Visser, Lydia

    2016-01-01

    Follicular lymphoma and diffuse large B cell lymphomas comprise the main entities of adult B cell malignancies. Although multiple disease driving gene aberrations have been identified by gene expression and genomic studies, only a few studies focused at the protein level. We applied 2 dimensional gel electrophoresis to compare seven GC B cell non Hodgkin lymphoma (NHL) cell lines with a lymphoblastoid cell line (LCL). An average of 130 spots were at least two folds different in intensity between NHL cell lines and the LCL. We selected approximately 38 protein spots per NHL cell line and linked them to 145 unique spots based on the location in the gel. 34 spots that were found altered in at least three NHL cell lines when compared to LCL, were submitted for LC-MS/MS. This resulted in 28 unique proteins, a substantial proportion of these proteins were involved in cell motility and cell metabolism. Loss of expression of B2M, and gain of expression of PRDX1 and PPIA was confirmed in the cell lines and primary lymphoma tissue. Moreover, inhibition of PPIA with cyclosporine A blocked cell growth of the cell lines, the effect size was associated with the PPIA expression levels. In conclusion, we identified multiple differentially expressed proteins by 2-D proteomics, and showed that some of these proteins might play a role in the pathogenesis of NHL. PMID:26752561

  4. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma.

    PubMed

    Arora, Mili; Gowda, Sonia; Tuscano, Joseph

    2016-08-01

    Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID:27493711

  5. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas.

    PubMed

    Pasqualucci, L; Neumeister, P; Goossens, T; Nanjangud, G; Chaganti, R S; Küppers, R; Dalla-Favera, R

    2001-07-19

    Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.

  6. Genetic drivers of NF-κB deregulation in diffuse large B-cell lymphoma.

    PubMed

    Pasqualucci, Laura; Zhang, Baochun

    2016-08-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of B cell non-Hodgkin lymphoma worldwide and comprises a heterogeneous group of malignancies that originate from the malignant transformation of germinal center (GC) B cells. Over the past decade, significant improvement has been achieved in our understanding of the molecular pathogenesis underlying this disease, thanks in part to the implementation of powerful genomic technologies allowing genome-wide structural and functional analyses. These studies revealed the presence of multiple oncogenic alterations dysregulating signal transduction pathways that are normally required for the normal biology of the cells from which these tumors are derived. Among the pathways identified as recurrent targets of genetic lesions in DLBCL, NF-κB has emerged as a central player in the development and maintenance of this disease, particularly in the less curable, activated B cell (ABC)- like subtype. These lesions reveal vulnerabilities of the lymphoma cells that can be exploited for the design of more rationale therapeutic approaches. The purpose of this review is to summarize recent progresses in understanding the role of NF-κB deregulation in the pathogenesis of DLBCL, with emphasis on the genetic basis underlying its aberrant activation, in relationship to the normal biology of B lymphocytes, and the modelling of these lesions in the mouse. PMID:27546290

  7. Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma

    PubMed Central

    Dunleavy, Kieron; Pittaluga, Stefania; Maeda, Lauren S.; Advani, Ranjana; Chen, Clara C.; Hessler, Julie; Steinberg, Seth M.; Grant, Cliona; Wright, George; Varma, Gaurav; Staudt, Louis M.; Jaffe, Elaine S.; Wilson, Wyndham H.

    2015-01-01

    BACKGROUND Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin’s lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy. METHODS We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes. RESULTS The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up. CONCLUSIONS Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.) PMID:23574119

  8. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

    PubMed Central

    Hailfinger, Stephan; Lenz, Georg; Ngo, Vu; Posvitz-Fejfar, Anita; Rebeaud, Fabien; Guzzardi, Montserrat; Penas, Eva-Maria Murga; Dierlamm, Judith; Chan, Wing C.; Staudt, Louis M.; Thome, Margot

    2009-01-01

    A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy. PMID:19897720

  9. Primary Diffuse Large B-Cell Lymphoma of the Liver in a Patient with Sjogren Syndrome

    PubMed Central

    Gorodetskiy, Vadim; Klapper, Wolfram; Probatova, Natalya; Vasilyev, Vladimir

    2016-01-01

    Sjögren's syndrome (SS) has the highest incidence of malignant lymphoproliferative disorders transformation among autoimmune diseases. We present a case of extranodal high grade lymphoma of the liver in a 52-year-old patient with long history of SS. Lymphoma manifested with sharp significant pain in the right hypochondrium, weakness, and profuse night sweats. Contrast-enhanced computed tomography scan (CT-scan) of the abdomen revealed multiple low density foci with homogeneous structure and clear contours in both lobes of the liver. Histologically, proliferation of medium sized lymphoma cells with round-oval and slightly irregular nuclei with fine chromatin was shown. Immunohistochemical and molecular features of the tumors allowed diagnosis of diffuse large B-cell lymphoma (DLBCL). To exclude secondary liver lesion by non-Hodgkin lymphoma, chest and small pelvis CT-scan, endoscopy of upper and lower gastrointestinal tract and study of bone marrow were performed. After 8 cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the complete remission was achieved, which persists after 45 months of follow-up. Primary hepatic lymphomas are extremely rare, and previously only low-grade hepatic lymphomas have been described in SS. To our knowledge, the patient described here represents the first reported case of DLBCL with primary liver involvement in SS. PMID:26998372

  10. Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes With Prognosis

    PubMed Central

    Dybkær, Karen; Bøgsted, Martin; Falgreen, Steffen; Bødker, Julie S.; Kjeldsen, Malene K.; Schmitz, Alexander; Bilgrau, Anders E.; Xu-Monette, Zijun Y.; Li, Ling; Bergkvist, Kim S.; Laursen, Maria B.; Rodrigo-Domingo, Maria; Marques, Sara C.; Rasmussen, Sophie B.; Nyegaard, Mette; Gaihede, Michael; Møller, Michael B.; Samworth, Richard J.; Shah, Rajen D.; Johansen, Preben; El-Galaly, Tarec C.; Young, Ken H.; Johnsen, Hans E.

    2015-01-01

    Purpose Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell–associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. Patients and Methods We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. Results Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP–treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell–like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1–signature and major histocompatibility complex class II–signature genes, which are known to have a positive impact on prognosis. Conclusion Further development of a diagnostic platform using

  11. A human follicular lymphoma B cell line hypermutates its functional immunoglobulin genes in vitro.

    PubMed

    Wu, H; Pelkonen, E; Knuutila, S; Kaartinen, M

    1995-12-01

    The functional immunoglobulin (Ig) genes of B lymphocytes undergo somatic mutations during immune responses. These mutations modify the antigen binding site of the immunoglobulins, thereby enhancing the average affinity of the antibodies produced. The molecular mechanism underlying these B cell hypermutations remains unresolved, partly because it is difficult to grow normal B cells in long-term cell cultures and because there is no suitable transformed or malignant B cell line which generates mutations in its immunoglobulin genes in vitro. Here, we show that the recently established follicular lymphoma line HF-1.3.4 generates somatic hypermutations in vitro at a high frequency of 0.7 x 10(-6) mutations per base pair per generation in standard cell cultures (RPMI 1640 + 5% fetal calf serum). This shows for the first time that B cell hypermutation can occur without T cells or T cell factors. The mutation frequency increased approximately tenfold to 1 x 10(-5) mutations/base pair/generation with B cell-specific growth factors (interleukins-2 and -4 and three antibodies stimulatory to HF-1.3.4 cells). This HF-1.3.4 lymphoma line may help to elucidate the molecular mechanism of Ig gene hypermutation.

  12. Diffuse large B-cell lymphoma of the mandible with periosteal reaction: a case report.

    PubMed

    Okahata, Ryoko; Shimamoto, Hiroaki; Marutani, Keisuke; Tomita, Seiki; Nakatani, Atsutoshi; Kishino, Mitsunobu; Kakimoto, Naoya; Murakami, Shumei; Furukawa, Souhei

    2014-02-01

    This report describes a rare case of a 63-year-old man with a lymphoma in the right mandibular ramus with periosteal reaction. Computed tomography (CT) images showed a soft tissue density (28 × 48 × 32 mm) around the right mandibular foramen. Bone-mode CT images showed diffuse bone destruction of the right mandibular ramus. Moreover, a periosteal reaction was seen on the lingual cortical bone of the right mandibular ramus. Histopathologic examination found a diffuse large B-cell lymphoma. PMID:24439924

  13. Diffuse large B cell lymphoma presenting as a peri-anal abscess.

    PubMed

    Jayasekera, Hasanga; Gorissen, Kym; Francis, Leo; Chow, Carina

    2014-01-01

    A non-healing peri-anal abscess can be difficult to manage and is often attributed to chronic disease. This case documents a male in his seventh decade who presented with multiple peri-anal collections. The abscess cavity had caused necrosis of the internal sphincter muscles resulting in faecal incontinence. Biopsies were conclusive for diffuse large B-cell lymphoma. A de-functioning colostomy was performed and the patient was initiated on CHOP-R chemotherapy. Anal lymphoma masquerading as a peri-anal abscess is rare. A high degree of suspicion must be maintained for an anal abscess which does not resolve with conservative management. PMID:24898408

  14. Managing Patients with Cutaneous B-Cell and T-Cell Lymphomas Other Than Mycosis Fungoides.

    PubMed

    Kheterpal, Meenal; Mehta-Shah, Neha; Virmani, Pooja; Myskowski, Patricia L; Moskowitz, Alison; Horwitz, Steven M

    2016-06-01

    Cutaneous lymphomas (CL) are a heterogeneous group of neoplasms characterized with clinical and histopathological variation, as well as overlap with benign dermatoses. Diagnosis and treatment of CLs is challenging and often requires a multidisciplinary approach. However, prognostic knowledge of these conditions and awareness of treatment options can help optimize appropriate use of available regimens, thereby improving care for patients. Here, we review the most recent literature and outline treatment themes for managing patients with cutaneous B-cell and T-cell lymphomas other than mycosis fungoides.

  15. B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.

    PubMed

    Li, Shaoying; Seegmiller, Adam C; Lin, Pei; Wang, Xuan J; Miranda, Roberto N; Bhagavathi, Sharathkumar; Medeiros, L Jeffrey

    2015-02-01

    Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P<0.01), less frequently expressed CD10 (P<0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations. PMID:25103070

  16. Anomalous expression of Thy1 (CD90) in B-cell lymphoma cells and proliferation inhibition by anti-Thy1 antibody treatment

    SciTech Connect

    Ishiura, Yoshihito; Kotani, Norihiro; Yamashita, Ryusuke; Yamamoto, Harumi; Kozutsumi, Yasunori; Honke, Koichi

    2010-05-28

    The anti-CD20 monoclonal antibody (Ab) rituximab is accepted to be an effective therapeutic Ab for malignant B-cell lymphoma; however, discovery of other cell surface antigens is required for the option of antibody medicine. Considering that many tumor-associated antigens are glycans, we have searched glycoconjugates for the candidate antigens that therapeutic Abs target. To this end, we first focused on the difference in the glycogenes expression in terms of Epstein-Barr virus (EBV) infection of a Burkitt's lymphoma cell line, Akata. Using DNA array, flow cytometry and Western blotting, we found that Thy1 was highly expressed in EBV-positive Akata cells. Subsequently, Thy1 was found to be expressed in other B-cell lymphoma cell lines: BJAB, MutuI, and MutuIII, irrespective of EBV infection. Treatment of these cells with an anti-Thy1 monoclonal antibody inhibited proliferation more strongly than the therapeutic Ab rituximab. The B-cell lymphoma cell lines were classified based on the extent of the proliferation inhibition, which was not correlated with the expression level of Thy1. It is suggested that stable residence of receptor tyrosine kinases in lipid rafts sustains cell growth in B-cell lymphoma cells.

  17. Immunohistochemistry and scoring of Ki-67 proliferative index and p53 expression in gastric B cell lymphoma from Northern African population: a pilot study

    PubMed Central

    Zeggai, Soumia; Tou, Abdelnacer; Sellam, Feriel; Mrabent, Meriem N.; Salah, Rachida

    2016-01-01

    Background This study aimed to clarify the Ki-67 distribution, p53 expression and their relationship with clinico-pathologic features of gastric B cell lymphoma from Northern African population. Methods Twenty paraffin blocks of gastric lymphoma were retrieved from the archival materials of Department of Pathology, Central University Hospital of Sidi Bel Abbes (Western Algeria) from 2007 to 2013. Four µm section specimens were stained by immunohistochemical (IHC) technique with Ki-67 and p53 tumor markers. P values <0.05 were considered statistically significant. Results Expression of p53 proteins and the mean proliferative index (PI) were compared between high grade gastric B cell lymphomas (DLBCL) and low grade gastric B cell lymphomas (gastric MALTs). p53 overexpression (P=0.007) and a high proliferation index Ki-67 (P=0.001) were significantly associated with gastric DLBCL. We found also a statistically significant correlation between p53 and Ki-67 (P=0.007) but no obvious relationships were found between Ki-67 PI and p53 expression as well as clinico-pathological features (age, sex, location, macroscopic type). Conclusions The IHC studies of Ki-67 and p53 expression in gastric B cell lymphoma can help in monitoring of patients at risk, and to give suitable treatment and management of patients. PMID:27284480

  18. Distinguishing of primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma using real-time quantitative polymerase chain reaction.

    PubMed

    Votavova, H; Forsterova, K; Campr, V; Sritesky, J; Velenska, Z; Pytlik, R; Kubackova, K; Prochazka, B; Kodet, R; Spicka, I; Krejcova, H; Trneny, M; Klener, P

    2010-01-01

    Primary mediastinal B-cell lymphoma (PMBL) seems to be reliably distinguished from diffuse large B-cell lymphoma (DLBCL) with microarray technology. We measured expression of Fcer2, Pdl2 and Blk genes using real-time quantitative polymerase chain reaction (RTqPCR) on formalin fixed, paraffin embedded material (FFPE) and suggested a formula to discriminate PMBL from DLBCL. For 39/82 included patients the diagnosis of PMBL was expected clinico-pathologically. Diagnosis of 10/39 and 2/43 of clinically considered PMBLs and DLBCLs, respectively, was not genetically confirmed. Compared to confirmed PMBLs, unconfirmed ones showed clinical features similar to DLBCLs, e.g. spleen infiltration (p=0,028) and decreased invasiveness in pericardium (p=0,045). They tended to have more common infradiaphragmatic involvement, less often tumor sclerosis or fluidothorax. There were no immunohistochemical differences between genetically confirmed and unconfirmed PMBLs. New approach of distinguishing PMBL and DLBCL is presented. It is based on expression of three genes in routinely available FFPE material using RTqPCR. PMID:20568899

  19. Extranodal large B cell lymphoma of the anterior maxilla. Case report and review of literature.

    PubMed

    Webber, Brian; Webber, Mariel; Keinan, David

    2015-01-01

    In the oral cavity, lymphoproliferative disorders can manifest in various ways, often as an extranodal externalization. In the case presented here, it was a B cell lymphoma originating in the periapical bone of the anterior maxilla. X-ray revealed a periapical radiolucency associated with an intact tooth with no decay, fillings or history of trauma. The tooth tested non-vital. After root canal treatment, an apicoectomy was performed with a biopsy. The most common diagnosis would be of dental etiology. The pathology report revealed a non-Hodgkin's B cell lymphoma. Most often, this disease appears as localized dental or oral pathology. Non-specific signs and symptoms present in association with lymphoproliferative disorders include lymphadenopathy, trismus, pain, swelling, sinusitis, fever, sepsis, prosthetic instability and paresthesia. Early detection results in decreased morbidity and a better prognosis for the patient. PMID:25707167

  20. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

    PubMed Central

    Brown, P J; Wong, K K; Felce, S L; Lyne, L; Spearman, H; Soilleux, E J; Pedersen, L M; Møller, M B; Green, T M; Gascoyne, D M; Banham, A H

    2016-01-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco–Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID:26500140

  1. Proliferation and apoptosis in malignant and normal cells in B-cell non-Hodgkin's lymphomas.

    PubMed Central

    Stokke, T.; Holte, H.; Smedshammer, L.; Smeland, E. B.; Kaalhus, O.; Steen, H. B.

    1998-01-01

    We have examined apoptosis and proliferation in lymph node cell suspensions from patients with B-cell non-Hodgkin's lymphoma using flow cytometry. A method was developed which allowed estimation of the fractions of apoptotic cells and cells in the S-phase of the cell cycle simultaneously with tumour-characteristic light chain expression. Analysis of the tumour S-phase fraction and the tumour apoptotic fraction in lymph node cell suspensions from 95 B-cell non-Hodgkin's lymphoma (NHL) patients revealed a non-normal distribution for both parameters. The median fraction of apoptotic tumour cells was 1.1% (25 percentiles 0.5%, 2.7%). In the same samples, the median fraction of apoptotic normal cells was higher than for the tumour cells (1.9%; 25 percentiles 0.7%, 4.0%; P = 0.03). The median fraction of tumour cells in S-phase was 1.4% (25 percentiles 0.8%, 4.8%), the median fraction of normal cells in S-phase was significantly lower than for the tumour cells (1.0%; 25 percentiles 0.6%, 1.9%; P = 0.004). When the number of cases was plotted against the logarithm of the S-phase fraction of the tumour cells, a distribution with two Gaussian peaks was needed to fit the data. One peak was centred around an S-phase fraction of 0.9%; the other was centred around 7%. These peaks were separated by a valley at approximately 3%, indicating that the S-phase fraction in NHL can be classified as 'low' (< 3%) or 'high' (> 3%), independent of the median S-phase fraction. The apoptotic fractions were log-normally distributed. The median apoptotic fraction was higher (1.5%) in the 'high' S-phase group than in the 'low' S-phase group (0.8%; P = 0.02). However, there was no significant correlation between the two parameters (P > 0.05). PMID:9667654

  2. Isolated Intravascular Large B-cell Lymphoma Presenting with Diffuse Ground Glass Pulmonary Infiltrates.

    PubMed

    Srivali, Narat; Pannu, Bibek S; Iyer, Vivek N

    2016-06-01

    A case of 44-year-old man with dyspnea and CT chest demonstrated bilateral infiltration. Patient was failed to improve with antibiotics and steroid. Finally, video-assisted thoracic surgery-guided lung biopsy was performed and surprisingly revealed intravascular large B cell lymphoma. The patient was subsequently started on chemotherapy with considerable clinical improvement. At the time of last follow-up (4 years from diagnosis); there was no clinical or radiologic evidence of tumor recurrence. PMID:27408440

  3. Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

    PubMed Central

    Visco, Carlo; Finotto, Silvia

    2014-01-01

    A significant association between hepatitis C virus (HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase

  4. A Case of De Novo CD5+ Disseminated Intravascular Large B-Cell Lymphoma Presenting as Multiorgan Failure

    PubMed Central

    Kapuria, Devika; Nanua, Suparna; Gaur, Rakesh

    2016-01-01

    Intravascular large B-cell lymphoma is an extremely rare extranodal lymphoma that proliferates in the lumen of the blood vessels while sparing the organ parenchyma. It usually presents with CNS and skin involvement. A 65-year-old Caucasian female presented with fevers and chills of 3-4 months' duration. Bone marrow biopsy done 3 months prior showed no significant myelodysplasia or lymphoid aggregates. The patient later died due to multiorgan failure. A bone marrow biopsy showed 20–30% CD5+ B cells consistent with infiltrative large B-cell lymphoma. An autopsy performed revealed diffuse intravascular invasion by lymphoma cells. Multiorgan involvement by intravascular B-cell lymphoma is very rare. Based on our literature review and to the best of our knowledge, there are only 5 case reports describing the presentation of this lymphoma with multiorgan failure. The immunophenotypic studies performed revealed that our patient had de novo CD5+ intravascular large B-cell lymphoma which is known to be aggressive with very poor prognosis. Although it is an extremely rare lymphoma, it should be considered as a potential cause of multiorgan failure when no other cause has been identified. A prompt tissue diagnosis and high-dose chemotherapy followed by ASCT can sometimes achieve remission. PMID:27777803

  5. Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma

    PubMed Central

    Ryan, Russell J.H.; Drier, Yotam; Whitton, Holly; Cotton, M. Joel; Kaur, Jasleen; Issner, Robbyn; Gillespie, Shawn; Epstein, Charles B.; Nardi, Valentina; Sohani, Aliyah R.; Hochberg, Ephraim P.; Bernstein, Bradley E.

    2015-01-01

    B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We utilized a novel approach, termed ‘Pinpointing Enhancer-Associated Rearrangements by Chromatin Immunoprecipitation’ or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma. PMID:26229090

  6. Whole blood EBV-DNA predicts outcome in diffuse large B-cell lymphoma.

    PubMed

    Tisi, Maria Chiara; Cupelli, Elisa; Santangelo, Rosaria; Maiolo, Elena; Alma, Eleonora; Giachelia, Manuela; Martini, Maurizio; Bellesi, Silvia; D'Alò, Francesco; Voso, Maria Teresa; Pompili, Maurizio; Leone, Giuseppe; Larocca, Luigi Maria; Hohaus, Stefan

    2016-01-01

    An association between Epstein-Barr Virus (EBV) infection and lymphoproliferative diseases has been reported with EBV + diffuse large B cell-lymphoma (DLBCL) of the elderly described as a distinct entity. In a cohort of 218 human immunodeficiency virus (HIV)-negative patients with diffuse large B-cell lymphomas, we detected EBV-DNA in 25% of whole blood (WB) samples at diagnosis. Presence and viral load in WB, mononuclear cells or plasma did not predict the presence of EBV in the tumor biopsy. Positive Hepatitis C virus (HCV) serology was associated with a higher frequency of EBV in WB. Patients with EBV-DNA in WB had a significantly shorter progression-free (p = 0.02) and overall survival (p = 0.05) after immunochemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone). We conclude that detection of EBV in WB is not a surrogate marker for EBV-association in diffuse large B-cell lymphoma, however it associates with worse outcome.

  7. [Expression and clinical significance of Ki-67 in diffuse large B cell lymphoma].

    PubMed

    Zhou, Ying; Zhao, Yu; Bo, Jian; Li, Yan-Fen; Ma, Chao; Shi, Ya-Nan

    2013-10-01

    This study was aimed to evaluate the proliferation-associated antigen Ki-67 expression in diffuse large B cell lymphoma (DLBCL) and its clinical significance. The Ki-67 expression and its correlation with prognosis in 50 patients with DLBCL treated with rituximab plus CHOP (R-CHOP) between January 2008 and December 2010 were analyzed retrospectively. The results indicated that there was no significant relationship between Ki-67 expression and clinical features, including age, sex, staging, B symptoms, LDH level, IPI, extranodal site involvement, presence of bulky tumors (>10 cm in diameter), bone marrow involvement, GCG nor GCB type, or response to first line treatment. The median survival was 50 months and 15 months in low Ki-67 expression group (<85%) and in high Ki-67 expression group ( ≥ 85%) respectively. The overall survival (OS) and progress-free survival (PFS) in low Ki-67 expression group were obviously longer than that in high Ki-67 expression group (P = 0.001; P = 0.027). In univariate analysis, the clinical factors associated with OS included Ann Arbor staging and Ki-67 expression. The clinical factors associated with PFS included Ann Arbor staging. IPI and Ki-67 expression. In multivariate analysis. The Ki-67 expression level was an independent prognostic factor for OS (HR = 4.90; 95% CI, 1.456-16.511; P = 0.0103). It is concluded that Ki-67 expression level seems to be an effective marker for evaluation of DLBCL prognosis. PMID:24156426

  8. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing

    PubMed Central

    Kurtz, David M.; Green, Michael R.; Bratman, Scott V.; Scherer, Florian; Liu, Chih Long; Kunder, Christian A.; Takahashi, Kazuhiro; Glover, Cynthia; Keane, Colm; Kihira, Shingo; Visser, Brendan; Callahan, Jason; Kong, Katherine A.; Faham, Malek; Corbelli, Karen S.; Miklos, David; Advani, Ranjana H.; Levy, Ronald; Hicks, Rodney J.; Hertzberg, Mark; Ohgami, Robert S.; Gandhi, Maher K.; Diehn, Maximilian

    2015-01-01

    Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and 18fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission. PMID:25887775

  9. Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy

    ClinicalTrials.gov

    2015-07-31

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  10. Genetic alterations in primary mediastinal B-cell lymphoma: an update.

    PubMed

    Scarpa, A; Moore, P S; Rigaud, G; Menestrina, F

    2001-03-01

    Primary mediastinal B-cell lymphoma (PMBL) is a distinct clinical entity among non-Hodgkin's lymphoma. The malignancy has received little attention from a standpoint of basic research due in part to its rarity. However, based on recent studies consistent trends are beginning to emerge regarding the molecular and chromosomal alterations commonly observed in this disease. By both CGH and AP-PCR, genetic gains involving chromosomes 2, 5, 7, 9p, 12, and Xq are among the most frequently observed events. From a molecular standpoint, alterations in the c-myc, p16(INK4) and p53 genes have been observed in up to 30% of cases. This information along with the well-established histological, immunological, and clinical features should convince the few remaining disbelievers that PMBL is a distinct pathological entity among non-Hodgkin's lymphomas. PMID:11342356

  11. Endoscopic biopsy of a B-cell lymphoma involving the entire ventricular system: A case report

    PubMed Central

    QIN, JIA-ZHEN; WU, YUE-KUI; YANG, ZHI-JUN; LV, JUN; DANG, YUAN-YUAN; ZHANG, HONG-TIAN; DAI, YI-WU

    2016-01-01

    A 62-year-old male suffering from vomiting and mild preceding nausea for 15 days was examined in the present case report. Magnetic resonance imaging revealed a homogeneously enhancing cluster-like lesion involving the lateral, third and fourth ventricles. An endoscopic biopsy was performed, and histopathological examination led to the diagnosis of a high-grade diffuse large B-cell lymphoma. To the best of our knowledge, the present study reports the first case of a primary lymphoma involving the entire ventricular system. Therefore, primary lymphomas should be considered in the list of ventricular tumors. An endoscopic biopsy requires minimal invasion to obtain an adequate tissue sample, and frequently leads to the correct diagnosis and subsequent treatment protocols. PMID:26889262

  12. Primary diffuse large B-cell lymphoma of the left ureter: A case report

    PubMed Central

    Chen, Ping; Jiang, Maoqing; Lin, Yuanwei; Ye, Xianwang; Ruan, Xinzhong; Huang, Qiuli

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma occurring in various sites, but rarely involving the ureters. Primary DLBCL is a rare entity. Imaging studies in a 82-year-old male patient revealed left hydronephrosis and an area of nodular soft tissue density in the upper ureteral wall. On enhanced computed tomography scans, the lesion exhibited early enhancement. As the lesion was considered to be malignant, a left nephroureterectomy was performed for the purpose of pathological diagnosis. Histological analysis and immunohistochemistry revealed DLBCL. Since the surgery, the patient has survived for 16 months without evidence of a relapse. Thus, in cases with ureteral stenosis or obstruction for which the cause is uncertain, the possibility of primary lymphoma of the ureter should be considered and further histopathological examination of bioptic samples should be performed as soon as possible. PMID:27588189

  13. Aberrant Circulating Th17 Cells in Patients with B-Cell Non-Hodgkin's Lymphoma.

    PubMed

    Lu, Ting; Yu, Shuang; Liu, Yan; Yin, Congcong; Ye, Jingjing; Liu, Zhi; Ma, Daoxin; Ji, Chunyan

    2016-01-01

    Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of neoplasm in which 90% are B-cell lymphomas and 10% T-cell lymphomas. Although T-helper 17 (Th17) cells have been implicated to be essential in the pathogenesis of autoimmune and inflammatory diseases, its role in B-cell non-Hodgkin's lymphoma (B-NHL) remains unknown. In this study, we observed a significantly decreased frequency of Th17 cells in peripheral blood from B-NHL patients compared with healthy individuals, accompanied with increased Th1 cells. IL-17AF plasma levels were remarkably decreased in B-NHL patients, accompanied with undetectable IL-17FF and unchangeable IL-17AA. Moreover, Th17 and Th1 cells became normalized after one or two cycles of chemotherapy. Interestingly, in B-NHL, circulating Th17 cells frequencies were significantly higher in relapsed patients than those in untreated patients or normal individuals. Meanwhile, there was no statistical difference regarding the frequencies of Th1 cells between relapsed and untreated patients. Taken these data together, circulating Th17 subset immune response may be associated with the response of patients to treatment and with different stages of disease. PMID:26812681

  14. Selective loss of B-cell phenotype in lymphocyte predominant Hodgkin lymphoma.

    PubMed

    Tedoldi, S; Mottok, A; Ying, J; Paterson, J C; Cui, Y; Facchetti, F; van Krieken, J H J M; Ponzoni, M; Ozkal, S; Masir, N; Natkunam, Y; Pileri, Sa; Hansmann, M-L; Mason, Dy; Tao, Q; Marafioti, T

    2007-12-01

    The neoplastic Reed-Sternberg cells characteristic of classical Hodgkin's lymphoma (cHL) are of B-cell origin but they almost always show striking loss of a range of B-cell-associated molecules. In contrast, the neoplastic cells found in lymphocyte predominant Hodgkin's lymphoma (LPHL) (L&H cells) are traditionally thought of as possessing the full repertoire of features associated with germinal centre B cells (eg BCL-6 expression, 'ongoing' Ig gene mutation). In the present paper, we report an extensive phenotypic analysis of L&H cells which revealed down-regulation of a number of markers associated with the B-cell lineage (eg CD19, CD37) and with the germinal centre maturation stage (eg PAG, LCK). The promoter methylation status of three of these down-regulated genes (CD10, CD19, and LCK) was further studied in microdissected L&H cells, and this revealed that their promoters were unmethylated. In contrast, these genes showed promoter methylation in cell lines derived from CHL. Further investigation of the mechanisms responsible for the deregulation of these molecules in L&H cells may provide new insights into the genetic abnormalities underlying LPHL. PMID:17935142

  15. Extranodal marginal-zone B-cell lymphoma of the salivary gland.

    PubMed

    Abbondanzo, S L

    2001-08-01

    Primary non-Hodgkin's lymphoma of the salivary gland is an uncommon tumor that most often occurs in the parotid gland. The most common subtype is marginal-zone B-cell lymphoma, extranodal, mucosa-associated lymphoid tissue type. This subtype has recently been included in the Revised European-American Classification of Lymphoid Neoplasms, as well as in the upcoming World Health Organization classification of hematopoietic and lymphoid neoplasms. This low-grade lymphoma usually arises in a background of benign lymphoepithelial lesion or myoepithelial sialadenitis that is associated with the autoimmune disease Sjögren's syndrome. It occasionally develops in patients who do not have a history of autoimmune disease. When mucosa-associated lymphoid tissue lymphoma occurs in the salivary gland, as in other extranodal sites such as the stomach, it is usually an indolent neoplasm that tends to remain localized for long periods of time, even without treatment. Eventually, however, the tumor may disseminate or transform to a higher grade. The histologic distinction of myoepithelial sialadenitis from low-grade B-cell mucosa-associated lymphoid tissue lymphoma can be a difficult diagnostic challenge and many of these lesions continue to be ambiguously diagnosed as "pseudolymphoma." Immunophenotypic or flow cytometric analysis may be useful in showing an aberrant phenotype or immunoglobulin light-chain restriction, which helps to support a diagnosis of malignant lymphoma in most cases. Molecular genetic analysis for immunoglobulin gene rearrangements also may be useful in showing monoclonality, although the exact significance of this finding in some cases remains controversial.

  16. Ixazomib Citrate and Rituximab in Treating Patients With Indolent B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-06-01

    Chronic Lymphocytic Leukemia; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

  17. Absence of missense mutations in activated c-myc genes in avian leukosis virus-induced B-cell lymphomas

    SciTech Connect

    Hahn, M.; Hayward, W.S.

    1988-06-01

    The authors determined the nucleotide sequences of two independent DNA clones which contained the activated c-myc genes from avian leukosis virus-induced B-cell lymphomas. Neither of these c-myce genes contained missense mutations. This strongly supports the notion that the c-myc photo-oncogene in avian leukosis virus-induced B-cell lymphomas can be oncogenically activated by altered expression of the gene without a change in the primary structure of the gene product.

  18. 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.

    PubMed

    Kapur, Sakshi; Levin, Miles B

    2014-01-01

    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.

  19. 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

    PubMed Central

    2014-01-01

    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. PMID:25161781

  20. IRF8 is associated with germinal center B-cell-like type of diffuse large B-cell lymphoma and exceptionally involved in translocation t(14;16)(q32.33;q24.1).

    PubMed

    Tinguely, Marianne; Thies, Svenja; Frigerio, Simona; Reineke, Tanja; Korol, Dimitri; Zimmermann, Dieter R

    2014-01-01

    Chromosomal translocations involving the immunoglobulin loci represent frequent oncogenic events in B-cell lymphoma development. Although IRF8 (ICSBP-1) protein expression has been demonstrated in germinal center B-cells and related lymphomas in a single report, the IRF8 gene was not described as an immunoglobulin heavy chain (IGH) translocation partner. In a discovery-driven approach we searched for new translocation partners of IGH in diffuse large B-cell lymphoma (DLBCL) by long distance inverse polymerase chain reaction (LDI-PCR) and Sanger sequencing. A t(14;16)(q32.33;q24.1) IGH/IRF8 was detected in a CD5+de novo DLBCL, confirmed by translocation specific PCR and fluorescence in situ hybridization (FISH) analysis. No further IRF8 aberration could be identified either by LDI-PCR in an additional five CD5+DLBCLs or by FISH on 78 formalin-fixed paraffin-embedded biopsies. Subsequent screening for IRF8 by immunohistochemistry revealed IRF8 expression in 18/78 (23%), correlating with a germinal center B-cell-like (GCB) type of DLBCL. This hitherto unknown translocation t(14;16)(q32.33;q24.1) is likely to represent the initiator of a multistep lymphomagenesis in a CD5+de novo DLBCL. PMID:23573829

  1. Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy

    PubMed Central

    2013-01-01

    Lenalidomide is an immunomodulatory agent which has been approved for multiple myeloma. Lenalidomide is also effective in and tolerated well by patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma. This review summarizes the results of current preclinical and clinical studies of lenalidomide, alone or in combination with the monoclonal antibody rituximab, as a therapeutic option for these three lymphoma types. This review will serve as a tool guiding future clinical investigations to improve survival rates for these three lymphomas. PMID:23915913

  2. Gastric B-cell mucosa associated lymphoid tissue lymphoma: a clinicopathological study in 56 patients.

    PubMed Central

    Castrillo, J M; Montalban, C; Obeso, G; Piris, M A; Rivas, M C

    1992-01-01

    Clinico-pathological features of 56 patients with primary gastric lymphoma were evaluated retrospectively. All cases were regraded according to a classification of Isaacson et al into high grade and low grade B-cell mucosa associated lymphoid tissue lymphoma. A third group of mixed grade was recognised in 11 patients with low grade who also had occasional areas of high grade. Low grade and mixed grade patients had a 100% actuarial survival at 156 months, which was significantly better (p < 0.01) than that of 52% for patients with high grade disease. Different treatment methods--surgery, chemotherapy, or a combination of both--did not significantly affect survival. Low grade tumours occurred mainly in men with a history of several years, and who presented with non-specific gastric symptoms without remarkable exploratory or laboratory findings: most patients were in stage IE-IIE and achieved remission and cure. High grade can have a shorter history, systemic symptoms, abnormal exploratory and laboratory findings, gastric tumour masses, stage IV disease, and a worse outcome. The only significant prognostic factors for survival were the type of lymphoma and stage IV disease. These findings support the Isaacson classification system which separates two extreme groups of gastric lymphomas with different morphology, behaviour, and outcome. The presence of limited areas of high grade in a specimen showing low grade does not change the outcome but suggests that primary gastric lymphoma forms a continuum between these extreme types. PMID:1446850

  3. [Diffuse large B-cell lymphoma of the testis relapsed 16 years after achieving complete response].

    PubMed

    Nagasaka, Isao; Mitsui, Takeki; Ishizaki, Takuma; Koiso, Hiromi; Yokohama, Akihiko; Saitoh, Takayuki; Hirato, Junko; Igarashi, Tadahiko; Kojima, Masaru; Tsukamoto, Norifumi; Nojima, Yoshihisa; Murakami, Hirokazu; Handa, Hiroshi

    2015-12-01

    Testicular lymphoma is a rare disease, accounting for 1-2% of non-Hodgkin lymphoma and 5-9% of all testicular tumors, and has a high relapse rate with a poor prognosis. We report a patient with testicular diffuse large B-cell lymphoma (DLBCL) who relapsed after being in remission for 16 years. He had undergone orchiectomy of the right testis and was diagnosed as having DLBCL (stage IAE) at 49 years of age. After 3 cycles of CHOP, he achieved a complete remission. Orchiectomy was performed because of a left testicular tumor, and he was again diagnosed with DLBCL at the age of 65. VH3-21 was detected in lymphoma cells at the times of both the first diagnosis and the relapse based on analysis of the variable region of the immunoglobulin heavy chain. Accordingly, the lymphoma cells at relapse were confirmed to be the same clone as that which had been documented at the first diagnosis. PMID:26725353

  4. [A case of pulmonary low-grade B cell lymphoma (MALT type) presenting seven years after gastric lymphoma resection].

    PubMed

    Tojima, Hirokazu; Shimura, Ryuhi; Nishiwaki, Tetsu; Kawabata, Yoshinori

    2003-02-01

    A 71-year-old man was admitted to our hospital because of systemic edema and exertional dyspnea. Chest radiographs revealed infiltrative shadows in both lung fields, pleural effusion, and pericardial effusion. Seven years before, he had undergone gastric surgery for a gastric ulcer with lymphoid hyperplasia. In the pathologic diagnosis based on the percutaneous lung biopsy, hyalinizing granuloma was suspected. For a more thorough diagnosis, the patient was subjected to an open lung biopsy, and the final diagnosis was low-grade B-cell lymphoma of the MALT (mucosa-associated lymphoid tissue) type. Gallium scintigraphy showed accentuated accumulation in the left neck and hypothyroidism was present. Histologic re-examination of the resected stomach revealed infiltration of centrocyte-like cells and lymphoepithelial lesions, compatible with the pathologic features of MALT lymphoma. We considered that the gastric neoplasm and the pulmonary, pleural, and thyroid tumors of MALT lymphoma had occurred seven years apart in this case. Thyroid hormone replacement and CHOP therapy improved the symptoms and decreased the lung tumor size by 73%. MALT lymphomas tend to remain localized for a long period. The multiorgan involvement seen in this case is rather rare. PMID:12722333

  5. Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma.

    PubMed

    Rue, Sarah M; Eckelman, Brendan P; Efe, Jem A; Bloink, Kristin; Deveraux, Quinn L; Lowery, David; Nasoff, Marc

    2015-04-15

    B-cell lymphoma is one of the most frequently observed non-cutaneous neoplasms in dogs. For both human and canine BCL, the standard of care treatment typically involves a combination chemotherapy, e.g. "CHOP" therapy. Treatment for human lymphoma greatly benefited from the addition of anti-CD20 targeted biological therapeutics to these chemotherapy protocols; this type of therapeutic has not been available to the veterinary oncologist. Here, we describe the generation and characterization of a rituximab-like anti-CD20 antibody intended as a candidate treatment for canine B-cell lymphoma. A panel of anti-canine CD20 monoclonal antibodies was generated using a mouse hybridoma approach. Mouse monoclonal antibody 1E4 was selected for construction of a canine chimeric molecule based on its rank ordering in a flow cytometry-based affinity assay. 1E4 binds to approximately the same location in the extracellular domain of CD20 as rituximab, and 1E4-based chimeric antibodies co-stain canine B cells in flow cytometric analysis of canine leukocytes using an anti-canine CD21 antibody. We show that two of the four reported canine IgG subclasses (cIgGB and cIgGC) can bind to canine CD16a, a receptor involved in antibody-dependent cellular cytotoxicity (ADCC). Chimeric monoclonal antibodies were assembled using canine heavy chain constant regions that incorporated the appropriate effector function along with the mouse monoclonal 1E4 anti-canine CD20 variable regions, and expressed in CHO cells. We observed that 1E4-cIgGB and 1E4-cIgGC significantly deplete B-cell levels in healthy beagle dogs. The in vivo half-life of 1E4-cIgGB in a healthy dog was ∼14 days. The antibody 1E4-cIgGB has been selected for further testing and development as an agent for the treatment of canine B-cell lymphoma.

  6. AUY922 effectively targets against activated B cell subtype of diffuse large B-cell lymphoma and low-grade lymphoma cells harboring genetic alteration-associated nuclear factor-κB activation.

    PubMed

    Tsai, Hui-Jen; Shih, Neng-Yao; Kuo, Sung-Hsin; Cheng, Ann-Lii; Lin, Hui-You; Chen, Tsai-Yun; Chang, Kung-Chao; Lin, Sheng-Fung; Chang, Jeffrey S; Chen, Li-Tzong

    2015-01-01

    Recurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-κB (NF-κB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-κB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas.

  7. Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype.

    PubMed

    Gregory, C D; Tursz, T; Edwards, C F; Tetaud, C; Talbot, M; Caillou, B; Rickinson, A B; Lipinski, M

    1987-07-01

    Fresh biopsy cells from cases of Burkitt's lymphoma (BL) display a homogeneous cell surface phenotype. The cells were found to be reactive with the pan B cell marker B1, and consistently co-expressed the BL-associated glycolipid antigen, BLA, and the common acute lymphoblastic leukemia antigen, CALLA, but lacked the B cell "activation" antigens characteristically expressed on EB virus-transformed normal B cells. Microscopic and cell sorter analysis of cells isolated from a series of fresh normal tonsils have identified a subpopulation of normal B cells carrying the same cell surface markers. That BLA and CALLA could be co-expressed on individual B cells was demonstrated by two-color immunofluorescence (IF) of tonsils in suspension, and immunoperoxidase (IP) staining of serial tonsil sections. These BLA+, CALLA+, "activation" antigen- cells were further characterized as B1+, sIgM+, sIgD-, C3d/EB virus receptor+ and were susceptible to virus-induced transformation in vitro. IF studies on Percoll-fractionated tonsillar cell populations and direct examination of IP-stained tonsil semi-thin sections indicated that the BLA+, CALLA+ cells were localized in germinal centers. Their morphological characteristics matched those of BL cells, and their location within germinal centers was consistent both with the known phenotype of germinal center tonsillar B cells and with the description of BL as a proliferation of centroblasts. We suggest that this population of tonsillar germinal center B cells provides the normal counterpart of BL tumor cells. PMID:2953817

  8. Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes.

    PubMed Central

    Klein, U.; Klein, G.; Ehlin-Henriksson, B.; Rajewsky, K.; Küppers, R.

    1995-01-01

    BACKGROUND: The developmental stage from which stems the malignant B cell population in Burkitt's lymphoma (BL) is unclear. An approach to answering this question is provided by the sequence analysis of rear-ranged immunoglobulin (Ig) variable region (V) genes from BL for evidence of somatic mutations, together with a phenotypic characterization. As somatic hypermutation of Ig V region genes occurs in germinal center B cells, somatically mutated Ig genes are found in germinal center B cells and their descendents. MATERIALS AND METHODS: Rearranged V kappa region genes from 10 kappa-expressing sporadic and endemic BL-derived cell lines (9 IgM and 1 IgG positive) and three kappa-expressing endemic BL biopsy specimens were amplified by polymerase chain reaction and sequenced. In addition, VH region gene sequences from these cell lines were determined. RESULTS: All BL cell lines and the three biopsy specimens carried somatically mutated V region genes. The average mutation frequency of rearranged V kappa genes from eight BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in five endemic cases (three biopsy specimens and two BL cell lines). CONCLUSIONS: The detection of somatic mutations in the rearranged V region genes suggests that both sporadic and endemic BL represent a B-cell malignancy originating from germinal center B cells or their descendants. Interestingly, the mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for mu chain-expressing germinal center B cells, whereas the mutation frequency found in endemic BL is significantly higher. PMID:8529116

  9. B-cell and T-cell lymphomas of the breast: clinical--pathological features of 53 cases.

    PubMed

    Gualco, Gabriela; Bacchi, Carlos E

    2008-10-01

    Breast involvement by non-Hodgkin lymphomas is rare. We studied the morphological, immunophenotypical, and clinical features of 53 cases of malignant lymphomas involving the breast in a population of Brazilian patients. Most of the cases were of B-cell phenotype. Four of the patients with primary breast lymphomas had T-cell lymphomas, 3 had CD30-positive anaplastic large cell lymphomas, and 1 had panniculitis-like T-cell lymphoma. Most patients presented with an incidental breast mass. Secondary breast lymphoma was seen in 19 patients and most commonly occurred as part of widespread nodal disease. Two patients presented with bilateral breast involvement. The most prevalent histological subtype was also diffuse large B-cell lymphoma, followed by follicular lymphoma. This study shows that the broad morphological and immunophenotypical spectrum of malignant lymphoma of the breast occurring in a large series of Brazilian patients has many similarities with that seen in Western countries, with a higher proportion of high-grade lymphomas in both primary and secondary cases.

  10. Common Viral Integration Sites Identified in Avian Leukosis Virus-Induced B-Cell Lymphomas

    PubMed Central

    Justice, James F.; Morgan, Robin W.

    2015-01-01

    ABSTRACT Avian leukosis virus (ALV) induces B-cell lymphoma and other neoplasms in chickens by integrating within or near cancer genes and perturbing their expression. Four genes—MYC, MYB, Mir-155, and TERT—have previously been identified as common integration sites in these virus-induced lymphomas and are thought to play a causal role in tumorigenesis. In this study, we employ high-throughput sequencing to identify additional genes driving tumorigenesis in ALV-induced B-cell lymphomas. In addition to the four genes implicated previously, we identify other genes as common integration sites, including TNFRSF1A, MEF2C, CTDSPL, TAB2, RUNX1, MLL5, CXorf57, and BACH2. We also analyze the genome-wide ALV integration landscape in vivo and find increased frequency of ALV integration near transcriptional start sites and within transcripts. Previous work has shown ALV prefers a weak consensus sequence for integration in cultured human cells. We confirm this consensus sequence for ALV integration in vivo in the chicken genome. PMID:26670384

  11. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential

    PubMed Central

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-01-01

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4+ DLBCL and one CD4+ primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4+ DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively. PMID:27679780

  12. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

    PubMed

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-09-26

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively. PMID:27679780

  13. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential

    PubMed Central

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-01-01

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4+ DLBCL and one CD4+ primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4+ DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.

  14. [Visceral leishmaniasis concurrent with splenic marginal zone B-cell lymphoma].

    PubMed

    Julhakyan, U L; Magomedova, A U; Dvirnyk, V N; Kravchenko, S K

    2016-01-01

    Splenic marginal zone B-cell lymphoma (SMZBCL) is a rare non-Hodgkin B-cell lymphoma that presents with morphologically mature lymphoid cells corresponding in their immunological characteristics to secondary follicular marginal zone lymphocytes. It is clinically characterized by splenomegaly, moderate lymphocytosis, usually focal bone marrow lesion, sometimes moderate of monoclonal immunoglobulin in the serum (generally IgM or IgG) and/or urea, and a relatively benign course. Leishmaniasis is a transmissible natural focal infectious endemic disease that has a great diversity of clinical manifestations. The authors describe Russia's first case of SMZBCL concurrent with visceral leishmaniasis in a 52-year-old female patient admitted to a hematology hospital with weakness, splenomegaly, and lymphadenopathy. The simultaneous detection of lymphoma and leishmaniasis in the same biopsy specimen is extremely rare. Visceral leishmaniasis should be borne in mind as an opportunistic infection in patients with malignancies, particularly in immunocompromised persons who live or have stayed in the endemic areas. PMID:27030189

  15. Primary high-grade B-cell lymphoma of the choroid plexus.

    PubMed

    Cecchi, Paolo C; Billio, Atto; Colombetti, Vito; Rizzo, Paolo; Ricci, Umberto M; Schwarz, Andreas

    2008-01-01

    Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma arising from and confined to the neuraxis. It represents about 3-4% of all primitive brain neoplasms and is mainly located in deep supratentorial regions. A ventricular involvement is quite frequent, but in the vast majority of cases it is secondary to an extension from a subependymal location. Amongst the primary ventricular forms occasionally reported, a choroid plexus origin is extremely rare; to date, only three cases have been described in the English literature. We report the case of a 71-year-old left-handed woman admitted to our department after a progressive 2-week history of confusion, motor speech disturbances and left hemiparesis. A brain MRI scan displayed an intraventricular lesion located in the right atrium, about 2.5cm in its major axis, homogeneously enhancing after gadolinium administration, surrounded by edema in the homolateral deep hemispheric region; the main diagnostic hypothesis was meningioma. She underwent a parieto-occipital craniotomy and a navigation-assisted posterior parietal transcortical approach, achieving complete removal of the intraventricular lesion originating from the choroid plexus. The histological diagnosis was of high-grade diffuse large B-cell lymphoma. Both an MRI scan of the entire craniospinal axis and a thoracic and abdominal CT scan showed no other neoplastic lesions; a bone marrow biopsy was normal; a final diagnosis of primary central nervous system lymphoma was made. CSF cytological analysis did not show any signs of lymphoma dissemination. Adjuvant chemotherapy with methotrexate was administered, and at the last follow-up (26 months) our patient is clinically and radiologically disease-free. Primary choroid plexus lymphoma is a very rare tumor that should be included in the differential diagnosis of intraventricular neoplasms. It usually occurs in the lateral ventricles (with a predilection for the atrium) of adult people (>50

  16. Gene expression-based risk score in diffuse large B-cell lymphoma.

    PubMed

    Bret, Caroline; Klein, Bernard; Moreaux, Jérôme

    2012-12-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and displays heterogeneous clinical and molecular characteristics. In this study, high throughput gene expression profiling of DLBCL tumor samples was used to design a 12-gene expression-based risk score (GERS) predictive for patient's overall survival. GERS allowed identifying a high-risk group comprising 46,4% of the DLBCL patients in two independent cohorts (n=414 and n=69). GERS was shown to be an independent predictor of survival when compared to the previously published prognostic factors, including the International Prognostic Index (IPI). GERS displayed a prognostic value in germinal-center B-cell-like subgroup (GCB) and activated B cell-like (ABC) molecular subgroups of patients as well as in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or rituximab-CHOP (R-CHOP) regimens. Combination of GERS and IPI lead to a potent prognostic classification of DLBCL patients. Finally, a genomic instability gene signature was highlighted in gene expression profiles of patients belonging to the high-risk GERS-defined group. PMID:23482333

  17. A Case of Primary Pulmonary Diffuse Large B-Cell Lymphoma Diagnosed by Transbronchial Biopsy

    PubMed Central

    Hirata, Tomomi; Takeuchi, Chie; Usuda, Jitsuo; Hosone, Masaru

    2015-01-01

    A 76-year-old man took a chest X-ray for his medical checkup and an abnormal shadow was detected in the right lower lung field. For more detailed examination, he was referred to our hospital. Chest computed tomography showed a 20-mm nodule with relatively regular margins in the right lower lobe. A compact proliferation of circular to polygonal cells with a high nucleus-cytoplasm ratio was evident in a transbronchial lung biopsy. Based on pathological findings, a mature large B-cell lymphoma was diagnosed. Thoracoscopic right lower lobectomy and mediastinal lymphadenectomy were performed. The post-surgical pathological examination showed that the tumor consisted of diffuse to compact proliferation of medium to large atypical lymphocyte-like cells. Immunohistochemical staining yielded positive results for B-cell lineage markers. Five months after surgical resection, neither local recurrence nor accumulation in remote organs was observed on gallium scintigraphy. The diagnosis of primary pulmonary diffuse large B-cell lymphoma was established. PMID:25912218

  18. Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma

    PubMed Central

    Cycon, Kelly A; Mulvaney, Kathleen; Rimsza, Lisa M; Persky, Daniel; Murphy, Shawn P

    2013-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma (NHL) diagnosed in the USA, consists of at least two distinct subtypes: germinal centre B (GCB) and activated B-cell (ABC). Decreased MHC class II (MHCII) expression on the tumours in both DLBCL subtypes directly correlates with significant decreases in patient survival. One common mechanism accounting for MHCII down-regulation in DLBCL is reduced expression of the MHC class II transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive regulatory domain-I-binding factor-1 (PRDI-BF1). However, the mechanisms underlying down-regulation of CIITA in GCB DLBCL are currently unclear. In this study, we demonstrate that neither PRDI-BF1 nor CpG hypermethylation at the CIITA promoters are responsible for decreased CIITA in GCB DLBCL. In contrast, histone modifications associated with an open chromatin conformation and active transcription were significantly lower at the CIITA promoters in CIITA− GCB cells compared with CIITA+ B cells, which suggests that epigenetic mechanisms contribute to repression of CIITA transcription. Treatment of CIITA− or CIITAlow GCB cells with several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDACi treatment can alleviate repression. These observations may have important implications for patient therapy. PMID:23789844

  19. Anti-CD137 enhances anti-CD20 therapy of systemic B-cell lymphoma with altered immune homeostasis but negligible toxicity.

    PubMed

    Souza-Fonseca-Guimaraes, Fernando; Blake, Stephen J; Makkouk, Amani; Chester, Cariad; Kohrt, Holbrook E; Smyth, Mark J

    2016-07-01

    Studies of sequential anti-CD137/anti-CD20 therapy have previously shown that the efficacy of anti-CD20 was heavily reliant upon anti-CD137; however, the exact mechanism of the anti-B-cell lymphoma efficacy, and whether this correlates with enhanced adverse effects or toxicity, had not been elucidated. Here, we observed that sequential anti-CD137 administration with anti-CD20 resulted in a synergistic therapy, largely dependent upon Fc receptors (FcR), to prolong survival in an experimental B-cell lymphoma therapy model. Tumor suppression was accompanied by B cell depletion, which was not dependent on one activating FcR. Surprisingly, the B-cell activating factor (BAFF) was elevated in the plasma of mice receiving anti-CD137 alone or in combination with anti-CD20, while a selective increase in some plasma cytokines was also noted and triggered by anti-CD137. These effects were independent of activating FcR. Sustained treatment of advanced lymphoma revealed increased lymphocyte infiltrates into the liver and a significant decrease in the metabolic capability of the liver in mice receiving anti-CD137. Importantly, these effects were not exacerbated in mice receiving the anti-CD20/CD137 combination, and elevations in classical liver damage markers such as alanine aminotransferase (ALT) were less than that caused by the lymphoma itself. Thus, combined anti-CD20/anti-CD137 treatment increases the therapeutic index of anti-CD20 or anti-CD137 alone. These mouse data were corroborated by ongoing clinical development studies to assess safety, tolerability and pharmacodynamic activity of human patients treated by this approach. Together, these data support the use of this sequential antibody therapeutic strategy to improve the efficacy of rituximab in B-cell lymphoma patients. PMID:27622048

  20. Primary cutaneous precursor B cell lymphoblastic lymphoma in a child, complicated by fatal disseminated varicella zoster virus.

    PubMed

    Rashidghamat, E; Robson, A

    2015-12-01

    Precursor B-cell lymphoblastic lymphoma (PBLL) is a rare subtype of childhood non-Hodgkin lymphoma (NHL). Most lymphoblastic lymphomas have a T-cell immunophenotype, but a small distinct proportion is of precursor B-cell origin. Skin and bone involvement is seen more commonly in this clinical variant. Primary cutaneous PBLL is rare. We describe an 8-year-old girl who presented with an asymptomatic nodule on the left upper arm. Histopathological features were consistent with pre-B-cell lymphoblastic lymphoma, and staging investigations excluded extracutaneous disease, resulting in a diagnosis of primary cutaneous PBLL. The child was started on induction chemotherapy, UKALL 2003 regimen B. She developed disseminated varicella zoster virus and died despite treatment. We discuss previously reported cases of primary cutaneous PBLL and their outcomes. PMID:25959984

  1. MYC gene rearrangements detected by interphase fluorescence in situ hybridization in diffuse large B-cell lymphomas.

    PubMed

    Misharina, J A; Sitko, V V; Klymenko, S V; Minchenko, J A; Kurchenko, A I; Silaev, Y O; Lyashenko, L O; Polyanska, V M; Bebeshko, V G

    2014-09-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, including approximately 30-40% of all B-cell non-Hodgkin lymphomas (B-NHL). Chromosomal translocations are the hallmark of genetic aberrations in B-lymphoma and are often associated with a specific subtype of B-NHL. MYC gene dysregulation due to chromosomal translocations is characteristic for the most cases of Burkitt's lymphoma. Objective. The goal of this study was to improve the diagnostic accuracy of DLBCL. Identification of chromosome 8 and 14 abnormalities including the translocation of MYC gene t(8; 14)(q24; q32) in substrate cells of lymph nodes was applied using the method of tri-color interphase fluorescence in situ hybridization (I-FISH). Materials and methods. Lymph node biopsy specimens of 17 patients with diffuse large B-cell lymphoma and three patients with Burkitt's lymphoma (including one participant of liquidation of consequences of the catastrophe at the Chornobyl NPP) were studied. The age of patients ranged from 10 to 66 years old (41.3 ± 3.7 average). Biopsy specimens fixed in paraffin. I-FISH-analysis was performed using the commercial test Vysis IGH/MYC, CEP 8 tri-color, dual fusion translocation probe (Abbott Molecular, USA). Results and conclusions. MYC gene and immunoglobulin heavy chain (IGH) gene translocations were found in four out of twenty persons. Consequently the I-FISH method allows identification of of MYC and IGH gene rearrangements in tissue cells substrate of lymphoma fixed in paraffin. Using this method the molecular-cytogenetic abnormalities were found in eight of twenty patients with B-cell lymphoma providing verification of the lymphoma diagnosis, prediction of their clinical course and advance in management i.e increase the effectiveness of therapy, in refractory lymphoma cases among others.

  2. Epigenetic Silencing of TFPI-2 in Canine Diffuse Large B-Cell Lymphoma

    PubMed Central

    Ferraresso, Serena; Bresolin, Silvia; Aricò, Arianna; Comazzi, Stefano; Gelain, Maria Elena; Riondato, Fulvio; Bargelloni, Luca; Marconato, Laura; te Kronnie, Geertruy; Aresu, Luca

    2014-01-01

    Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibitor 2 (TFPI-2) is a tumor suppressor involved in invasiveness inhibition. Although TFPI-2 transcriptional silencing, through promoter hypermethylation, has been widely reported in several human malignancies, it has never been explored in lymphoma. In the present study TFPI-2 methylation and gene expression have been investigated in canine Diffuse Large B-cell lymphomas (cDLBCL). The methylation level of 23 CpGs located within the TFPI-2 promoter was investigated by bisulfite-specific PCR and next generation amplicon deep sequencing (GS Junior 454, Roche) in 22 cDLBCLs and 9 controls. For the same specimens, TFPI-2 gene expression was assessed by means of Real-time RT-PCR. Sequence analysis clearly demonstrated that TFPI2 is frequently hypermethylated in cDLBCL. Hypermethylation of the TFPI-2 promoter was found in 77% of DLBCLs (17 out of 22) and in one normal lymph node. Globally, dogs with DLBCL showed a mean methylation level significantly increased compared to controls (p<0.01) and analysis of hypermethylation by site identified 19 loci out of 23 (82%) with mean methylation levels from 2- to 120-fold higher in cDLBCL. Gene expression analysis confirmed a significant down-regulation of TFPI-2 (p<0.05) in DLBCLs compared with normal lymph nodes, suggesting that TFPI-2 hypermethylation negatively regulates its transcription. In addition, a significant positive correlation (p<0.01) was found between TFPI-2 methylation levels and age providing the first indication of age-associated epigenetic modifications in canine DLBCL. To conclude, our findings demonstrated that epigenetic dysregulation of TFPI-2, leading to its reduced expression, is frequently detected in canine DLBCL

  3. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

    PubMed

    Harrington, Bonnie K; Gardner, Heather L; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C; Russell, Duncan S; Zhang, Xiaoli; Urie, Bridget K; London, Cheryl A; Byrd, John C; Johnson, Amy J; Kisseberth, William C

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  4. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma

    PubMed Central

    Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C.; Russell, Duncan S.; Zhang, Xiaoli; Urie, Bridget K.; London, Cheryl A.; Byrd, John C.; Johnson, Amy J.; Kisseberth, William C.

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  5. Memory-enriched CAR-T Cells Immunotherapy for B Cell Lymphoma

    ClinicalTrials.gov

    2016-04-25

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  6. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas.

    PubMed

    Chong, Lauren C; Twa, David D W; Mottok, Anja; Ben-Neriah, Susana; Woolcock, Bruce W; Zhao, Yongjun; Savage, Kerry J; Marra, Marco A; Scott, David W; Gascoyne, Randy D; Morin, Ryan D; Mungall, Andrew J; Steidl, Christian

    2016-09-01

    Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.

  7. Ultrasonographic features of aggressive primary thyroid diffuse B-cell lymphoma: A report of two cases

    PubMed Central

    HU, GUOBING; ZHU, XIANGMING

    2016-01-01

    Primary thyroid lymphoma (PTL) is a relatively rare malignant tumor. Aggressive PTL is extremely rare, and there is limited literature regarding the imaging features of PTL with invasion into adjacent structures, including internal jugular vein, muscles, esophagus, trachea and carotid artery. In addition, the ultrasonographic features of the cases presented in the current report differ from those reported in previous studies. In the present study, two cases of PTL, who presented to The First Affiliated Hospital of Wannan Medical College (Wuhu, China) with a short history of a rapidly growing mass in the front of their neck, are reported. Both patients had undergone ultrasound examination, and the subsequent histopathological and immunohistochemical examinations confirmed that the two masses were primary diffuse large B-cell lymphoma. The ultrasonographic findings of these two cases are discussed in the present report. PMID:27073503

  8. Ileocecal Obstruction Due to B-cell Non-Hodgkin Lymphoma.

    PubMed

    Negrean, Vasile; Graur, Florin; Moiş, Emil; Al-Hajjar, Nadim

    2016-01-01

    We report a rare case of non-Hodgkin lymphoma presented as an ileocecal mass. The patient was a 77-year-old man with history of symptoms of partial bowel obstruction, intermittent right iliac fossa pain, loss of weight, vomiting and fatigue. Clinical signs included moderate abdominal tenderness with a palpable mass in the right iliac fossa at the physical examination. Colonoscopy revealed an intussusception of the right colon causing a complete stenosis. The patient developed complete bowel obstruction during hospitalization that required emergent surgical intervention. Intraoperatively an ileocecal mass was found measuring 10-12 cm in diameter, causing complete stenosis at its level and bowel dilatation proximally. Multiple nodules were found in the liver and the parietal peritoneum as well. An ileotransverso-anastomosis was performed and biopsies of the nodules were taken. Pathological evaluation revealed a diffuse large B cell non-Hodgkin'™s lymphoma of the ileocecum and the parietal peritoneum. PMID:26988544

  9. Immune pancytopenia after chemotherapy in a patient with diffuse large B-cell lymphoma.

    PubMed

    Nagashima, Kazuyo; Tanaka, Hiroaki; Nagai, Yurie; Sugita, Yasumasa

    2016-01-01

    During treatment for malignant lymphoma, cytopenia can develop for several reasons. In the treatment of cytopenia, various possibilities should be considered because inadequate treatment causes exacerbation of cytopenia and can lead to fatal conditions, such as infection and bleeding. Herein, we describe immune pancytopenia 3 months after the last exposure to chemotherapy in a patient with diffuse large B-cell lymphoma (DLBCL). She suffered from severe pancytopenia after two courses of rituximab and bendamustine therapy for a second relapse of DLBCL. Immune pancytopenia was diagnosed with bone marrow tests and the presence of autoantibodies; it promptly resolved after initiation of prednisolone therapy. Clinicians should be aware of immune cytopenia and monitor for it carefully, even if patients have already finished chemotherapy treatment. PMID:27651408

  10. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma

    PubMed Central

    Trabucco, Sally E.; Gerstein, Rachel M.; Evens, Andrew M.; Bradner, James E.; Shultz, Leonard D.; Greiner, Dale L.; Zhang, Hong

    2014-01-01

    Purpose Approximately 50% of patients with diffuse large B-cell lymphoma (DLBCL) enter long-term remission after standard chemotherapy. DLBCL patients who do not respond to chemotherapy have few treatment options. There remains a critical need to identify effective and targeted therapeutics for DLBCL. Experimental Design Recent studies have highlighted the incidence of increased c-MYC protein in DLBCL and the correlation between high levels of c-MYC protein and poor survival prognosis of DLBCL patients, suggesting that c-MYC is a compelling target for DLBCL therapy. The small molecule JQ1 suppresses c-MYC expression through inhibition of the bromodomain and extra-terminal (BET) family of bromodomain proteins. We investigated whether JQ1 can inhibit proliferation of DLBCL cells in culture and xenograft models in vivo. Results We show that JQ1 at nanomolar concentrations efficiently inhibited proliferation of human DLBCL cells in a dose-dependent manner regardless of their molecular subtypes, suggesting a broad effect of JQ1 in DLBCL. The initial G1 arrest induced by JQ1 treatment in DLBCL cells was followed by either apoptosis or senescence. The expression of c-MYC was suppressed as a result of JQ1 treatment from the natural, chromosomally-translocated or amplified loci. Furthermore, JQ1 treatment significantly suppressed growth of DLBCL cells engrafted in mice and improved survival of engrafted mice. Conclusion Our results demonstrate that inhibition of the BET family of bromodomain proteins by JQ1 has potential clinical utility in the treatment of DLBCL. PMID:25009295

  11. Jaw1/LRMP, a germinal centre-associated marker for the immunohistological study of B-cell lymphomas.

    PubMed

    Tedoldi, S; Paterson, J C; Cordell, J; Tan, S-Y; Jones, M; Manek, S; Dei Tos, A P; Roberton, H; Masir, N; Natkunam, Y; Pileri, S A; Facchetti, F; Hansmann, M-L; Mason, D Y; Marafioti, T

    2006-08-01

    Jaw1, also known as lymphoid-restricted membrane protein (LRMP), is an endoplasmic reticulum-associated protein. High levels of Jaw1/LRMP mRNA have been found in germinal centre B-cells and in diffuse large B-cell lymphomas of 'germinal centre' subtype. This paper documents Jaw1/LRMP expression at the protein level in human tissues by immunohistochemical and western blotting analysis using an antibody reactive with paraffin-embedded tissues. Jaw1/LRMP was highly expressed in germinal centre B-cells (in keeping with gene expression data), in 'monocytoid B-cells', and in splenic marginal zone B-cells. It was absent, or present at only low levels, in mature T-cells, although cortical thymocytes were weakly positive. Among lymphoid neoplasms, Jaw1/LRMP was found in germinal centre-derived lymphomas (follicle centre lymphoma, Burkitt's lymphoma, lymphocyte-predominant Hodgkin's disease) but not in T-cell neoplasms (with the exception of a single T lymphoblastic lymphoma). Classical Hodgkin's disease and myeloma lacked Jaw1/LRMP but many cases of chronic lymphocytic leukaemia (but not mantle zone lymphoma) were Jaw1/LRMP-positive. Approximately half of the marginal zone lymphomas were Jaw1/LRMP-positive. In diffuse large B-cell lymphomas, Jaw1/LRMP was found in three-quarters (24/32) of the cases classified phenotypically as being of 'germinal centre' type, but it was also expressed in almost half (13/28) of the 'non-germinal centre' cases. A similar proportion of 'non-germinal centre' cases were positive for the protein products of two other genes expressed highly in germinal centre cells (HGAL/GCET2 and PAG). The fact that all three of these proteins are expressed in a significant proportion of diffuse large B-cell lymphomas assigned to the 'non-germinal centre' category indicates that the immunophenotypic categorization of diffuse large B-cell lymphoma according to cellular origin may be more complicated than currently understood. Finally, the expression of Jaw1/LRMP

  12. Genetic determinant of rapid-onset B-cell lymphoma by avian leukosis virus.

    PubMed Central

    Smith, M R; Smith, R E; Dunkel, I; Hou, V; Beemon, K L; Hayward, W S

    1997-01-01

    Infection of 10 day-old chicken embryos with the recombinant avian leukosis virus (ALV) EU-8 induces a high incidence of rapid-onset B-cell lymphoma by insertional activation of the c-myb gene. LR-9, a related ALV with differences from EU-8 in the gag and pol genes, induces rapid-onset lymphoma at only a low incidence. To localize the viral determinant(s) responsible for this biologic difference, we constructed and tested a series of reciprocal chimeras between EU-8 and LR-9 ALVs. The ability to induce rapid-onset lymphoma efficiently was localized to a 925-nucleotide (nt) region of the EU-8 gag gene. Sequence analysis of the region revealed a 42-nt deletion in EU-8 relative to LR-9, as well as some single-nucleotide changes. A mutant virus, delta LR-9, constructed by deleting these 42 nt from LR-9, also induced rapid-onset lymphoma at a high frequency, confirming the biologic significance of this deletion. This deletion removed nt 735 to 776, which lies within a cis-acting RNA element that negatively regulates splicing (NRS). The deletion was shown to cause an increase in splicing efficiency, which may lead to increased production of a truncated myb gene product from an ALV-myb readthrough RNA. PMID:9261373

  13. Gambogic acid induces apoptosis in diffuse large B-cell lymphoma cells via inducing proteasome inhibition

    PubMed Central

    Shi, Xianping; Lan, Xiaoying; Chen, Xin; Zhao, Chong; Li, Xiaofen; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Zang, Dan; Liao, Yuning; Zhang, Peiquan; Wang, Xuejun; Liu, Jinbao

    2015-01-01

    Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL). Therefore it is urgent to search for novel agents for the treatment of DLBCL. Gambogic acid (GA), a small molecule derived from Chinese herb gamboges, has been approved for Phase II clinical trial for cancer therapy by Chinese FDA. In the present study, we investigated the effect of GA on cell survival and apoptosis in DLBCL cells including both GCB- and ABC-DLBCL cells. We found that GA induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction. These findings provide significant pre-clinical evidence for potential usage of GA in DLBCL therapy particularly in ABC-DLBCL treatment. PMID:25853502

  14. CCR 20th anniversary commentary: Radioactive Drones for B-cell lymphoma.

    PubMed

    Knox, Susan J; Levy, Ronald

    2015-02-01

    In a study published in the March 1, 1996, issue of Clinical Cancer Research, Knox and colleagues (1) demonstrated the safety and efficacy of Yttirium-90 ((90)Y)-anti-CD20 monoclonal antibody therapy, as well as the benefit of preinfusion of unlabeled antibody on radiolabeled antibody biodistribution. Subsequent clinical trials with this radiolabeled antibody led to regulatory approval of this treatment for B-cell lymphoma. See related article by Knox et al., Clin Cancer Res 1996;2(3) Mar 1996; 457-70.

  15. Intestinal Intravascular Large B-cell Lymphoma Mimicking Ulcerative Colitis with Secondary Membranoproliferative Glomerulonephritis.

    PubMed

    Kaneyuki, Daisuke; Komeno, Yukiko; Yoshimoto, Hiroshi; Yoshimura, Naoki; Iihara, Kuniko; Ryu, Tomiko

    2016-01-01

    A 47-year-old woman with ulcerative colitis (UC) was admitted to our hospital for renal dysfunction and progressive anemia. Colonoscopy revealed intestinal lesions and pathological findings showed intravascular large B-cell lymphoma (IVLBCL). According to the polymerase chain reaction analysis of sequential rectal specimens, we concluded that she suffered from intestinal BCL, not UC. After chemotherapy, her renal function progressed to nephrotic syndrome. The pathological findings of renal biopsy specimens indicated membranoproliferative glomerulonephritis (MPGN). Chemotherapy was continued and led to the remission of BCL and MPGN. We herein describe the first case of intestinal IVLBCL mimicking UC with secondary MPGN. PMID:27580553

  16. CCR 20th anniversary commentary: Radioactive Drones for B-cell lymphoma.

    PubMed

    Knox, Susan J; Levy, Ronald

    2015-02-01

    In a study published in the March 1, 1996, issue of Clinical Cancer Research, Knox and colleagues (1) demonstrated the safety and efficacy of Yttirium-90 ((90)Y)-anti-CD20 monoclonal antibody therapy, as well as the benefit of preinfusion of unlabeled antibody on radiolabeled antibody biodistribution. Subsequent clinical trials with this radiolabeled antibody led to regulatory approval of this treatment for B-cell lymphoma. See related article by Knox et al., Clin Cancer Res 1996;2(3) Mar 1996; 457-70. PMID:25646179

  17. Vaccinia Virus N1l Protein Resembles a B Cell Lymphoma-2 (Bcl-2) Family Protein

    SciTech Connect

    Aoyagi, M.; Zhai, D.; Jin, C.; Aleshin, A.E.; Stec, B.; Reed, J.C.; Liddington, R.C.; /Burnham Inst.

    2007-07-03

    Poxviruses encode immuno-modulatory proteins capable of subverting host defenses. The poxvirus vaccinia expresses a small 14-kDa protein, N1L, that is critical for virulence. We report the crystal structure of N1L, which reveals an unexpected but striking resemblance to host apoptotic regulators of the B cell lymphoma-2 (Bcl-2) family. Although N1L lacks detectable Bcl-2 homology (BH) motifs at the sequence level, we show that N1L binds with high affinity to the BH3 peptides of pro-apoptotic Bcl-2 family proteins in vitro, consistent with a role for N1L in modulating host antiviral defenses.

  18. Identification of Primary Mediastinal Large B-cell Lymphoma at Nonmediastinal Sites by Gene Expression Profiling.

    PubMed

    Yuan, Ji; Wright, George; Rosenwald, Andreas; Steidl, Christian; Gascoyne, Randy D; Connors, Joseph M; Mottok, Anja; Weisenburger, Dennis D; Greiner, Timothy C; Fu, Kai; Smith, Lynette; Rimsza, Lisa M; Jaffe, Elaine S; Campo, Elias; Martinez, Antonio; Delabie, Jan; Braziel, Rita M; Cook, James R; Ott, German; Vose, Julie M; Staudt, Louis M; Chan, Wing C

    2015-10-01

    Mediastinal involvement is considered essential for the diagnosis of primary mediastinal large B-cell lymphoma (PMBL). However, we have observed cases of diffuse large B-cell lymphoma (DLBCL) with features of PMBL but without detectable mediastinal involvement. The goal was to assess our previously established gene expression profiling (GEP) signature for PMBL in classifying these cases. In a large series of DLBCL cases, we identified 24 cases with a GEP signature of PMBL, including 9 cases with a submission diagnosis of DLBCL consistent with PMBL (G-PMBL-P) and 15 cases with a submission diagnosis of DLBCL. The pathology reviewers agreed with the diagnosis in the 9 G-PMBL-P cases. Among the other 15 DLBCL cases, 11 were considered to be PMBL or DLBCL consistent with PMBL, 3 were considered to be DLBCL, and 1 case was a gray-zone lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. All 9 G-PMBL-P and 9 of the 15 DLBCL cases (G-PMBL-M) had demonstrated mediastinal involvement at presentation. Interestingly, 6 of the 15 DLBCL cases (G-PMBL-NM) had no clinical or radiologic evidence of mediastinal involvement. The 3 subgroups of PMBL had otherwise similar clinical characteristics, and there were no significant differences in overall survival. Genetic alterations of CIITA and PDL1/2 were detected in 26% and 40% of cases, respectively, including 1 G-PMBL-NM case with gain of PDL1/2. In conclusion, PMBL can present as a nonmediastinal tumor without evidence of mediastinal involvement, and GEP offers a more precise diagnosis of PMBL. PMID:26135560

  19. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma.

    PubMed

    Guiter, Chrystelle; Dusanter-Fourt, Isabelle; Copie-Bergman, Christiane; Boulland, Marie-Laure; Le Gouvello, Sabine; Gaulard, Philippe; Leroy, Karen; Castellano, Flavia

    2004-07-15

    Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the functional state of the signal transducer and activator of transcription 6 (STAT6), mediating IL-4/IL-13 transcriptional effects. Constitutive STAT6 phosphorylation and DNA-binding activity were detected in PMBL cell lines but not DLBCL cell lines. Moreover, immunohistochemical analysis revealed nuclear phosphorylated STAT6 (P-STAT6) in 8 of 11 PMBL, compared with 1 of 10 DLBCL primary tumors (P =.01). IL-4 and IL-13 transcripts were absent in PMBL cell lines and expressed at low levels in tumors, indicating that, contrary to classical Hodgkin lymphoma (cHL), STAT6 activation is not due to an autocrine IL-4/IL-13 secretion. We demonstrated an amplification of the JAK2 gene in 2 of 6 PMBL cases, and showed higher JAK2 mRNA levels in PMBL compared with DLBCL (P =.005). The Janus kinase 2 (JAK2) was constitutively phosphorylated in the PMBL MedB1 cell line. MedB1 treatment with JAK2 inhibitor AG490 partially decreased STAT6 phosphorylation, suggesting that JAK2 is partially involved in STAT6 activation in these cells. Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas. PMID:15044251

  20. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.

    PubMed

    Machiela, Mitchell J; Lan, Qing; Slager, Susan L; Vermeulen, Roel C H; Teras, Lauren R; Camp, Nicola J; Cerhan, James R; Spinelli, John J; Wang, Sophia S; Nieters, Alexandra; Vijai, Joseph; Yeager, Meredith; Wang, Zhaoming; Ghesquières, Hervé; McKay, James; Conde, Lucia; de Bakker, Paul I W; Cox, David G; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Giles, Graham G; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Purdue, Mark P; Vajdic, Claire M; Albanes, Demetrius; Kelly, Rachel S; Zucca, Mariagrazia; Bertrand, Kimberly A; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M; Link, Brian K; Novak, Anne J; Dogan, Ahmet; Asmann, Yan W; Liebow, Mark; Thompson, Carrie A; Ansell, Stephen M; Witzig, Thomas E; Tilly, Hervé; Haioun, Corinne; Molina, Thierry J; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans-Olov; Roos, Göran; Bracci, Paige M; Riby, Jacques; Smith, Martyn T; Holly, Elizabeth A; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M; Severson, Richard K; Tinker, Lesley F; North, Kari E; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J; Villano, Danylo J; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R; Turner, Jenny; Southey, Melissa C; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Boeing, Heiner; Tjønneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; De Vivo, Immaculata; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Liang, Liming; Park, Ju-Hyun; Chung, Charles C; Weisenburger, Dennis D; Fraumeni, Joseph F; Salles, Gilles; Glenn, Martha; Cannon-Albright, Lisa; Curtin, Karen; Wu, Xifeng; Smedby, Karin E; de Sanjose, Silvia; Skibola, Christine F; Berndt, Sonja I; Birmann, Brenda M; Chanock, Stephen J; Rothman, Nathaniel

    2016-04-15

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk. PMID:27008888

  1. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.

    PubMed

    Lenz, Georg; Wright, George W; Emre, N C Tolga; Kohlhammer, Holger; Dave, Sandeep S; Davis, R Eric; Carty, Shannon; Lam, Lloyd T; Shaffer, A L; Xiao, Wenming; Powell, John; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Connors, Joseph M; Campo, Elias; Jaffe, Elaine S; Delabie, Jan; Smeland, Erlend B; Rimsza, Lisa M; Fisher, Richard I; Weisenburger, Dennis D; Chan, Wing C; Staudt, Louis M

    2008-09-01

    Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. PMID:18765795

  2. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways

    PubMed Central

    Lenz, Georg; Wright, George W.; Emre, N. C. Tolga; Kohlhammer, Holger; Dave, Sandeep S.; Davis, R. Eric; Carty, Shannon; Lam, Lloyd T.; Shaffer, A. L.; Xiao, Wenming; Powell, John; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Rimsza, Lisa M.; Fisher, Richard I.; Weisenburger, Dennis D.; Chan, Wing C.; Staudt, Louis M.

    2008-01-01

    Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. PMID:18765795

  3. Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas.

    PubMed

    Tandon, Bevan; Peterson, Loann; Gao, Juehua; Nelson, Beverly; Ma, Shuo; Rosen, Steven; Chen, Yi-Hua

    2011-11-01

    Lymphoid-enhancer-binding factor 1 (LEF1), coupling with β-catenin, functions as a key nuclear mediator of WNT/β-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5- cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5+ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of β-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear β-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic

  4. Two-Dimensional Matrix Algorithm Using Detrended Fluctuation Analysis to Distinguish Burkitt and Diffuse Large B-Cell Lymphoma

    PubMed Central

    Yeh, Rong-Guan; Lin, Chung-Wu; Abbod, Maysam F.; Shieh, Jiann-Shing

    2012-01-01

    A detrended fluctuation analysis (DFA) method is applied to image analysis. The 2-dimensional (2D) DFA algorithms is proposed for recharacterizing images of lymph sections. Due to Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), there is a significant different 5-year survival rates after multiagent chemotherapy. Therefore, distinguishing the difference between BL and DLBCL is very important. In this study, eighteen BL images were classified as group A, which have one to five cytogenetic changes. Ten BL images were classified as group B, which have more than five cytogenetic changes. Both groups A and B BLs are aggressive lymphomas, which grow very fast and require more intensive chemotherapy. Finally, ten DLBCL images were classified as group C. The short-term correlation exponent α1 values of DFA of groups A, B, and C were 0.370 ± 0.033, 0.382 ± 0.022, and 0.435 ± 0.053, respectively. It was found that α1 value of BL image was significantly lower (P < 0.05) than DLBCL. However, there is no difference between the groups A and B BLs. Hence, it can be concluded that α1 value based on DFA statistics concept can clearly distinguish BL and DLBCL image. PMID:23365623

  5. Suppression of Human B Cell Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Involves Altered Regulation of B Cell Lymphoma-6

    PubMed Central

    Phadnis-Moghe, Ashwini S.; Crawford, Robert B.; Kaminski, Norbert E.

    2015-01-01

    The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces marked suppression of the primary humoral immune response in virtually every animal species evaluated thus far. In addition, epidemiological studies performed in areas of dioxin contamination have identified an association between TCDD exposure and an increased incidence of non-Hodgkin’s lymphoma (NHL). Recent studies using an in vitro CD40 ligand model of human B cell differentiation have shown that TCDD impairs both B cell activation and differentiation. The present study extends these findings by identifying B cell lymphoma-6 [BCL-6] as a putative cellular target for deregulation by TCDD, which may contribute to suppression of B cell function as well as NHL. BCL-6 is a multifunctional transcriptional repressor frequently mutated in NHLs and known to regulate critical events of B cell activation and differentiation. In the presence of TCDD, BCL-6 protein levels were elevated and concurrently the same population of cells with high BCL-6 levels showed decreased CD80 and CD69 expression indicative of impaired cellular activation. The elevated BCL-6 levels resulted in a concomitant increase in BCL-6 DNA binding activity at its cognate binding site within an enhancer region for CD80. Furthermore, a small molecule inhibitor of BCL-6 activity reversed TCDD-mediated suppression of CD80 expression in human B cells. In the presence of a low-affinity ligand of the aryl hydrocarbon receptor (AHR), suppression of B cell activation and altered BCL-6 regulation were not observed. These results provide new mechanistic insights into the role of BCL-6 in the suppression of human B cell activation by TCDD. PMID:25543051

  6. Clinical Significance of “Double-hit” and “Double-protein” expression in Primary Gastric B-cell Lymphomas

    PubMed Central

    He, Miaoxia; Chen, Keting; Li, Suhong; Zhang, Shimin; Zheng, Jianming; Hu, Xiaoxia; Gao, Lei; Chen, Jie; Song, Xianmin; Zhang, Weiping; Wang, Jianmin; Yang, Jianmin

    2016-01-01

    BACKGROUND AND AIMS: Primary gastric B-cell lymphoma is the second most common malignancy of the stomach. There are many controversial issues about its diagnosis, treatment and clinical management. “Double-hit” and “double-protein” involving gene rearrangement and protein expression of c-Myc and bcl2/bcl6 are the most used terms to describe DLBCL poor prognostic factors in recent years. However, very little is known about the role of these prognostic factors in primary gastric B-cell lymphomas. This study aims to obtain a molecular pathology prognostic model of gastric B-cell lymphoma for clinical stratified management by evaluating how the “double-hit” and “double-protein” in tumor cells as well as microenvironmental reaction of tumor stromal tissue affect clinical outcome in primary gastric B-cell lymphomas. METHODS: Data and tissues of 188 cases diagnosed with gastric B-cell lymphomas were used in this study. Tumor tissue microarray (TMA) of formalin fixed and paraffin embedded (FFPE) tissues was constructed for fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) analysis with a serial of biomarkers containing MYC, BCL2, BCL6, CD31, SPARC, CD10, MUM1 and Ki-67. Modeled period analysis was used to estimate 3-year and 5-year overall survival (OS) and disease-free survival (DFS) distributions. RESULTS: There was no definite “double-hit” case though the gene rearrangement of c-Myc (5.9%), bcl2 (0.1%) and bcl6 (7.4%) was found in gastric B-cell lymphomas. The gene amplification or copy gains of c-Myc (10.1%), bcl-2 (17.0%) and bcl-6 (0.9%) were present in these lymphomas. There were 12 cases of the lymphomas with the “double-protein” expression of MYC and BCL2/BCL6. All patients with “double-protein” gastric B-cell lymphomas had poor outcome compared with those without. More importantly, “MYC-BCL2-BCL6” negative group of gastric B-cell lymphoma patients had favorable clinical outcome regardless clinical stage

  7. High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin's lymphoma.

    PubMed

    Chen, Ming-Huang; Hsiao, Liang-Tsai; Chiou, Tzeon-Jye; Liu, Jin-Hwang; Gau, Jyh-Pyng; Teng, Hao-Wei; Wang, Wei-Shu; Chao, Ta-Chung; Yen, Chueh-Chuan; Chen, Po-Min

    2008-06-01

    Several reports recently found that patients with B cell non-Hodgkin's lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL. PMID:18327583

  8. GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo

    PubMed Central

    Healy, Jane A.; Nugent, Adrienne; Rempel, Rachel E.; Moffitt, Andrea B.; Davis, Nicholas S.; Jiang, Xiaoyu; Shingleton, Jennifer R.; Zhang, Jenny; Love, Cassandra; Datta, Jyotishka; McKinney, Matthew E.; Tzeng, Tiffany J.; Wettschureck, Nina; Offermanns, Stefan; Walzer, Katelyn A.; Chi, Jen-Tsan; Rasheed, Suhail A. K.; Casey, Patrick J.; Lossos, Izidore S.

    2016-01-01

    GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development. PMID:26989201

  9. Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-09-29

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  10. Halogenated benzimidazole carboxamides target integrin alpha4 beta1 on T and B cell lymphomas3456

    PubMed Central

    Carpenter, Richard D.; Natarajan, Arutselvan; Lau, Edmond Y.; Andrei, Mirela; Solano, Danielle M.; Lightstone, Felice C.; DeNardo, Sally J.; Lam, Kit S.; Kurth, Mark J.

    2011-01-01

    Integrin alpha-4 beta-1 (alpha4 beta1, alpha(4)beta(1), α4β1) is an attractive but poorly understood target for selective diagnosis and treatment of T and B cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin α4β1 antagonists. We documented tumor uptake of derivatives labelled with I-125 in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin α4β1 predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic (18F) or radiotherapeutic (131I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies. PMID:20530664

  11. Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas.

    PubMed

    Dighiero, G; Hart, S; Lim, A; Borche, L; Levy, R; Miller, R A

    1991-08-01

    Previous work with monoclonal Igs (MIgs) has demonstrated that a high proportion of paraproteins bind to self-antigens such as the Fc fragment of IgG, Ii blood group antigens, cytoskeleton proteins, DNA, and myelin-associated glycoprotein (MAG). Recent work in CLL indicates that CD5+ B lymphocytes are frequently committed to production of autoantibodies. We have examined the antibody specificity of MIgs derived from the tumor cells of 31 different patients with CD5- B-cell lymphomas. Our results indicate that the tumor cells from 8 of these 31 patients (25.8%) express Igs with autoantibody activity. In two cases antibody activity was multispecific. In four cases, antibody activity was exclusively directed against the Fc fragment of IgG, whereas the two other cases bound to both Fc fragment of IgG and nuclear antigens. Most non-Hodgkin's lymphomas (NHL) are derived from CD5- B cells. These results indicate that like CLL, NHL also express Igs that frequently have autoantibody activity.

  12. Chlamydophila psittaci-negative ocular adnexal marginal zone lymphomas express self polyreactive B-cell receptors.

    PubMed

    Zhu, D; Bhatt, S; Lu, X; Guo, F; Veelken, H; Hsu, D K; Liu, F-T; Alvarez Cubela, S; Kunkalla, K; Vega, F; Chapman-Fredricks, J R; Lossos, I S

    2015-07-01

    The pathogenesis of Chlamydophila psittaci-negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B-cell receptor (BCR) may have a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase high-performance liquid chromatography nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (for example, galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings indicate that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall, our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci-negative OAEMZLs. PMID:25676418

  13. [Current understanding and future prospects for intravascular large B-cell lymphoma].

    PubMed

    Shimada, Kazuyuki

    2015-08-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare distinct disease entity of the extranodal large B-cell lymphoma type, characterized by the selective growth of tumor cells in the lumina of small vessels of various organs. Lack of remarkable lymphadenopathy and non-specific clinical abnormalities including fever of unknown origin and lactate dehydrogenase elevation generally make timely and accurate diagnosis difficult. Recent diagnostic advances in the detection of this disease using FDG-PET/CT and random skin biopsies are expected to increase the diagnostic yield. Regarding the therapeutic aspects of this disease, improvement of clinical outcomes by the application of anti-CD20 monoclonal antibody, rituximab, and a high risk of CNS recurrence have been indicated. Thus, a prospective phase II trial of immunochemotherapy combined with CNS prophylaxis is now ongoing. Previously, the difficulty of obtaining sufficient tumor samples hampered biological investigations but the novel technique developing xenograft models is opening the door to uncovering the underlying mechanisms by focusing on the fundamental biological question: "Why do tumor cells become lodged in the lumina of vessels?" This review describes the current understanding of research on IVLBCL and discusses the future prospects for this disease entity. PMID:26345563

  14. Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

    PubMed

    Todorovic Balint, Milena; Jelicic, Jelena; Mihaljevic, Biljana; Kostic, Jelena; Stanic, Bojana; Balint, Bela; Pejanovic, Nadja; Lucic, Bojana; Tosic, Natasa; Marjanovic, Irena; Stojiljkovic, Maja; Karan-Djurasevic, Teodora; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Raicevic, Sava; Bila, Jelena; Antic, Darko; Andjelic, Bosko; Pavlovic, Sonja

    2016-01-01

    The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach. PMID:27164089

  15. Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

    PubMed Central

    Todorovic Balint, Milena; Jelicic, Jelena; Mihaljevic, Biljana; Kostic, Jelena; Stanic, Bojana; Balint, Bela; Pejanovic, Nadja; Lucic, Bojana; Tosic, Natasa; Marjanovic, Irena; Stojiljkovic, Maja; Karan-Djurasevic, Teodora; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Raicevic, Sava; Bila, Jelena; Antic, Darko; Andjelic, Bosko; Pavlovic, Sonja

    2016-01-01

    The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach. PMID:27164089

  16. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas.

    PubMed

    Naylor, Tara L; Tang, Huaping; Ratsch, Boris A; Enns, Andreas; Loo, Alice; Chen, Liqing; Lenz, Peter; Waters, Nigel J; Schuler, Walter; Dörken, Bernd; Yao, Yung-Mae; Warmuth, Markus; Lenz, Georg; Stegmeier, Frank

    2011-04-01

    The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-κB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-κB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-κB pathway inhibition and were mediated by induction of G₁-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities.

  17. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.

    PubMed

    Zhang, Jenny; Jima, Dereje; Moffitt, Andrea B; Liu, Qingquan; Czader, Magdalena; Hsi, Eric D; Fedoriw, Yuri; Dunphy, Cherie H; Richards, Kristy L; Gill, Javed I; Sun, Zhen; Love, Cassandra; Scotland, Paula; Lock, Eric; Levy, Shawn; Hsu, David S; Dunson, David; Dave, Sandeep S

    2014-05-01

    In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer. PMID:24682267

  18. Primary mediastinal large B-cell lymphoma: a single-center experience in Korea

    PubMed Central

    Ahn, Heui June; Yoon, Dok-Hyun; Kim, Shin; Lee, Kyoungmin; Kang, EunHee; Huh, Jooryung; Park, Chan-Sik

    2014-01-01

    Background Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of non-Hodgkin lymphoma, which has no consensus for its ideal treatment or prognosis. Methods We reviewed the clinicopathologic features and clinical outcomes of 25 PMBL cases diagnosed at a single institution between 1993 and 2009 and compared them with 588 cases of non-mediastinal, diffuse large B-cell lymphoma (DLBCL, control group) diagnosed during the same period. Results Thirteen (52.0%) PMBL patients had Ann Arbor stage III or IV disease, and 10 (40.0%) had B symptoms. Thirteen (52%) PMBL patients were classified as high-intermediate/high-risk according to the International Prognostic Index. There was a significant prevalence of young (median: 31 years; range, 15-78 years; P<0.001), female (68%; P=0.014) patients in the PMBL group compared to the control group (median: 56 years; range, 15-85 years; 43.2% female). Bulky disease and elevated levels of lactate dehydrogenase (LDH) were more frequent in the PMBL group (P<0.001 and P=0.003, respectively). Nineteen (76%) PBML patients achieved complete remission, and 18 were alive at the last follow-up (median: 43 months; range, 1-92 months). There was no difference in the 3-year, overall survival rate (72%, 95% confidence interval [CI]: 54.0-83.0 versus 70.1%, 95% CI, 109.0-126.0; P=0.686) between PMBL and control patients, respectively. Conclusion Compared to patients with non-mediastinal DLBCL, Korean patients with PMBL are predominantly young women with bulky disease and high LDH levels but with no significant difference in survival. PMID:24724065

  19. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation. PMID:21796626

  20. Survival in patients with oral and maxillofacial diffuse large B-cell lymphoma.

    PubMed

    Guevara-Canales, Janet Ofelia; Morales-Vadillo, Rafael; Cava-Vergiú, Carlos Enrique; Leite, Fabiola Pessoa Pereira; Miranda Chaves Netto, Henrique Duque de; Soares, Fernando Augusto; Chaves, Maria das Graças Afonso Miranda

    2013-01-01

    The purpose of this study was to determine the survival and prognostic factors of patients with diffuse large B-cell lymphoma (DLBCL) of the oral cavity and maxillofacial region. Retrospectively, the clinical records of patients with a primary diagnosis of DLBCL of the oral cavity and maxillofacial region treated at the A.C. Camargo Hospital for Cancer, São Paulo, Brazil, between January 1980 and December 2005 were evaluated to determine (A) overall survival (OS) at 2 and 5 years and the individual survival percentage for each possible prognostic factor by means of the actuarial technique (also known as mortality tables), and the Kaplan Meier product limit method (which provided the survival value curves for each possible prognostic factor); (B) prognostic factors subject to univariate evaluation with the log-rank test (also known as Mantel-Cox), and multivariate analysis with Cox's regression model (all the variables together). The data were considered significant at p≤0.05. From 1980 to 2005, 3513 new cases of lymphomas were treated, of which 151 (4.3%) occurred in the oral cavity and maxillofacial region. Of these 151 lesions, 48 were diffuse large B-cell lymphoma, with 64% for OS at 2 years and 45% for OS at 5 years. Of the variables studied as possible prognostic factors, multivariate analysis found the following variables have statistically significant values: age (p=0.042), clinical stage (p=0.007) and performance status (p=0.031). These data suggest that patients have a higher risk of mortality if they are older, at a later clinical stage, and have a higher performance status.

  1. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.

  2. Anterior panhypopituitarism in diffuse large B-cell stage IV lymphoma.

    PubMed

    Valeros, Katherine A; Khoo, Eric

    2014-08-01

    The most common presentation of metastases to the pituitary gland in systemic lymphoma is diabetes insipidus resulting from infiltration of the infundibulum/posterior lobe. We describe a 69-year-old man with diffuse large B-cell stage IV lymphoma who presented with anterior pituitary hypofunction, without features of posterior pituitary involvement. He presented with a few months of postural dizziness and hypotension, weight loss, fever, strabismus of right eye and a superficial abdominal wall mass. At this time he had no history of malignancy. Biochemically he had hypovolemic hyponatremia, secondary hypothyroidism and adrenal insufficiency. Further hormonal work-up revealed panhypopituitarism but no diabetes insipidus. Imaging of the brain, thorax and abdomen demonstrated diffuse intracranial pachymeningeal thickening and enhancement, multiple lymphadenopathies, a bulky right adrenal gland and a large left suprarenal mass, which were indicative of an infiltrative disease. Imaging of the pituitary showed heterogeneous enhancement of the anterior lobe with an unremarkable pituitary stalk and posterior lobe. Biopsy of the superficial abdominal wall mass revealed diffuse large B-cell lymphoma confirmed by bone marrow aspiration biopsy. Positron emission tomography (PET) scan confirmed diffuse systemic disease involving the right orbital apex, bilateral adrenal glands, bone and bone marrow, retroperitoneum and subcutaneous tissues; however, the pituitary gland, infundibulum and hypothalamus did not show any lesions on the PET scan. The patient was commenced on two cycles of chemotherapy but unfortunately died, thus recovery of pituitary function was not tested. Pure anterior pituitary hypofunction can uncommonly present in individuals with metastases to the pituitary gland, in contrast to the more common posterior pituitary/infundibulum involvement.

  3. Stage IV intramucosal gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type.

    PubMed

    Ohtaka, Masahiko; Sato, Tadashi; Kobayashi, Shouji; Sueki, Ryouta; Yamaguchi, Tatsuya; Uetake, Tomoyoshi; Ohtsuka, Hiroyuki; Iwao, Noriaki; Kirito, Keita; Enomoto, Nobuyuki

    2013-04-01

    A 45-year-old woman with no symptoms underwent upper gastrointestinal endoscopy. A discolored area was noted at the greater curvature of the gastric upper body. Endoscopic ultrasonography demonstrated thickening of the second sonographic layer indicating that the depth of invasion was confined to the mucosa. A urea breath test and anti-Helicobacter pylori antibody test were negative. A computed tomography scan showed a consolidation at the right lung. Gastric biopsy and transbronchial lung biopsy (TBLB) demonstrated a monotonous proliferation of atypical small lymphocytes. A diagnosis of gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) was made. The clinical stage was stage IV. A genetic analysis showed rearrangement of the joining region of the immunoglobulin heavy chain gene and identical clones in both lesions. An API2-MALT1 fusion gene was detected in the gastric lesion. After H. pylori eradication treatment, combination treatment with rituximab plus CHOP (R-CHOP) was performed; 6 months later an endoscopy revealed complete disappearance of the lesion. Multiple gastric biopsies showed no infiltrating atypical lymphocytes. Similarly, the lesion in the lung showed complete remission (CR) on CT and TBLB. This report shows that a gastric MALT lymphoma located in the mucosa and disseminated to the lung maintained CR by R-CHOP. PMID:26181449

  4. Functional role of regulatory T cells in B cell lymphoma and related mechanisms.

    PubMed

    Wu, Wei; Wan, Jun; Xia, Ruixiang; Huang, Zhenqi; Ni, Jing; Yang, Mingzhen

    2015-01-01

    B cell lymphoma (BCL) has a higher degree of malignancy and complicated pathogenic mechanism. Regulatory T cells (Treg cells) are known to exert certain immune suppression functions, in addition to immune mediating effects. Recent studies have revealed the role of Treg cells in pathogenesis and progression of multiple malignant tumors. This study therefore investigated the functional role and related mechanism of Treg cells in BCL. A cohort of thirty patients who were diagnosed with BCL in our hospital between January 2013 and December 2014. Another thirty healthy individuals were recruited. Peripheral blood mononuclear cells (PBMCs) were separated and analyzed for the ratio of CD4+/CD25+ Treg cells. The mRNA expression levels of Foxp3, transforming growth factor (TGF)-β1 and interleukin (IL)-10 genes were quantified by real-time PCR, while their serum levels were determined by enzyme-linked immunosorbent assay (ELISA). Meanwhile all laboratory indexes for patients were monitored during the complete remission (CR) stage. BCL patients significantly elevated ratio of CD4+/CD25+ Treg cells, which were decreased at CR stage. mRNA levels of Foxp3, TGF-β1 and IL-10, in addition to protein levels of TGF-β1 and IL-10 were potentiated in lymphoma patients but decreased in CR patients (P<0.05 in all cases). CD4+/CD25+ Treg cells exert immune suppressing functions in BCL via regulating cytokines, thereby facilitating the pathogenesis and progression of lymphoma. PMID:26464657

  5. Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

    PubMed

    Testo, Natalia; Olson, Luke C; Subramaniyam, Shivakumar; Hanson, Ty; Magro, Cynthia M

    2016-10-01

    Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation. PMID:27391453

  6. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein.

    PubMed

    Weniger, Marc A; Gesk, Stefan; Ehrlich, Steve; Martin-Subero, José I; Dyer, Martin J S; Siebert, Reiner; Möller, Peter; Barth, Thomas F E

    2007-04-01

    Gains or amplifications of the REL locus are frequently seen in primary mediastinal B-cell lymphoma (PMBL). In classical Hodgkin's lymphoma, genomic overrepresentation of REL correlated with nuclear REL protein accumulation. To investigate the correlation between REL gene copies and its RNA and protein expression in PMBL, we analyzed genomic, transcriptional, and protein levels in 20 PMBLs and the PMBL derived cell lines MedB-1 and Karpas1106P. We found gains/amplifications in 75% of the PMBLs by fluorescence in situ hybridization (FISH) and genomic REL overrepresentation in the PMBL lines. Three of the five PMBLs with amplifications displayed elevated REL transcripts, while only 3/10 PMBLs with gains showed increased REL transcripts by real-time PCR. One PMBL without gains displayed increased REL transcription. REL protein expression exhibited a variable pattern across the PMBLs except for a single case that was completely negative by immunohistochemistry despite having gained REL. Although transcript levels were generally low and nuclear REL staining was weak in the lymphoma cell lines, these nevertheless exhibited high NF-kappaB activation. By fluorescence immunophenotyping and interphase cytogenetics as a tool for investigation of neoplasms, genomic gains/amplifications of REL significantly correlated with nuclear REL expression (P < 0.05). In conclusion, the frequent genomic overrepresentation of REL in PMBL does not necessarily trigger an increased transcription/translation of REL. However, combined genomic and protein analysis revealed a significant association of gained REL and nuclear REL accumulation at the single cell level. PMID:17243160

  7. Coexistent rearrangements of c-MYC, BCL2, and BCL6 genes in a diffuse large B-cell lymphoma.

    PubMed

    Ueda, Chiyoko; Nishikori, Momoko; Kitawaki, Toshio; Uchiyama, Takashi; Ohno, Hitoshi

    2004-01-01

    We present a patient with stage III de novo diffuse large B-cell lymphoma. The lymphoma cells showed mature B-cell immunophenotype but lacked surface immunoglobulin (Ig) expression. Long-distance and long-distance inverse polymerase chain reaction assays to detect the oncogene/Ig gene rearrangement revealed that the cells carried 3 independent fusion genes, namely, c-MYC/Ig heavy chain gene (IgH), BCL2/IgH, and Ig lambda light chain gene/BCL6. Thus, the lymphoma cells concurrently carried t(8;14)(q24;q32), t(14;18)(q32;q21), and t(3;22)(q27;q11), which developed in association with class switching, V/D/J recombination, and somatic hypermutation, respectively. The lymphoma responded to chemoradiotherapy, and the patient has been well for 2 years, suggesting that multiple oncogene rearrangements may not necessarily be associated with poor clinical outcome.

  8. CD7 Positive Diffuse Large B-Cell Lymphoma Arising in a Background of Follicular Lymphoma: A Case Report and Review of the Literature

    PubMed Central

    Rashidi, Hooman H.

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large B-lymphocytes with a diffuse growth pattern. The neoplastic cells express B-cell markers such as CD20 and PAX-5 and there may be coexpression of BCL-2, BCL-6, CD10, and MUM-1. With the exception of CD5, other T-cell markers are not commonly expressed in this neoplasm. Here, we describe the first reported case of a DLBCL with abnormal expression CD7 arising in a background of follicular lymphoma in an 81-year-old male who presented with a nontender left axillary mass. Additionally, no other T-cell antigens were expressed in this B-cell lymphoma. Expression of CD7 in DLBCL is exceptionally rare and its prognostic significance is unknown. Here, we describe this rare case with review of literature of known DLBCLs with expression of T-cell antigens.

  9. Tracheal ulcer due to Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

    PubMed

    Ito, Takeo; Fujisaki, Hideaki; Nishio, Suehiro; Hiroshige, Shigeo; Miyazaki, Eishi; Kadota, Jun-ichi

    2014-03-01

    A 74-year-old man was referred to our hospital because of a tracheal stenosis circumscribed with soft tissue density and a left pulmonary nodule. Open biopsy of a right submandibular lymph node revealed diffuse large B-cell lymphoma, and the malignant cells were positive for Epstein-Barr virus gene products. Bronchofiberscopy revealed a tracheal necrotizing ulcer. After chemotherapy, the tracheal ulcer resolved. To our knowledge, this is the first report of a case of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly with a tracheal ulcer.

  10. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

    PubMed Central

    Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

    2015-01-01

    Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

  11. Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling

    PubMed Central

    Deffenbacher, Karen E.; Iqbal, Javeed; Sanger, Warren; Shen, Yulei; Lachel, Cynthia; Liu, Zhongfeng; Liu, Yanyan; Lim, Megan S.; Perkins, Sherrie L.; Fu, Kai; Smith, Lynette; Lynch, James; Staudt, Louis M.; Rimsza, Lisa M.; Jaffe, Elaine; Rosenwald, Andreas; Ott, German K.; Delabie, Jan; Campo, Elias; Gascoyne, Randy D.; Cairo, Mitchell S.; Weisenburger, Dennis D.; Greiner, Timothy C.; Gross, Thomas G.

    2012-01-01

    Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, −6q), and abnormalities unique to the pediatric cases (−4p14, −19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma. PMID:22374697

  12. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

    PubMed

    Ortega-Molina, Ana; Boss, Isaac W; Canela, Andres; Pan, Heng; Jiang, Yanwen; Zhao, Chunying; Jiang, Man; Hu, Deqing; Agirre, Xabier; Niesvizky, Itamar; Lee, Ji-Eun; Chen, Hua-Tang; Ennishi, Daisuke; Scott, David W; Mottok, Anja; Hother, Christoffer; Liu, Shichong; Cao, Xing-Jun; Tam, Wayne; Shaknovich, Rita; Garcia, Benjamin A; Gascoyne, Randy D; Ge, Kai; Shilatifard, Ali; Elemento, Olivier; Nussenzweig, Andre; Melnick, Ari M; Wendel, Hans-Guido

    2015-10-01

    The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways. PMID:26366710

  13. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development

    PubMed Central

    Ortega-Molina, Ana; Boss, Isaac W.; Canela, Andres; Pan, Heng; Jiang, Yanwen; Zhao, Chunying; Jiang, Man; Hu, Deqing; Agirre, Xabier; Niesvizky, Itamar; Lee, Ji-Eun; Chen, Hua-Tang; Ennishi, Daisuke; Scott, David W.; Mottok, Anja; Hother, Christoffer; Liu, Shichong; Cao, Xing-Jun; Tam, Wayne; Shaknovich, Rita; Garcia, Benjamin A.; Gascoyne, Randy D.; Ge, Kai; Shilatifard, Ali; Elemento, Olivier; Nussenzweig, Andre; Melnick, Ari M.; Wendel, Hans-Guido

    2015-01-01

    The lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). However, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center (GC) involution, impedes B cell differentiation and class switch recombination (CSR). Integrative genomic analyses indicate that KMT2D affects H3K4 methylation and expression of a specific set of genes including those in the CD40, JAK-STAT, Toll-like receptor, and B cell receptor pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3, and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell activating pathways. PMID:26366710

  14. Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief review and recent update

    PubMed Central

    Hong, Jung Yong; Suh, Cheolwon; Kim, Won Seog

    2016-01-01

    Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL. PMID:27606052

  15. Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief review and recent update

    PubMed Central

    Hong, Jung Yong; Suh, Cheolwon; Kim, Won Seog

    2016-01-01

    Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL.

  16. Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief review and recent update.

    PubMed

    Hong, Jung Yong; Suh, Cheolwon; Kim, Won Seog

    2016-01-01

    Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL. PMID:27606052

  17. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.

    PubMed

    Schmitz, Roland; Hansmann, Martin-Leo; Bohle, Verena; Martin-Subero, Jose Ignacio; Hartmann, Sylvia; Mechtersheimer, Gunhild; Klapper, Wolfram; Vater, Inga; Giefing, Maciej; Gesk, Stefan; Stanelle, Jens; Siebert, Reiner; Küppers, Ralf

    2009-05-11

    Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor kappaB (NF-kappaB). NF-kappaB activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus-positive (EBV(+)) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV(-) cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-kappaB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-kappaB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-kappaB activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV(-) than EBV(+) cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis. PMID:19380639

  18. Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells.

    PubMed

    Strömberg, Thomas; Feng, Xiaoying; Delforoush, Maryam; Berglund, Mattias; Lin, Yingbo; Axelson, Magnus; Larsson, Olle; Georgii-Hemming, Patrik; Lennartsson, Johan; Enblad, Gunilla

    2015-07-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by

  19. Primary Cutaneous B-Cell Lymphoma: Management and Patterns of Recurrence at the Multimodality Cutaneous Lymphoma Clinic of The Ohio State University

    PubMed Central

    Tyler, Kelly; Gru, Alejandro A.; Winardi, Francisca Kartono; Frederickson, Julie; Hastings, Justin; Elkins, Camille; Zhang, Xiaoli; Xu-Welliver, Meng; Wong, Henry K.

    2015-01-01

    Background. The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear. Materials and Methods. We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality. We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or ≥T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the risk of recurrence. Results. We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria for PCBCL and were classified as having systemic B-cell lymphoma with cutaneous involvement. The remaining 55 patients included 25 with PCMZL, 24 with PCFCL, 2 with primary cutaneous large B-cell lymphoma leg type, and 4 with unclassifiable disease. According to the International Society of Cutaneous Lymphoma-European Organization for Research and Treatment of Cancer staging, 30 cases were T1 (55%), 14 T2 (25%), and 11 T3 (20%). Comparing the time to first recurrence (TFR) by indolent PCBCL subtypes, we found no difference in the recurrence risk for either stage (T1, p = .51 vs. T2/T3, p = .30). Comparing TFR by treatment modality, we found no difference in TFR within T1 patients (p = .34) or T2/T3 patients (p = .44). Conclusion. Our limited analysis highlights the importance of complete staging at diagnosis and suggests that the treatment modality does not affect the risk of recurrence in T1 indolent PCBCL. Implications for Practice: Primary cutaneous B-cell lymphoma (PCBCL) is a

  20. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma.

    PubMed

    Iqbal, Javeed; Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C; Vose, Julie M; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M; Cook, James R; Tubbs, Raymond R; Armitage, James O; Weisenburger, Dennis D; Staudt, Louis M; Gascoyne, Randy D; McKeithan, Timothy W; Chan, Wing C

    2015-02-12

    We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID:25498913

  1. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

    PubMed Central

    Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M.; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C.; Vose, Julie M.; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Armitage, James O.; Weisenburger, Dennis D.; Staudt, Louis M.; Gascoyne, Randy D.; McKeithan, Timothy W.; Chan, Wing C.

    2015-01-01

    We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)–DLBCL compared with activated B-cell (ABC)–DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the “gold standard” GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID:25498913

  2. Extra-nodal Diffuse Large B-cell Lymphoma (Germinal Center Type) Manifesting as Non-healing Extraction Socket.

    PubMed

    Syamala, Manasa; Basavarajappa, Manjunath Anekonda; Pathan, Sana; Raheem, Ahmed Mujib Bangalore; Godavarthy, Divyasri

    2016-08-01

    Lymphomas occurring in the oral cavity are rare. They account only for about 2% of extra-nodal sites. Most of the lymphomas occur in the lymph nodes and in the oral cavity, the most commonly affected region is the Waldeyer's ring. Its occurrence in the mandibular gingiva is rare. Here, we describe a case of Diffuse Large B-cell Lymphoma manifested as a non-healing extraction socket in the mandibular right posterior region in a 62-year-old male patient. PMID:27656575

  3. Extra-nodal Diffuse Large B-cell Lymphoma (Germinal Center Type) Manifesting as Non-healing Extraction Socket

    PubMed Central

    Basavarajappa, Manjunath Anekonda; Pathan, Sana; Raheem, Ahmed Mujib Bangalore; Godavarthy, Divyasri

    2016-01-01

    Lymphomas occurring in the oral cavity are rare. They account only for about 2% of extra-nodal sites. Most of the lymphomas occur in the lymph nodes and in the oral cavity, the most commonly affected region is the Waldeyer’s ring. Its occurrence in the mandibular gingiva is rare. Here, we describe a case of Diffuse Large B-cell Lymphoma manifested as a non-healing extraction socket in the mandibular right posterior region in a 62-year-old male patient. PMID:27656575

  4. Calcitriol-mediated hypercalcemia in a patient with bilateral adrenal non-Hodgkin's B-cell lymphoma case report

    PubMed Central

    Abaroa-Salvatierra, Ana; Shaikh, Bilal; Deshmukh, Mrunalini; Alweis, Richard; Patel, Arti

    2016-01-01

    Calcitriol-mediated hypercalcemia is a frequent manifestation of hematological malignancies. However, there are a few reports of cases presenting with increased angiotensin-converting enzyme (ACE) level, which suggests a possible mechanism similar to that of granulomatous diseases. We present a patient with hypercalcemia, normal parathyroid hormone, and parathyroid hormone-related protein levels but high calcitriol and ACE levels that, after further investigation, was diagnosed with bilateral adrenal non-Hodgkin's B-cell lymphoma. Primary adrenal lymphoma represents only 1% of all non-Hodgkin's lymphomas and is usually asymptomatic but should be considered by clinicians among the malignancies that cause calcitriol-mediated hypercalcemia. PMID:27124160

  5. Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B Cell Lymphoma

    PubMed Central

    Clozel, Thomas; Yang, ShaoNing; Elstrom, Rebecca L.; Tam, Wayne; Martin, Peter; Kormaksson, Matthias; Banerjee, Samprit; Vasanthakumar, Aparna; Culjkovic, Biljana; Scott, David W.; Wyman, Sarah; Leser, Michael; Shaknovich, Rita; Chadburn, Amy; Tabbo, Fabrizio; Godley, Lucy A.; Gascoyne, Randy D.; Borden, Katherine L.; Inghirami, Giorgio; Leonard, John P.; Melnick, Ari; Cerchietti, Leandro

    2013-01-01

    Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. The combination was well tolerated and yielded a high rate of complete remission. Pre and post azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs. PMID:23955273

  6. Molecular Classification, Pathway Addiction, and Therapeutic Targeting in Diffuse Large B-cell Lymphoma

    PubMed Central

    Puvvada, Soham; Kendrick, Samantha; Rimsza, Lisa

    2015-01-01

    The rapid emergence of molecularly-based techniques to detect changes in the genetic landscape of diffuse large B-cell lymphoma (DLBCL) including gene expression, DNA and RNA sequencing, and epigenetic profiling, has significantly impacted the understanding and therapeutic targeting of DLBCL. In this review, we will briefly discuss the new methods used in the study of DLBCL. We will describe the influence of the generated data on DLBCL classification and the identification of new entities and altered cell survival strategies with a focus on the renewed interest in some classic oncogenic pathways that are currently targeted for new therapy. Lastly, we will examine the molecular genomic studies that revealed the importance of the tumor microenvironment in the pathogenesis of DLBCL. PMID:24080457

  7. SEOM clinical guidelines for the treatment of diffuse large B-cell lymphoma.

    PubMed

    Gómez Codina, José; Sabín Domínguez, Pilar; Provencio Pulla, Mariano; Rueda Domínguez, Antonio; Isla Casado, Dolores

    2010-11-01

    Diffuse large B-cell non-Hodgkin's lymphoma (LDCGB) is one of the best examples of chemotherapy curable malignant diseases. This "Oncoguía SEOM" summarizes the basic directions of staging and recommended treatment options. The staging study should be thorough and includes clinical, laboratory, diagnostic imaging and nuclear medicine. Treatment depends on patient characteristics and comorbidity and on disease extension and prognostic factors. In localized cases, chemoimmunotherapy (CHOP-R) of short duration, followed by involved-field irradiation is the preferred option. In advanced stages, the association of CHOP-like chemotherapy and Rituximab has been a major breakthrough in terms of cure rate. It is important do not forget the supportive treatment in these patients. PMID:20974570

  8. Next-generation prognostic assessment for diffuse large B-cell lymphoma

    PubMed Central

    Staton, Ashley D; Kof, Jean L; Chen, Qiushi; Ayer, Turgay; Flowers, Christopher R

    2015-01-01

    Current standard of care therapy for diffuse large B-cell lymphoma (DLBCL) cures a majority of patients with additional benefit in salvage therapy and autologous stem cell transplant for patients who relapse. The next generation of prognostic models for DLBCL aims to more accurately stratify patients for novel therapies and risk-adapted treatment strategies. This review discusses the significance of host genetic and tumor genomic alterations seen in DLBCL, clinical and epidemiologic factors, and how each can be integrated into risk stratification algorithms. In the future, treatment prediction and prognostic model development and subsequent validation will require data from a large number of DLBCL patients to establish sufficient statistical power to correctly predict outcome. Novel modeling approaches can augment these efforts. PMID:26289217

  9. Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma

    PubMed Central

    Lindemann, R. K.; Newbold, A.; Whitecross, K. F.; Cluse, L. A.; Frew, A. J.; Ellis, L.; Williams, S.; Wiegmans, A. P.; Dear, A. E.; Scott, C. L.; Pellegrini, M.; Wei, A.; Richon, V. M.; Marks, Paul A.; Lowe, S. W.; Smyth, M. J.; Johnstone, R. W.

    2007-01-01

    Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Eμ-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Eμ-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents. PMID:17470784

  10. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas

    PubMed Central

    Culjkovic-Kraljacic, Biljana; Fernando, Tharu M.; Marullo, Rossella; Calvo-Vidal, Nieves; Verma, Akanksha; Yang, ShaoNing; Tabbò, Fabrizio; Gaudiano, Marcello; Zahreddine, Hiba; Goldstein, Rebecca L.; Patel, Jayeshkumar; Taldone, Tony; Chiosis, Gabriela; Ladetto, Marco; Ghione, Paola; Machiorlatti, Rodolfo; Elemento, Olivier; Inghirami, Giorgio; Melnick, Ari; Borden, Katherine L. B.

    2016-01-01

    Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo. PMID:26603836

  11. Aberrant expression of the CHFR prophase checkpoint gene in human B-cell non-Hodgkin lymphoma.

    PubMed

    Song, Aiqin; Ye, Junli; Zhang, Kunpeng; Yu, Hongsheng; Gao, Yanhua; Wang, Hongfang; Sun, Lirong; Xing, Xiaoming; Yang, Kun; Zhao, Min

    2015-05-01

    Checkpoint with FHA and Ring Finger (CHFR) is a checkpoint protein that reportedly initiates a cell cycle delay in response to microtubule stress during prophase in mitosis, which has become an interesting target for understanding cancer pathogenesis. Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. In the present study, we examined the expression of CHFR in B-cell non-Hodgkin lymphoma (B-NHL) in vitro and in vivo. Our results showed that the expression level of CHFR mRNA and protein was reduced in B-NHL tissue samples and B cell lines. Furthermore, CHFR methylation was detected in 39 of 122 B-NHL patients, which was not found in noncancerous reactive hyperplasia of lymph node (RH) tissues. CHFR methylation correlated with the reduced expression of CHFR, high International Prognostic Index (IPI) scores and later pathologic Ann Arbor stages of B-NHL. Treatment with demethylation reagent, 5-Aza-dC, could eliminate the hypermethylation of CHFR, enhance CHFR expression and cell apoptosis and inhibit the cell proliferation of Raji cells, which could be induced by high expression of CHFR in Raji cells. Our results indicated that aberrant methylation of CHFR may be associated with the pathogenesis, progression for B-NHL, which might be a novel molecular marker as prognosis and treatment for B-NHL. PMID:25798877

  12. Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma.

    PubMed

    Ezell, Scott A; Wang, Suping; Bihani, Teeru; Lai, Zhongwu; Grosskurth, Shaun E; Tepsuporn, Suprawee; Davies, Barry R; Huszar, Dennis; Byth, Kate F

    2016-02-23

    Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL. PMID:26824321

  13. Pediatric Burkitt's lymphoma and diffuse B-cell lymphoma: are surveillance scans required?

    PubMed

    Eissa, H M; Allen, C E; Kamdar, K; Simko, S; Goradia, P; Dreyer, Z; Steuber, P; McClain, K L; Guillerman, R P; Bollard, Catherine M

    2014-04-01

    Outcomes in pediatric B-Non-Hodgkin Lymphoma (B NHL) have improved with intensive chemotherapy protocols, with long-term survival now over 80%. However, long-term adverse effects of therapy and poor outcomes for patients who relapse remain challenges. In this study, we aimed to evaluate the potential risks and benefits of routine relapse surveillance imaging after the completion of therapy. We reviewed 44 B NHL patients diagnosed and treated at Texas Children's Cancer Center in the period between 2000 to 2011. All cross-sectional diagnostic imaging examinations performed for disease assessment after completion of chemotherapy were reviewed and cumulative radiation dosage from these examinations and the frequency of relapse detection by these examinations were recorded. Only 3 patients of the 44 relapsed (6.8%), though none of the relapses were initially diagnosed by computed tomography (CT) or fludeoxyglucose positron emission tomography (FDG-PET) scans. Median effective dose of ionizing radiation per patient was 40.3 mSv with an average of 49.1 mSv (range 0-276 mSv). This single-institution study highlights the low relapse rate in pediatric B-NHL with complete response at the end of therapy, the low sensitivity of early detection of relapse with surveillance CT or FDG-PET imaging, and the costs and potential increased risk of secondary malignancies from cumulative radiation exposure from surveillance imaging. We propose that routine surveillance CT or FDG-PET scans for these patients may not be necessary. PMID:24087880

  14. Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma.

    PubMed

    Slezak-Prochazka, Izabella; Kluiver, Joost; de Jong, Debora; Smigielska-Czepiel, Katarzyna; Kortman, Gertrud; Winkle, Melanie; Rutgers, Bea; Koerts, Jasper; Visser, Lydia; Diepstra, Arjan; Kroesen, Bart-Jan; van den Berg, Anke

    2016-01-19

    Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, NIAM, TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the novel miR-155 target gene NIAM increased proliferation of BL cells. In primary B-cell lymphoma NIAM-positive cases have significant lower levels of miR-155 as compared to NIAM-negative cases, suggesting that NIAM is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate an oncogenic role for miR-155 in B-cell lymphoma which involves targeting the tumor suppressor NIAM.

  15. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.

    PubMed

    Knittel, Gero; Liedgens, Paul; Korovkina, Darya; Seeger, Jens M; Al-Baldawi, Yussor; Al-Maarri, Mona; Fritz, Christian; Vlantis, Katerina; Bezhanova, Svetlana; Scheel, Andreas H; Wolz, Olaf-Oliver; Reimann, Maurice; Möller, Peter; López, Cristina; Schlesner, Matthias; Lohneis, Philipp; Weber, Alexander N R; Trümper, Lorenz; Staudt, Louis M; Ortmann, Monika; Pasparakis, Manolis; Siebert, Reiner; Schmitt, Clemens A; Klatt, Andreas R; Wunderlich, F Thomas; Schäfer, Stephan C; Persigehl, Thorsten; Montesinos-Rongen, Manuel; Odenthal, Margarete; Büttner, Reinhard; Frenzel, Lukas P; Kashkar, Hamid; Reinhardt, H Christian

    2016-06-01

    The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. PMID:27048211

  16. Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.

    PubMed

    Jardin, Fabrice; Pujals, Anais; Pelletier, Laura; Bohers, Elodie; Camus, Vincent; Mareschal, Sylvain; Dubois, Sydney; Sola, Brigitte; Ochmann, Marlène; Lemonnier, François; Viailly, Pierre-Julien; Bertrand, Philippe; Maingonnat, Catherine; Traverse-Glehen, Alexandra; Gaulard, Philippe; Damotte, Diane; Delarue, Richard; Haioun, Corinne; Argueta, Christian; Landesman, Yosef; Salles, Gilles; Jais, Jean-Philippe; Figeac, Martin; Copie-Bergman, Christiane; Molina, Thierry Jo; Picquenot, Jean Michel; Cornic, Marie; Fest, Thierry; Milpied, Noel; Lemasle, Emilie; Stamatoullas, Aspasia; Moeller, Peter; Dyer, Martin J S; Sundstrom, Christer; Bastard, Christian; Tilly, Hervé; Leroy, Karen

    2016-09-01

    Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc. PMID:27312795

  17. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis.

    PubMed

    Goel, Shalini; Sachdev, Ritesh; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-07-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer's ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  18. [Recent advances in the understanding and treatment of diffuse large B-cell lymphoma].

    PubMed

    Gergely, Lajos; Illés, Árpád

    2016-07-01

    Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. Using the conventional cyclophosphamide adriablastin vincristin prednisolon polychemotherapy about 50% of the patients were cured. The addition of rituximab to the regimen increased the cure rate to 60%. This is a major improvement, however, further advance is still needed to increase the cure rate. The extensive genetic testing performed recently revealed several important pathognomic mutations as potential targets in this disease. Routine diagnosis of patients now includes the use of (18)Fluor-deoxy-glucose positron emission computer tomography, according to the recent Lugano classification system. With all these data we can better predict the prognosis of patients, and we can select candidates for novel targeted therapies as well. Answering these questions, and utilizing novel therapies possibly will further increase the cure rate in the near future. This paper summarizes current diagnostic and therapeutic approaches and describes recent understanding in the mutations and pathognomic changes resulting in the disease. The authors also summarize the data available on experimental therapies possibly entering clinical pratice in the forthcoming years. Orv. Hetil., 2016, 157(31), 1232-1241. PMID:27476519

  19. T Cell/Histiocyte-Rich Large B Cell Lymphoma of the Thymus: A Diagnostic Pitfall

    PubMed Central

    Xu, Jie; Wu, Xiaojun; Reddy, Vishnu

    2016-01-01

    T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is predominantly a nodal disease, with extranodal involvement, such as bone marrow, spleen, and liver. However, primary THRLBCL has never been reported in the thymus in the English literature. Here we report a case of THRLBCL presenting as mediastinal mass and lymphadenopathy. Based on the frozen section diagnosis of “thymoma,” a 12 cm mass was excised. A year later she developed multiple enlarged lymph nodes and pulmonary nodules. Consultant review of the excised mediastinal mass showed scattered large atypical cells that were CD20+ and PAX-5+ and negative for pan-cytokeratin, AE1, and AE3, compatible with THRLBCL and excluding thymoma. The excised lymph nodes were replaced by diffuse infiltrate of small CD3+ lymphocytes and histiocytes with intermingled large CD20+ B lymphoma cells scattered throughout the section. A diagnosis of THRLBCL was made in lymph node, similar to previous thymic lesion. A clonal rearrangement of immunoglobulin heavy chain (IGH) gene was detected, further supporting the diagnosis. This is the first reported case of THRLBCL in thymus. Correct recognition of this entity is critical, because of the difference in therapeutic impact on these patients. PMID:26904321

  20. SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients

    PubMed Central

    Kohler, Christian W.; Bentink, Stefan; Kreuz, Markus; Melzner, Ingo; Ritz, Olga; Trümper, Lorenz; Loeffler, Markus; Spang, Rainer; Möller, Peter

    2013-01-01

    Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL. PMID:23296022

  1. Prognostic significance of immunophenotypes and a nodular pattern in primary mediastinal large B-cell lymphoma.

    PubMed

    Maeshima, Akiko Miyagi; Taniguchi, Hirokazu; Miyamoto, Ken-Ichi; Fukuhara, Suguru; Munakata, Wataru; Maruyama, Dai; Kim, Sung-Won; Kobayashi, Yukio; Tobinai, Kensei; Kushima, Ryoji

    2014-08-01

    To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival (PFS) rate was 78%, and the 4-year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6(+) (P = 0.013), MUM1(+) (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6(+) (P = 0.051) and MUM1(+) (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6(+) , MUM1(+) , Bcl2(-) , and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL. PMID:25143126

  2. Rituximab in the treatment of diffuse large B-cell lymphoma primary of the lung.

    PubMed

    Aviles, Agustin; Nambo, Maria J; Huerta-Guzman, Judith; Silva, Luis; Neri, Natividad

    2013-03-01

    Diffuse large B-cell lymphoma primary of lung (DLBCL-PL) is a rare presentation of extranodal lymphoma, in most cases chemotherapy-based anthracyclines: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment, with excellent outcome. The addition of rituximab to CHOP (R-CHOP) has been considered the gold standard in the treatment of nodal DLBCL. Thus, we assess in a large number of cases of DLBCL-PL whether the use of R-CHOP could improve survival in this setting of patients. Forty-two patients with DLBCL-PL, stage IE, age 65 years or younger, were treated with standard R-CHOP, no consolidation radiotherapy or maintenance therapy were considered. They were matched with patients who received CHOP alone to assess efficacy and toxicity. Complete response was observed in 35 patients (83%), and 7 patients were considered failure (16%). The study has a median follow-up of 42.8 months. Actuarial curves at 5 years showed that progression-free survival was 88 % and overall survival was 70 %. The results were not statistically different when compared retrospectively with patients who received CHOP alone. Treatment was well tolerated. The addition of rituximab to chemotherapy did not improve outcome in patients with DLBCL-PL. PMID:23394581

  3. Regulation of CD45-induced signaling by galectin-1 in Burkitt lymphoma B cells.

    PubMed

    Fouillit, M; Joubert-Caron, R; Poirier, F; Bourin, P; Monostori, E; Levi-Strauss, M; Raphael, M; Bladier, D; Caron, M

    2000-04-01

    It has been well established that Galectin-1 (GAL1), a beta-galactoside-binding protein, regulates the viability of lymphoid cells. However, the signaling pathway governed by the binding of GAL1 to the cell membrane is not understood. As a first step towards the elucidation of GAL1-initiated signaling events leading to a reduced viability of Burkitt lymphoma B cells, we tried to characterize the initial events induced by the binding of GAL1 to its receptor. This characterization was performed in BL36 cells, a Burkitt lymphoma cell line sensitive to GAL1. The results were as follows: (1) when solubilized cell membrane lysates were affinity bound to immobilized GAL1 and eluted by competition, the tyrosine phosphatase glyco-protein CD45 was found in the eluate, highlighting the role of CD45 as a receptor of GAL1; (2) the phosphatase activity of cell membranes diminished after incubation with GAL1; (3) immunoprecipitation experiments demonstrated that the phosphotyrosine kinase Lyn was dysregulated in cells that have been cultured in medium containing 700 nM GAL1, and (4) that the ratio between two isoforms of Lyn was modified during the treatment with GAL1. The regulation of Lyn therefore seems to be a key event in the action of GAL1.

  4. The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma

    PubMed Central

    Zhang, Jianqing; Medina-Cleghorn, Daniel; Bernal-Mizrachi, Leon; Bracci, Paige M.; Hubbard, Alan; Conde, Lucia; Riby, Jacques; Nomura, Daniel K.; Skibola, Christine F.

    2016-01-01

    Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m2; 118%, P < 0.001) compared to those with a BMI < 25 kg/m2. DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs. PMID:26973858

  5. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL.

  6. SILAC-Based Quantitative Proteomic Analysis of Diffuse Large B-Cell Lymphoma Patients

    PubMed Central

    Rüetschi, Ulla; Stenson, Martin; Hasselblom, Sverker; Nilsson-Ehle, Herman; Hansson, Ulrika; Fagman, Henrik; Andersson, Per-Ola

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a heterogeneous disease where the outcome for patients with early relapse or refractory disease is very poor, even in the era of immunochemotherapy. In order to describe possible differences in global protein expression and network patterns, we performed a SILAC-based shotgun (LC-MS/MS) quantitative proteomic analysis in fresh-frozen tumor tissue from two groups of DLBCL patients with totally different clinical outcome: (i) early relapsed or refractory and (ii) long-term progression-free patients. We could identify over 3,500 proteins; more than 1,300 were quantified in all patients and 87 were significantly differentially expressed. By functional annotation analysis on the 66 proteins overexpressed in the progression-free patient group, we found an enrichment of proteins involved in the regulation and organization of the actin cytoskeleton. Also, five proteins from actin cytoskeleton regulation, applied in a supervised regression analysis, could discriminate the two patient groups. In conclusion, SILAC-based shotgun quantitative proteomic analysis appears to be a powerful tool to explore the proteome in DLBCL tumor tissue. Also, as progression-free patients had a higher expression of proteins involved in the actin cytoskeleton protein network, such a pattern indicates a functional role in the sustained response to immunochemotherapy. PMID:26060582

  7. PET Scans for Staging and Restaging in Diffuse Large B-Cell and Follicular Lymphomas.

    PubMed

    Barrington, Sally F; Mikhaeel, N George

    2016-06-01

    Positron emission tomography (PET)-CT was recommended in updated international guidelines for staging/restaging of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In FL, PET was previously regarded as a research application only. This review concentrates on new publications related to PET in these diseases. In DLBCL, PET appears appropriate for staging using prognostic indices established with CT and baseline PET parameters, e.g. metabolic tumour volume, are prognostic of outcome. Early complete metabolic response (CMR) predicts end-of-treatment CMR with excellent prognosis. Patients without CMR at interim should not have treatment altered, but have a worse prognosis, and patients with other high risk features may need closer monitoring. The end-of-treatment scan is confirmed as the standard for remission assessment using Deauville criteria, which are also predictive for patients undergoing ASCT. In FL, PET is more sensitive for staging than CT but misses bone marrow involvement. PET-CT identifies patients at risk of progression after induction chemotherapy better than CT. PMID:27095319

  8. Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins.

    PubMed

    Montesinos-Rongen, Manuel; Purschke, Frauke G; Brunn, Anna; May, Caroline; Nordhoff, Eckhard; Marcus, Katrin; Deckert, Martina

    2015-08-01

    Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-α, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-κB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS. PMID:26116512

  9. Diffuse Large B-Cell Lymphoma of Maxilla – A Case Report of Late Relapse

    PubMed Central

    Kumar, Medikonda Suresh; Chandragiri, Anuradha; Amarnath, Konda

    2016-01-01

    Diffuse Large B Cell Lymphomas (DLBCL) encompasses a heterogeneous group of tumors that together constitute the commonest of all Non Hodgkin Lymphoma (NHL) and the proclivity of DLBCL to oral cavity is unknown. They mostly arise from soft tissues as asymptomatic lesions, mostly without ‘B’ symptoms and involvement of jaw bones is uncommon. Most studies and case reports of oral DLBCL’s are based on, manifestation of primary extra-nodal disease or a component of a disseminated disease process involving regional lymph nodes. Many investigators have proposed that patients with this cell type who maintain a complete response for 24 consecutive months are cured because late relapses seldom occur. With advances in treatment modalities, many patients with NHL become long-term survivors and the risk of relapses or second tumors are of growing concern. We present a case of DLBCL which relapsed after five years of initial lesion in a 41 year old female patient and presented as a nonspecific bilateral anterior maxillary radiolucency. DLBCL usually express pan-B markers with small percentage expressing T-cell markers. Few rare cases of DLBCL have shown CD3 expression, which is a most sensitive T-cell marker which was focally expressed in the present case. PMID:27190967

  10. Improving outcomes for patients with diffuse large B-cell lymphoma.

    PubMed

    Flowers, Christopher R; Sinha, Rajni; Vose, Julie M

    2010-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world. Until the mid 1990s the incidence of DLBCL increased in both sexes, across racial categories, and across all age groups except the very young, the etiology of most cases remains unknown. DLBCL is associated with an aggressive natural history, but it can be cured with combination chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which has been the mainstay of therapy for several decades. Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy. Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses, and the addition of the monoclonal antibody, rituximab, to CHOP has markedly improved outcomes. Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease.

  11. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  12. JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms

    PubMed Central

    Stupack, Dwayne G.; Bai, Nan; Xun, Jing; Ren, Guosheng; Han, Jihong; Li, Luyuan; Luo, Yunping; Xiang, Rong; Tan, Xiaoyue

    2016-01-01

    JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes. PMID:27102442

  13. Diagnosis of a multifocal B cell lymphoma with preceding demyelinating central nervous system lesions by single voxel proton MR spectroscopy

    PubMed Central

    Kuhlmann, T; Schroter, A; Dechent, P; Weber, F; Rustenbeck, H; Fuzesi, L; Bruck, W; Ehrenreich, H; Frahm, J

    2001-01-01

    Single voxel proton magnetic resonance spectroscopy (MRS) provides a rapid non-invasive fingerprint of tissue chemistry. A case history is presented in which a B cell lymphoma with antecedent demyelinating lesions of the CNS was suspected by MRS and confirmed by neuropathological examination and immunoglobulin gene rearrangement.

 PMID:11160483

  14. Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing | Office of Cancer Genomics

    Cancer.gov

    Abstract: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer comprising at least two molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease.

  15. Prospective Study of FLT PET for Early Interim Response Assessment in Advanced Stage B-cell Lymphoma

    PubMed Central

    Schöder, Heiko; Zelenetz, Andrew D.; Hamlin, Paul; Gavane, Somali; Horwitz, Steven; Matasar, Matthew; Moskowitz, Alison; Noy, Ariela; Palomba, Lia; Portlock, Carol; Straus, David; Grewal, Ravinder; Migliacci, Jocelyn C.; Larson, Steven M.; Moskowitz, Craig H.

    2016-01-01

    Purpose Current clinical and imaging tools remain suboptimal for early assessment of prognosis and treatment response in aggressive lymphomas. Positron emission tomography (PET) with 18F-fluorothymidine (FLT) can be used to measure tumor cell proliferation and treatment response. In a prospective study in patients with advanced stage B-cell lymphoma we investigated the prognostic and predictive value of FLT PET in comparison to standard imaging with FDG PET and clinical outcome. Patients and Methods 65 patients were treated with an induction/consolidation regimen consisting of four cycles of R-CHOP-14 followed by 3 cycles of ICE. FLT PET was performed at baseline and at interim (iPET) after 1–2 cycles of therapy. FDG PET was performed at baseline, after cycle 4, and at the end of therapy. The relationship between PET findings, progression free survival (PFS) and overall survival (OS) was investigated. Results With a median follow-up of 51 months, PFS and OS were 71% and 86% respectively. FLT iPET, analyzed visually, using a 5-point score, or semi-quantitatively, using SUV and ΔSUV, predicted both PFS and OS (p<0.01 for all parameters). Residual FLT SUVmax on iPET was associated with an inferior PFS (HR: 1.26, p=0.001) and OS (HR: 1.27, p=0.002). Using FDG PET, findings in the end of treatment scan were better predictors of PFS and OS than findings on interim scan. Baseline PET imaging parameters, including SUV, proliferative or metabolic tumor volume, did not correlate with outcome. Conclusion FLT PET after 1–2 cycles of chemotherapy predicts PFS and OS, and a negative FLT iPET may potentially help design risk-adapted therapies in patients with aggressive lymphomas. In contrast, the positive predictive value of FLT iPET remains too low to justify changes in patient management. PMID:26719374

  16. B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma.

    PubMed

    van der Velden, Vincent H J; Hoogeveen, Patricia G; de Ridder, Dick; Schindler-van der Struijk, Magdalena; van Zelm, Menno C; Sanders, Mathijs; Karsch, Dennis; Beverloo, H Berna; Lam, King; Orfao, Alberto; Lugtenburg, Pieternella J; Böttcher, Sebastian; van Dongen, Jacques J M; Langerak, Anton W; Kappers-Klunne, Mies; van Lom, Kirsten

    2014-07-17

    B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell malignancy that may be hard to distinguish from mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). B-PLL cases with a t(11;14) were redefined as MCL in the World Health Organization 2008 classification. We evaluated 13 B-PLL patients [7 being t(11;14)-positive (B-PLL+) and 6 negative (B-PLL-)] and compared them with MCL and CLL patients. EuroFlow-based immunophenotyping showed significant overlap between B-PLL+ and B-PLL-, as well as between B-PLL and MCL, whereas CLL clustered separately. Immunogenotyping showed specific IGHV gene usage partly resembling MCL. Gene expression profiling showed no separation between B-PLL+ and B-PLL- but identified 3 subgroups. One B-PLL subgroup clustered close to CLL and another subgroup clustered with leukemic MCL; both were associated with prolonged survival. A third subgroup clustered close to nodal MCL and was associated with short survival. Gene expression profiles of both B-PLL+ and B-PLL- showed best resemblance with normal immunoglobulin M-only B-cells. Our data confirm that B-PLL+ is highly comparable to MCL, indicate that B-PLL- also may be considered as a specific subgroup of MCL, and suggest that B-PLL is part of a spectrum, ranging from CLL-like B-PLL, to leukemic MCL-like B-PLL, to nodal MCL-like B-PLL.

  17. Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis.

    PubMed

    Scholtysik, René; Kreuz, Markus; Hummel, Michael; Rosolowski, Maciej; Szczepanowski, Monika; Klapper, Wolfram; Loeffler, Markus; Trümper, Lorenz; Siebert, Reiner; Küppers, Ralf

    2015-03-01

    The pathogenesis of diffuse large B-cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)-chips to characterize genomic imbalances. Seventy-nine cases were of the germinal center B-cell like (GCB) type of DLBCL, 49 of the activated B-cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty-four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC-DLBCL and 19 per case for GCB-DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB- and ABC-DLBCL subgroups, including gains of HDAC7A predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC-DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance.

  18. Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma

    PubMed Central

    Green, Michael R; Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Liu, Chih Long; Dai, Bo; González-Herrero, Inés; García-Ramírez, Idoia; Alonso-Escudero, Esther; Iqbal, Javeed; Chan, Wing C; Campos-Sanchez, Elena; Orfao, Alberto; Pintado, Belén; Flores, Teresa; Blanco, Oscar; Jiménez, Rafael; Martínez-Climent, Jose Angel; Criado, Francisco Javier García; Cenador, María Begoña García; Zhao, Shuchun; Natkunam, Yasodha; Lossos, Izidore S; Majeti, Ravindra; Melnick, Ari; Cobaleda, César; Alizadeh, Ash A.; Sánchez-García, Isidro

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal center B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human hematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by hit-and-run oncogenesis. We model this by transiently expressing Bcl6 within murine HSPCs, and find it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together these results suggest that Bcl6 may function in a hit-and-run role in lymphomagenesis. PMID:24887457

  19. Next generation sequencing and the management of diffuse large B-cell lymphoma: from whole exome analysis to targeted therapy.

    PubMed

    Jardin, Fabrice

    2014-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the IGH gene and the deregulation of rearranged oncogenes. Recent advances in next generation sequencing (NGS) have provided a vast and comprehensive catalogue of cancer genes involved in DLBCL pathogenesis. Whole exome sequencing (WES) of more than two hundred DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities for the germinal center B-cell like (GCB), activated B-cell like (ABC), or primary mediastinal B-cell (PMBL) molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (BCR signaling, NF-κB pathway, NOTCH signaling, Toll-like receptor signaling, and the PI3K pathway), immunity, cell cycle/apoptosis, or chromatin modification. In this review, we present an overview of the mutations recently discovered by NGS in DLBCL and discuss their biological relevance and possible impacts on clinical management. PMID:25091488

  20. Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma.

    PubMed

    Green, Michael R; Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Long Liu, Chih; Dai, Bo; González-Herrero, Inés; García-Ramírez, Idoia; Alonso-Escudero, Esther; Iqbal, Javeed; Chan, Wing C; Campos-Sanchez, Elena; Orfao, Alberto; Pintado, Belén; Flores, Teresa; Blanco, Oscar; Jiménez, Rafael; Martínez-Climent, Jose Angel; Criado, Francisco Javier García; Cenador, María Begoña García; Zhao, Shuchun; Natkunam, Yasodha; Lossos, Izidore S; Majeti, Ravindra; Melnick, Ari; Cobaleda, César; Alizadeh, Ash A; Sánchez-García, Isidro

    2014-06-02

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by 'hit-and-run' oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a 'hit-and-run' role in lymphomagenesis.

  1. Bilateral Bronchiectasis as a Presentation Form of Pulmonary Marginal Zone B-Cell Lymphoma of Bronchus Associated Lymphoid Tissue

    PubMed Central

    Ernst, Glenda; Torres, Carla; Borsini, Eduardo; Vigovich, Félix; Downey, Daniel; Salvado, Alajandro; Bosio, Martín

    2015-01-01

    The pulmonary marginal zone B-cell lymphoma of bronchus associated lymphoid tissue of the lung (BALT) is a rare illness that can remain without symptoms. Radiological findings of pulmonary lymphoma are heterogeneous. In literature, bronchiectasis is only described in one patient who also had besides adenomegalies. We reported on a 48-year-old female patient. She showed symptoms consistent with dyspnea with productive cough; there were crepitant sounds in the auscultation. Pulmonary functional test has shown a severe restrictive pattern with a low FVC and DLCO. CT scan showed bronchiectasis in the medium lobule without adenomegalies. Echocardiogram was normal, and the laboratory findings only showed leukocytosis. There were no findings in the bronchoscopy, but the lung biopsy showed a B-cell pulmonary lymphoma (positive to CD20 and CD79a in immunostaining). A wide variety of radiological manifestations has been previously described; however, we have presented this rare case, with bronchiectasis, as unique radiological finding. PMID:26839723

  2. Clinicopathological features of primary hepatic diffuse large B-cell lymphoma: a report of seven cases and a literature review

    PubMed Central

    Zheng, Jinfeng; Hou, Yiliang; Zhou, Ruting; Zhong, Dingrong

    2015-01-01

    We studied the imaging and histopathological features of primary hepatic diffuse large B-cell lymphoma in order to explore the clinicopathological features, diagnosis, differential diagnoses, and treatment. Immunolabelling was performed in seven cases of primary hepatic diffuse large B-cell lymphoma using histological and immunohistochemical techniques. The clinical manifestations; imaging, histopathological, and immunohistochemical features; treatment; and prognosis of primary hepatic diffuse large B-cell lymphoma were observed and analyzed in light of the relevant literature. The average age of the seven patients was 63.4 years. Moreover, bulge of the upper right abdomen and progressive athrepsia and anemia were observed in all seven patients. Computed tomography (CT) revealed the presence of multiple solid hypodense lesions. Further, CT also revealed an enhanced irregular focus. Histopathological analysis revealed the following characteristics: heavy infiltration composed mainly of medium-sized round cells with a lightly stained cytoplasm, prominent nucleoli and vesicular nuclei, nuclear fission and visible sky star phenomena. The tumor cells showed diffuse expression of CD19, CD20, and CD79a, with the percentage of Ki67-positive cells being 75%-80%. All these findings indicated that primary hepatic diffuse large B-cell lymphoma is rare and generally has a poor prognosis. Biopsy and immunohistochemical staining are helpful in its diagnosis. Further, the differential diagnoses include secondary liver diffuse large B-cell lymphoma, low/undifferentiated cancer of the liver, hepatoblastoma, leukemia of the liver, and other tumors. Early surgery and chemotherapy can have a good curative effect. PMID:26722490

  3. Isolated sciatic neuropathy as an initial manifestation of a high grade B-cell lymphoma: A case report and literature review.

    PubMed

    He, Wenzhuan; Wang, Weizhen; Gustas, Cristy; Malysz, Jozef; Kaur, Divpreet

    2016-10-01

    Sciatic nerve neuropathy due to infiltrating of a high grade B-cell lymphoma is a very rare situation and has not often been reported. We report a case with a previous history of indolent lymphoma who presented with isolated sciatic nerve neuropathy and was found to have diffuse large B cell lymphoma involving the sciatic nerve. Although the current case is not a primary sciatic nerve lymphoma given the systematic involvement shown on MRI and PET/CT scan, the case represents a neurolymphomatosis of the sciatic nerve given the direct invasion of the lymphoma cells into the sciatic nerve. Due to the rarity of this condition, we subsequently reviewed related literatures.

  4. A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

    PubMed

    Salaverria, Itziar; Martin-Guerrero, Idoia; Wagener, Rabea; Kreuz, Markus; Kohler, Christian W; Richter, Julia; Pienkowska-Grela, Barbara; Adam, Patrick; Burkhardt, Birgit; Claviez, Alexander; Damm-Welk, Christine; Drexler, Hans G; Hummel, Michael; Jaffe, Elaine S; Küppers, Ralf; Lefebvre, Christine; Lisfeld, Jasmin; Löffler, Markus; Macleod, Roderick A F; Nagel, Inga; Oschlies, Ilske; Rosolowski, Maciej; Russell, Robert B; Rymkiewicz, Grzegorz; Schindler, Detlev; Schlesner, Matthias; Scholtysik, René; Schwaenen, Carsten; Spang, Rainer; Szczepanowski, Monika; Trümper, Lorenz; Vater, Inga; Wessendorf, Swen; Klapper, Wolfram; Siebert, Reiner

    2014-02-20

    The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.

  5. A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

    PubMed

    Salaverria, Itziar; Martin-Guerrero, Idoia; Wagener, Rabea; Kreuz, Markus; Kohler, Christian W; Richter, Julia; Pienkowska-Grela, Barbara; Adam, Patrick; Burkhardt, Birgit; Claviez, Alexander; Damm-Welk, Christine; Drexler, Hans G; Hummel, Michael; Jaffe, Elaine S; Küppers, Ralf; Lefebvre, Christine; Lisfeld, Jasmin; Löffler, Markus; Macleod, Roderick A F; Nagel, Inga; Oschlies, Ilske; Rosolowski, Maciej; Russell, Robert B; Rymkiewicz, Grzegorz; Schindler, Detlev; Schlesner, Matthias; Scholtysik, René; Schwaenen, Carsten; Spang, Rainer; Szczepanowski, Monika; Trümper, Lorenz; Vater, Inga; Wessendorf, Swen; Klapper, Wolfram; Siebert, Reiner

    2014-02-20

    The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q. PMID:24398325

  6. Malignant hematopoietic cell lines: in vitro models for the study of primary mediastinal B-cell lymphomas.

    PubMed

    Drexler, Hans G; Ehrentraut, Stefan; Nagel, Stefan; Eberth, Sonja; MacLeod, Roderick A F

    2015-01-01

    Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive disease with a unique set of biological, clinical, morphological, immunological and in particular genetic features that in the molecular era of defining lymphomas clearly distinguishes it as a separate entity from other diffuse large B-cell lymphomas (DLBCL). A precise molecular diagnosis of PMBL can be achieved by gene expression profiling. The signature gene expression profile of PMBL is more closely related to classic Hodgkin lymphoma (cHL) than to other DLBCL subgroups. A number of common genetic aberrations in PMBL and cHL further underscore their close relationship. To investigate the pathobiology of lymphomas in depth, many groups have turned to cell lines that are suitable models facilitating molecular studies and providing unique insights. For the purposes of the current perspective, we focus on four bona fide PMBL-derived cell lines (FARAGE, KARPAS-1106, MEDB-1, U-2940) that we identified and validated as such through hierarchical cluster analysis among a large collection of leukemia-lymphoma cell lines. These gene expression profiles showed that the four PMBL cell lines represent a distinct entity and are most similar to cHL cell lines, confirming derivation from a related cell type. A validated cell line resource for PMBL should assist those seeking druggable targets in this entity. This review aims to provide a comprehensive overview of the currently available cellular models for the study of PMBL. PMID:25480038

  7. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising in the lateral ventricle.

    PubMed

    Kelley, Todd W; Prayson, Richard A; Barnett, Gene H; Stevens, Glen H J; Cook, James R; Hsi, Eric D

    2005-10-01

    Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas are a well-described type of low-grade B-cell non-Hodgkin lymphoma. They typically arise adjacent to mucosal surfaces in the gastrointestinal tract, lung and conjunctiva, and, less frequently, in the skin, salivary gland and thyroid gland. Unusual locations, such as the genitourinary tract, thymus and meninges, have also been reported. We recently encountered a case of an intracranial MALT lymphoma in a 53-year-old man who presented with persistent headaches and a seizure. The lesion developed as a mass within the lateral ventricle, appeared to be arising from the choroid plexus, and was not associated with meninges. Histologically, there was a vaguely nodular, dense lymphoid infiltrate with occasional benign follicles colonized by marginal zone lymphoma, suggesting derivation from a focus of prior inflammation. Translocations involving the MALT1 gene were not identified but karyotypic evaluation highlighted a complex cytogenetic profile with many chromosomal abnormalities. This rare case provides insight into the pathophysiology of MALT lymphomas.

  8. Differential expression of Toll-like receptor (TLR) and B cell receptor (BCR) signaling molecules in primary diffuse large B-cell lymphoma of the central nervous system.

    PubMed

    Akhter, Ariz; Masir, Noraidah; Elyamany, Ghaleb; Phang, Kean-Chang; Mahe, Etienne; Al-Zahrani, Ali Matar; Shabani-Rad, Meer-Taher; Stewart, Douglas Allan; Mansoor, Adnan

    2015-01-01

    Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a distinct and aggressive lymphoma that is confined to CNS. Since, central nervous system is barrier-protected and immunologically silent; role of TLR/BCR signaling in pathogenesis and biology of CNS DLBCL is intriguing. Genomic mutations in key regulators of TLR/BCR signaling pathway (MYD88/CD79B/CARD11) have recently been reported in this disease. These observations raised possible implications in novel targeted therapies; however, expression pattern of molecules related to TLR/BCR pathways in this lymphoma remains unknown. We have analyzed the expression of 19 genes encoding TLR/BCR pathways and targets in CNS DLBCLs (n = 20) by Nanostring nCounter™ analysis and compared it with expression patterns in purified reactive B-lymphocytes and systemic diffuse large B cell lymphoma (DLBCL) (n = 20). Relative expression of TLR4, TLR5, TLR9, CD79B and BLNK was higher in CNS DLBCLs than in control B-lymphocytes; where as TLR7, MALT1, BCL10, CD79A and LYN was lower in CNS DLBCLs (P < 0.0001). When compared with systemic DLBCL samples, higher expression of TLR9, CD79B, CARD11, LYN and BLNK was noted in CNS DLBCL (>1.5 fold change; P < 0.01). The B cell receptor molecules like BLNK and CD79B were also associated with higher expression of MYD88 dependent TLRs (TLR4/5/9). In conclusion, we have shown over expression of TLR/BCR related genes or their targets, where genomic mutations have commonly been identified in CNS DLBCL. We have also demonstrated that TLR over expression closely relate with up regulation of genes associated with BCR pathway like CD79B/BLNK and CARD11, which play an important role in NF-kB pathway activation. Our results provide an important insight into the possibility of TLR and/or B-cell receptor signaling molecules as possible therapeutic targets in CNS DLBCL. PMID:25391967

  9. BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

    PubMed Central

    Iqbal, Javeed; Sanger, Warren G.; Horsman, Douglas E.; Rosenwald, Andreas; Pickering, Diane L.; Dave, Bhavana; Dave, Sandeep; Xiao, Li; Cao, Kajia; Zhu, Quiming; Sherman, Simon; Hans, Christine P.; Weisenburger, Dennis D.; Greiner, Timothy C.; Gascoyne, Randy D.; Ott, German; Müller-Hermelink, H. Konrad; Delabie, Jan; Braziel, Rita M.; Jaffe, Elaine S.; Campo, Elias; Lynch, James C.; Connors, Joseph M.; Vose, Julie M.; Armitage, James O.; Grogan, Thomas M.; Staudt, Louis M.; Chan, Wing C.

    2004-01-01

    Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup. PMID:15215171

  10. NFκB expression is a feature of both activated B-cell-like and germinal center B-cell-like subtypes of diffuse large B-cell lymphoma.

    PubMed

    Odqvist, Lina; Montes-Moreno, Santiago; Sánchez-Pacheco, Roxana E; Young, Ken H; Martín-Sánchez, Esperanza; Cereceda, Laura; Sánchez-Verde, Lydia; Pajares, Raquel; Mollejo, Manuela; Fresno, Manuel F; Mazorra, Francisco; Ruíz-Marcellán, Carmen; Sánchez-Beato, Margarita; Piris, Miguel A

    2014-10-01

    The activation of nuclear factor kappa B (NFκB) transcription factor family is considered to have a key role in diffuse large B-cell lymphoma (DLBCL) pathogenesis and is associated with a specific molecular subtype, the activated B-cell-like (ABC) subtype. We evaluated the expression of NFκB by immunohistochemistry in a large series of DLBCL cases. The five different NFκB family members (NFκB1, NFκB2, RELA, RELB, and REL) showed a heterogeneous expression pattern with the vast majority of cases being positive for at least one factor. Two independent series of tumor samples were classified into germinal center B-cell-like (GCB) or ABC subtypes using different approaches, immunohistochemistry, or gene expression profiling, and the expression of NFκB family members was assessed. Notably, no significant differences regarding the expression of the different NFκB members were detected between the two subtypes, suggesting that NFκB signaling is a prominent feature not only in the ABC subtype, but also in the GCB tumors. Of the five transcription factors, only REL expression had a significant clinical impact on R-CHOP-treated diffuse large B-cell lymphoma, identifying a subgroup of patients with superior clinical outcome.

  11. The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma

    PubMed Central

    Hunter, J E; Butterworth, J A; Zhao, B; Sellier, H; Campbell, K J; Thomas, H D; Bacon, C M; Cockell, S J; Gewurz, B E; Perkins, N D

    2016-01-01

    The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel–/– mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel–/– Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel–/– Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel–/– TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel–/– mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF

  12. Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas

    PubMed Central

    2012-01-01

    Background Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL). Methodology The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL). Results αIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by αIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The αIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses

  13. Inactivating Mutations in GNA13 and RHOA in Burkitt’s Lymphoma and Diffuse Large B cell Lymphoma: A Tumor Suppressor Function for the Gα13/RhoA Axis in B Cells

    PubMed Central

    O’Hayre, Morgan; Inoue, Asuka; Kufareva, Irina; Wang, Zhiyong; Mikelis, Constantinos M.; Drummond, Rebecca A.; Avino, Silvia; Finkel, Kira; Kalim, Khalid; DiPasquale, Giovanni; Guo, Fukun; Aoki, Junken; Zheng, Yi; Lionakis, Michail S.; Molinolo, Alfredo A.; Gutkind, J. Silvio

    2015-01-01

    G-proteins and their cognate G-protein coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G-proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G-protein Gα13, in Burkitt’s lymphoma and Diffuse Large B cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt’s lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild type Gα13 in B cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt’s lymphoma and DLBCL. PMID:26616858

  14. Case Report of Diffuse Large B Cell Lymphoma of Uterine Cervix Treated at a Semiurban Cancer Centre in North India.

    PubMed

    Sharma, Vibhor; Dora, Tapas; Patel, Mehul; Sancheti, Sankalp; Sridhar, Epari

    2016-01-01

    Lymphoma of the uterine cervix is very rare. We report a case of diffuse large B cell lymphoma (DLBCL) involving the uterine cervix treated at a newly commissioned semiurban cancer centre in north India in 2015. Data for this study was obtained from the hospital electronic medical records and the patient's case file. We also reviewed published case reports of uterine and cervical lymphoma involving forty-one patients. We treated a case of stage IV DLBCL cervix with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and intrathecal methotrexate followed by consolidation with radiotherapy. The patient showed complete response to chemotherapy. We conclude that, in advanced stage lymphoma involving uterus and cervix, combination of chemotherapy and radiotherapy is effective in short term. PMID:27597906

  15. Molecular subtyping of diffuse large B-cell lymphoma: update on biology, diagnosis and emerging platforms for practising pathologists.

    PubMed

    Gifford, Grace K; Gill, Anthony J; Stevenson, William S

    2016-01-01

    Molecular classification of diffuse large B-cell lymphoma (DLBCL) is critical. Numerous methodologies have demonstrated that DLBCL is biologically heterogeneous despite morphological similarities. This underlies the disparate outcomes of treatment response or failure in this common non-Hodgkin lymphoma. This review will summarise historical approaches to lymphoma classifications, current diagnosis of DLBCL, molecular techniques that have primarily been used in the research setting to distinguish and subclassify DLBCL, evaluate contemporary diagnostic methodologies that seek to translate lymphoma biology into clinical practice, and introduce novel diagnostic platforms that may overcome current issues. The review concludes with an overview of key molecular lesions currently identified in DLBCL, all of which are potential targets for drug treatments that may improve survival and cure.

  16. Case Report of Diffuse Large B Cell Lymphoma of Uterine Cervix Treated at a Semiurban Cancer Centre in North India

    PubMed Central

    Sridhar, Epari

    2016-01-01

    Lymphoma of the uterine cervix is very rare. We report a case of diffuse large B cell lymphoma (DLBCL) involving the uterine cervix treated at a newly commissioned semiurban cancer centre in north India in 2015. Data for this study was obtained from the hospital electronic medical records and the patient's case file. We also reviewed published case reports of uterine and cervical lymphoma involving forty-one patients. We treated a case of stage IV DLBCL cervix with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and intrathecal methotrexate followed by consolidation with radiotherapy. The patient showed complete response to chemotherapy. We conclude that, in advanced stage lymphoma involving uterus and cervix, combination of chemotherapy and radiotherapy is effective in short term. PMID:27597906

  17. Retrospective analysis of protein kinase C-beta (PKC-β) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas

    PubMed Central

    Li, Shuyu; Phong, Mark; Lahn, Michael; Brail, Leslie; Sutton, Susan; Lin, Boris K; Thornton, Donald; Liao, Birong

    2007-01-01

    Background Both mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, particularly in B-cell malignancies. To evaluate the role of this gene in lymphoid malignancies, we analyzed global gene expression data to quantify PKC-β expression across diagnostic groups and, when possible, determined correlations between PKC-β expression and survival. Results Our analysis showed that the level of PKC-β expression was highest in chronic lymphocytic leukemia and follicular lymphoma. Within diffuse large-B cell lymphoma (DLBCL), PKC-β expression was significantly higher in activated B-cell- like subtype than germinal center B-cell- like subtype (P < 0.0001). Elevated PKC-β appeared to be associated with worse survival in both of these subtypes. When analyzed within clinically defined risk groups established by the International Prognostic Index (IPI), PKC-β expression was lowest in patients with low IPI scores (0–1). Within intermediate- and high-risk IPI groups, elevated PKC-β expression was associated with worse survival, suggesting that PKC-β may expand the prognostic value of the IPI. Results of global gene expression analyses of DLBCL samples corroborate previous observations that anti-apoptosis, cell proliferation, and B-cell proliferation signaling pathways are functionally related to PKC-β. Conclusion We present a first detailed pharmacogenomics report comparing PKC-β mRNA expression across different lymphoid malignancies and evaluating it as an outcome predictor. Our findings suggest that DLBCL patients with elevated PKC-β have a worse prognosis, indicating that further evaluation of PKC-β as a chemotherapeutic target for lymphoid malignancies is warranted. Reviewers This article was reviewed by Dr. Pierre Pontarotti, Dr. Kateryna Makova, and Dr. Matthew Coleman (nominated by Dr. Sandrine Dudoit). PMID:17313671

  18. Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.

    PubMed

    Koues, Olivia I; Kowalewski, Rodney A; Chang, Li-Wei; Pyfrom, Sarah C; Schmidt, Jennifer A; Luo, Hong; Sandoval, Luis E; Hughes, Tyler B; Bednarski, Jeffrey J; Cashen, Amanda F; Payton, Jacqueline E; Oltz, Eugene M

    2015-01-20

    Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.

  19. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas.

    PubMed

    Kluiver, Joost; Poppema, Sibrand; de Jong, Debora; Blokzijl, Tjasso; Harms, Geert; Jacobs, Susan; Kroesen, Bart-Jan; van den Berg, Anke

    2005-10-01

    In a previous study we demonstrated high expression of the non-coding BIC gene in the vast majority of Hodgkin's lymphomas (HLs). Evidence suggesting that BIC is a primary microRNA transcript containing the mature microRNA-155 (miR-155) as part of a RNA hairpin is now accumulating. We therefore analysed HL cell lines and tissue samples to determine whether miR-155 is also expressed in HL. High levels of miR-155 could be demonstrated, indicating that BIC is processed into a microRNA in HL. Most non-HL subtypes were negative for BIC as determined by RNA-ISH. However, in diffuse large B cell lymphoma (DLBCL) and primary mediastinal B cell lymphoma (PMBL), significant percentages of positive tumour cells were observed in 12/18 and 8/8 cases. A higher proportion of tumour cells were positive for BIC in DLBCL with activated B cell-like phenotype than in DLBCL with germinal centre B cell-like phenotype. Differential BIC expression was confirmed by qRT-PCR analysis. Northern blot analysis showed expression of miR-155 in all DLBCL and PMBL derived cell lines and tissue samples analysed. In summary, we demonstrate expression of primary microRNA BIC and its derivative miR-155 in HL, PMBL and DLBCL. PMID:16041695

  20. Nanoscale mapping and organization analysis of target proteins on cancer cells from B-cell lymphoma patients

    SciTech Connect

    Li, Mi; Xiao, Xiubin; Liu, Lianqing; Xi, Ning; Wang, Yuechao; Dong, Zaili; Zhang, Weijing

    2013-11-01

    CD20, a membrane protein highly expressed on most B-cell lymphomas, is an effective target demonstrated in clinical practice for treating B-cell non-Hodgkin's lymphoma (NHL). Rituximab is a monoclonal antibody against CD20. In this work, we applied atomic force microscopy (AFM) to map the nanoscale distribution of CD20 molecules on the surface of cancer cells from clinical B-cell NHL patients under the assistance of ROR1 fluorescence recognition (ROR1 is a specific cell surface marker exclusively expressed on cancer cells). First, the ROR1 fluorescence labeling experiments showed that ROR1 was expressed on cancer cells from B-cell lymphoma patients, but not on normal cells from healthy volunteers. Next, under the guidance of ROR1 fluorescence, the rituximab-conjugated AFM tips were moved to cancer cells to image the cellular morphologies and detect the CD20-rituximab interactions on the cell surfaces. The distribution maps of CD20 on cancer cells were constructed by obtaining arrays of (16×16) force curves in local areas (500×500 nm{sup 2}) on the cell surfaces. The experimental results provide a new approach to directly investigate the nanoscale distribution of target protein on single clinical cancer cells. - Highlights: • Cancer cells were recognized from healthy cells by ROR1 fluorescence labeling. • The nanoscale distribution of CD20 on cancer cells was characterized. • The distribution of CD20 was non-uniform on the surface of cancer cells.

  1. Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

    PubMed

    Mito, Takayuki; Kikkawa, Yoshiaki; Shimizu, Akinori; Hashizume, Osamu; Katada, Shun; Imanishi, Hirotake; Ota, Azusa; Kato, Yukina; Nakada, Kazuto; Hayashi, Jun-Ichi

    2013-01-01

    Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0)) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

  2. STAT6-mediated BCL6 repression in primary mediastinal B-cell lymphoma (PMBL)

    PubMed Central

    Ritz, Olga; Rommel, Karolin; Dorsch, Karola; Kelsch, Elena; Melzner, Julia; Buck, Michaela; Leroy, Karen; Papadopoulou, Vasiliki; Wagner, Simon; Marienfeld, Ralf; Brüderlein, Silke; Lennerz, Jochen K.; Möller, Peter

    2013-01-01

    Primary mediastinal B-cell lymphoma (PMBL) is characterized by aberrant activation of JAK/STAT-signaling resulting in constitutive presence of phosphorylated STAT6 (pSTAT6). In primary PMBL samples pSTAT6 is only expressed in a sub-population of lymphoma cells in a pattern that is reminiscent of that of the BCL6 oncogene. Double-fluorescence staining was carried out to determine the association between these two proteins in ten primary PMBL cases and three available PMBL cell line models. Surprisingly, only a minute fraction of double-positive nuclei was observed, while each sample contained considerable fractions of single-positive pSTAT6 and BCL6 nuclei. The intratumoral coexistence of BCL6+/pSTAT6− and BCL6−/pSTAT6+ subpopulations suggests a negative interaction between these factors. In silico screening of the STAT6 /BCL6 promoters for DNA consensus binding sites identified five STAT-binding-sites in the BCL6 promoter. We confirmed STAT6 binding to the BCL6 promoter in vitro and in vivo by band shift / super shift assays and chromatin immunoprecipitations. Using BCL6 luciferase reporter assays, depletion of STAT6 by siRNA, and ectopic overexpression of a constitutive active STAT6 mutant, we proved that pSTAT6 is sufficient to transcriptionally repress BCL6. Recently developed small molecule inhibitors 79-6 and TG101348 that increases BCL6 target gene expression and decreases pSTAT6 levels, respectively, demonstrate that a combined targeting results in additive efficacy regarding their negative effect on cell viability. The delineated pSTAT6-mediated molecular repression mechanism links JAK/STAT to BCL6-signaling in PMBL and may carry therapeutic potential. PMID:23852366

  3. STAT6-mediated BCL6 repression in primary mediastinal B-cell lymphoma (PMBL).

    PubMed

    Ritz, Olga; Rommel, Karolin; Dorsch, Karola; Kelsch, Elena; Melzner, Julia; Buck, Michaela; Leroy, Karen; Papadopoulou, Vasiliki; Wagner, Simon; Marienfeld, Ralf; Brüderlein, Silke; Lennerz, Jochen K; Möller, Peter

    2013-07-01

    Primary mediastinal B-cell lymphoma (PMBL) is characterized by aberrant activation of JAK/STAT-signaling resulting in constitutive presence of phosphorylated STAT6 (pSTAT6). In primary PMBL samples pSTAT6 is only expressed in a sub-population of lymphoma cells in a pattern that is reminiscent of that of the BCL6 oncogene. Double-fluorescence staining was carried out to determine the association between these two proteins in ten primary PMBL cases and three available PMBL cell line models. Surprisingly, only a minute fraction of double-positive nuclei was observed, while each sample contained considerable fractions of single-positive pSTAT6 and BCL6 nuclei. The intratumoral coexistence of BCL6+/pSTAT6- and BCL6-/pSTAT6+ subpopulations suggests a negative interaction between these factors. In silico screening of the STAT6 /BCL6 promoters for DNA consensus binding sites identified five STAT-binding-sites in the BCL6 promoter. We confirmed STAT6 binding to the BCL6 promoter in vitro and in vivo by band shift / super shift assays and chromatin immunoprecipitations. Using BCL6 luciferase reporter assays, depletion of STAT6 by siRNA, and ectopic overexpression of a constitutive active STAT6 mutant, we proved that pSTAT6 is sufficient to transcriptionally repress BCL6. Recently developed small molecule inhibitors 79-6 and TG101348 that increases BCL6 target gene expression and decreases pSTAT6 levels, respectively, demonstrate that a combined targeting results in additive efficacy regarding their negative effect on cell viability. The delineated pSTAT6-mediated molecular repression mechanism links JAK/STAT to BCL6-signaling in PMBL and may carry therapeutic potential. PMID:23852366

  4. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era

    PubMed Central

    Vaidya, R.; Witzig, T. E.

    2014-01-01

    Background The introduction of rituximab (R) to conventional CHOP chemotherapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) led to an unequivocal improvement in survival, establishing RCHOP as the standard of care. Still, nearly 40% of DLBCL patients will eventually die of relapsed disease. Efforts to improve outcomes by addition of new biologic agents (X) to the RCHOP backbone are underway. In this era of R(X)CHOP, it is imperative to develop prognostic and predictive markers, not only to identify patients who will suffer a particularly aggressive course, but also to accurately select patients for clinical trials from which they will most benefit. Design The following review was undertaken to describe prognostic factors in DLBCL, with emphasis on markers that are accurate, relatively available, and clinically applicable in 2014. Results The International Prognostic Index retains its validity in the era of RCHOP, although with limited ability to predict those with <50% chance of long-term survival. Gene expression profiling has provided novel insights into the biology of DLBCL and led to the development of immunohistochemistry (IHC) algorithms that are in routine practice. Identification of a ‘double-hit’ (DH) lymphoma by fluorescent in situ hybridization with aberrations involving MYC and/or BCL2 and BCL6 genes has important implications due to its extremely dismal prognosis with RCHOP. Other markers such as the absolute lymphocyte count (ALC), serum immunoglobulin free light chains, vitamin D levels, serum cytokines/chemokines, and imaging with positron emission tomography (PET) have all shown promise as future predictive/prognostic tests. Conclusions The future for new treatment options in DLBCL is promising with current clinical trials testing novel targeted agents such as bortezomib, lenalidomide, and ibrutinib as the ‘X’ in R(X)CHOP. Predictive factors are required to select and randomize patients appropriately for these trials. We

  5. Regulatory B cells correlate with HIV disease progression.

    PubMed

    Jiao, Yanmei; Wang, Xi; Zhang, Tong; Sun, Lijun; Wang, Rui; Li, Wei; Ji, Yunxia; Wu, Hao; Liu, Cuie

    2014-08-01

    A rare subset of IL-10-producing B cells, named Breg, was recently identified in mice and humans. Currently, there are no unified cell surface markers to identify Breg, and the relationship between the frequency of Breg and HIV disease progression in chronic HIV infection is unclear. In the present study, we determined whether the cell surface markers of Breg reported for other diseases are suitable for identifying Breg in HIV-infected patients. In addition, we examined the relationship between Breg and HIV disease progression. We found that Breg frequency correlated positively with viral load and negatively with CD4 count in chronic HIV infection. Following antiretroviral treatment, the CD4 count increased and the frequency of Breg decreased stepwise. There was no difference in IL-10 expression of CD1d(hi) or CD1d(lo) cells isolated from HIV-infected patients. Therefore, CD1d may not be a marker of Breg in HIV-infected patients.

  6. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas

    PubMed Central

    Ding, B. Belinda; Yu, J. Jessica; Yu, Raymond Y.-L.; Mendez, Lourdes M.; Shaknovich, Rita; Zhang, Yonghui; Cattoretti, Giorgio

    2008-01-01

    Diffuse large B-cell lymphoma (DLBCL) consists of at least 2 phenotypic subtypes; that is, the germinal center B-cell–like (GCB-DLBCL) and the activated B-cell–like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-κB, and tends to be refractory to chemotherapy. Here, we report that the STAT3 gene is a transcriptional target of BCL6. As a result, high-level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB, and Mcl-1, and increased expression of the cell- cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define a second oncogenic pathway, STAT3 activation, which operates in ABC-DLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas. PMID:17951530

  7. Large B-cell lymphoma in a dog: A cyto-histopathological evaluation and Immunophenotyping according to WHO classification for canine lymphomas

    PubMed Central

    Nikousefat, Zahra; Hashemnia, Mohammad; Javdani, Moosa

    2016-01-01

    In the present study, we described cyto-histopathological features and immunophenotyping of the large B-cell lymphoma in an 8-year-old mixed breed dog with applying the World Health Organization (WHO) system of classification of canine lymphomas. In fine-needle aspiration (FNA), lymph nodes were involved by neoplastic cells of intermediate to large size with deep blue cytoplasm; consist of centroblasts, immunoblast and medium-sized cells. Histopathologically, the follicles and sinuses of lymph nodes were replaced by sheets of numerous immunoblasts (less than 90.0% of total cells) and centroblasts. Numerous mitotic figures were also observed. Immunohistochemical analysis presented that the neoplastic cells express B-cell phenotype CD20 and CD79a, but do not stain for T phenotype CD3. On the basis of cytology, histopathology and immunohistochemical findings, the present tumor was diagnosed as diffuse large B-cell lymphoma, high-grade centroblastic type (DLBCL-CB) according to WHO histological classification. Applying this classification system for diagnosis of canine lymphomas is very useful and has a high accuracy and consistency. However, further co-operative studies between clinicians and pathologists should be performed, in order to improve the effectiveness of this classification. PMID:27226892

  8. Epstein-Barr Virus-Induced Gene 3 (EBI3): A Novel Diagnosis Marker in Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma

    PubMed Central

    Bastard, Christian; Picquenot, Jean-Michel; Couturier, Jérôme; Radford-Weiss, Isabelle; Dietrich, Céline; Brousse, Nicole; Vacher-Lavenu, Marie-Cécile; Devergne, Odile

    2011-01-01

    The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations. PMID:21931777

  9. miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients.

    PubMed

    Troppan, Katharina; Wenzl, Kerstin; Pichler, Martin; Pursche, Beata; Schwarzenbacher, Daniela; Feichtinger, Julia; Thallinger, Gerhard G; Beham-Schmid, Christine; Neumeister, Peter; Deutsch, Alexander

    2015-08-05

    Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR-16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma

  10. Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma

    PubMed Central

    Veal, Gareth J.; Cole, Michael; Chinnaswamy, Girish; Sludden, Julieann; Jamieson, David; Errington, Julie; Malik, Ghada; Hill, Christopher R.; Chamberlain, Thomas; Boddy, Alan V.

    2016-01-01

    Introduction Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology. Methods A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤18 years receiving cyclophosphamide (250 mg/m2), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed. Results A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m2, respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m2 versus 2.20 ± 0.31 L/h/m2, P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m2 versus 4.35 ± 0.37 L/h/m2, P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival. Conclusion The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome. PMID:26773420

  11. Is bone marrow biopsy always indicated in patients with primary cutaneous marginal zone B-cell lymphoma?

    PubMed

    Muniesa, C; Hernández-Machín, B

    2013-10-01

    Bone marrow involvement at the time of diagnosis is uncommon in patients with primary cutaneous marginal zone B-cell lymphoma (PCMZL). Moreover, in these patients such involvement is rarely found in isolation on diagnosis. Typically the few patients with PCMZL who have early bone marrow involvement also present secondary nodal or visceral involvement, which is detected by other staging studies (usually computed tomography). In recent years, this has given rise to some debate about whether a bone marrow biopsy should be routinely performed in patients diagnosed with PCMZL in view of the good prognosis and low incidence of bone marrow infiltration and/or extracutaneous involvement in this type of lymphoma.

  12. Jejunal stricture: a rare complication of chemotherapy in pediatric gastrointestinal B-cell non-Hodgkin lymphoma.

    PubMed

    Gupta, Gaurav; Agarwala, Sandeep; Thulkar, Sanjay; Shukla, Bhaskar; Bakhshi, Sameer

    2011-03-01

    The use of intensive chemotherapy has led to remarkable improvements in the treatment of high-grade B-cell Non-Hodgkin lymphoma (NHL); however, it is associated with significant side effects such as myelosuppression and mucositis. Gastrointestinal NHL rarely leads to the development of aneurysmal dilatation of the bowel, as desmoplastic reaction is not a feature of NHL. Strictures and fibrosis are not a manifestation of NHL involvement. Here, we report a child with primary gastrointestinal B-cell NHL who presented with jejunal stricture developing as a sequela of severe chemotherapy-induced mucositis. The patient improved with surgical resection of stricture and end-to-end anastomosis. PMID:21127430

  13. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

    PubMed

    Pizzi, Marco; Piazza, Francesco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A

    2015-03-30

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

  14. FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma.

    PubMed

    Walker, Matthew P; Stopford, Charles M; Cederlund, Maria; Fang, Fang; Jahn, Christopher; Rabinowitz, Alex D; Goldfarb, Dennis; Graham, David M; Yan, Feng; Deal, Allison M; Fedoriw, Yuri; Richards, Kristy L; Davis, Ian J; Weidinger, Gilbert; Damania, Blossom; Major, Michael B

    2015-02-03

    The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry-coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates β-catenin-dependent, Wnt-dependent gene expression. Gain- and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved enhancer of Wnt signaling. In a Wnt-dependent fashion, FOXP1 formed a complex with β-catenin, TCF7L2 (transcription factor 7-like 2), and the acetyltransferase CBP [CREB (adenosine 3',5'-monophosphate response element-binding protein)-binding protein], and this complex bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking β-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with β-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.

  15. Primary breast diffuse large B-cell lymphoma in the era of rituximab

    PubMed Central

    Zhang, Na; Cao, Caineng; Zhu, Yuan; Liu, Peng; Liu, Luying; Lu, Ke; Luo, Jialin; Zhou, Ning

    2016-01-01

    Background and objective The aim of this study was to summarize the clinical characteristics and evaluate the management approaches of primary breast diffuse large B-cell lymphoma (DLBCL) in the era of rituximab. Patients and methods A total of 24 female patients with newly diagnosed primary breast DLBCL treated between April 2006 and May 2013 were analyzed retrospectively. Ten patients (41.7%) received rituximab. Results For the whole group, the median age was 50 years (range 24–69 years). All patients had the disease detected with a palpable mass. The estimated 5-year overall survival and progression-free survival (PFS) rates of all the patients were 78.9% and 79.2%, respectively. A nonstatistically significant increase in PFS and overall survival was observed when rituximab was administered (5-year PFS: 90% vs 71.4%, P=0.285; 5-year overall survival: 90% vs 71.4%, P=0.239). Conclusion Primary breast DLBCL appears to be a rare disease. Adding rituximab might improve survival in patients with primary breast DLBCL. Further prospective studies are needed to evaluate the role of rituximab for primary breast DLBCL. PMID:27785056

  16. Treatment of nonepitheliotropic cutaneous B-cell lymphoma in an umbrella cockatoo (Cacatua alba).

    PubMed

    Rivera, Samuel; McClearen, James R; Reavill, Drury R

    2009-12-01

    A 3.5-year-old umbrella cockatoo (Cacatua alba) was presented because of the development of widely disseminated subcutaneous nodules. The diagnostic work-up included a complete blood count, plasma biochemical analysis, and whole body radiographs. Biopsy samples of the skin lesions were submitted for histopathologic evaluation, bacterial culture and sensitivity testing, immunohistochemistry staining, and acid-fast staining. The diagnosis was nonepitheliotropic cutaneous B-cell lymphoma with a leukemic blood picture. The bird was treated with a chemotherapeutic regimen consisting of vincristine and chlorambucil for 17 weeks. During treatment, the complete blood count was monitored every 1-3 weeks, and the plasma biochemical analysis was monitored every 3-4 weeks. The bird was in partial remission on week 9. On week 17, the bird became acutely ill and was fluffed, depressed, anorectic, and anemic. The chemotherapeutic regimen was discontinued. At this time, the bird had a consistent lymphocytosis but no neoplastic lymphocytes were seen in the general circulation. At week 29 the bird was in complete remission and remains in complete remission 8 years after chemotherapy was discontinued. PMID:20235461

  17. Intravascular Large B-Cell Lymphoma Coexisting with an Ovarian Carcinoma.

    PubMed

    Uchiyama, Tomoko; Nakamine, Hirokazu; Morita, Kohei; Itami, Hiroe; Nakai, Tokiko; Takano, Masato; Takeda, Maiko; Hatakeyama, Kinta; Takahama, Junko; Tanase, Yasuhito; Kobayashi, Hiroshi; Ohbayashi, Chiho

    2016-01-01

    We report an incidental case of intravascular large B-cell lymphoma (IVLBCL) coexisting with an ovarian carcinoma in a 76-year-old woman. She visited our hospital with difficulty in defecation. Magnetic resonance imaging and computerized tomography scan revealed a solid and cystic mass probably arising from the left ovary. Gross examination of the tumor obtained by an exploratory surgery showed a solid area in a simple cyst. The ovarian tumor was diagnosed as a high-grade serous carcinoma (HGSC). Early in the post-operative course, this patient developed fever of unknown origin with central nervous system manifestations. Magnetic resonance imaging of the brain showed multiple space-occupying lesions. When we reviewed the histological sections, atypical lymphocytes were found in the lumina of small vessels of almost the entire ovary. These cells were positive for CD20 and CD79a by immunohistochemistry. A diagnosis of IVLBCL coexisting with HGSC was finally made. Although radiation therapy for brain lesions was performed and rituximab was administered, she died two months after the operation. To the best of our knowledge, this is the first case of IVLBCL incidentally identified in HGSC through microscopic examination. This case serves to create awareness of the rare event where IVLBCL may involve the ovary of patients who also have carcinoma in the organ. PMID:27334860

  18. Nonrandom chromosomal imbalances in primary mediastinal B-cell lymphoma detected by arbitrarily primed PCR fingerprinting.

    PubMed

    Scarpa, A; Taruscio, D; Scardoni, M; Iosi, F; Paradisi, S; Ennas, M G; Rigaud, G; Moore, P S; Menestrina, F

    1999-11-01

    We used arbitrarily primed polymerase chain reaction (AP-PCR) fingerprinting to identify chromosomal imbalances in six primary mediastinal B-cell lymphomas (PMBLs). Seventy-four chromosomal imbalances were detected, consisting of 49 sequence gains and 25 losses. Amplifications on chromosome X were seen in five cases, four of which involved the same chromosomal locus. Nonrandom gains at the same locus were also identified on chromosomes 2 and 7 in four cases and on chromosomes 5, 9, and 12 in three cases. Five PMBLs were also analyzed by comparative genomic hybridization (CGH), which found chromosome arm 9p amplification as the only nonrandom imbalance. Our data demonstrate that chromosomal amplifications outnumber losses in PMBL. These mainly involve chromosomes 9 and X and may reflect more complex phenomena, such as translocations or other chromosomal rearrangements, as AP-PCR found coexistent gains and losses on these chromosomes. Comparison between AP-PCR and CGH suggests that anomalies affecting the same chromosomal regions may occur at much higher frequencies than expected by CGH, suggesting that genomic amplifications are usually confined to DNA segments smaller than the megabase long segments required for detection in CGH. Modest increases in genetic material may be as effective as higher-level amplifications when affecting sites where a proto-oncogene resides.

  19. FOXP1 Potentiates Wnt/β-catenin Signaling in Diffuse Large B-cell Lymphoma

    PubMed Central

    Walker, Matthew P.; Stopford, Charles M.; Cederlund, Maria; Fang, Fang; Jahn, Christopher; Rabinowitz, Alex D.; Goldfarb, Dennis; Graham, David M.; Yan, Feng; Deal, Allison M.; Fedoriw, Yuri; Richards, Kristy L.; Davis, Ian J.; Weidinger, Gilbert; Damania, Blossom; Major, Michael B.

    2015-01-01

    The transcription factor FOXP1 is a master regulator of stem and progenitor cell biology. In diffuse large B-cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased FOXP1 protein abundance in DLBCL predicts poor prognosis and resistance to therapy. To connect gene overexpression with phenotype, we developed a genome-wide mass spectrometry-coupled gain-of-function genetic screen, revealing that FOXP1 potentiates β-catenin-dependent Wnt signal transduction. Gain-of-function and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved co-activator of Wnt signaling. In a Wnt-dependent fashion, FOXP1 co-complexed with β-catenin, TCF7L2, and the acetyltransferase CBP, and bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors and knockdown of FOXP1 or Wnt signaling slowed xenograft tumor growth. These data connect FOXP1 overexpression with β-catenin-dependent signal transduction, and provide a new molecular rationale for Wnt-directed therapy in DLBCL. PMID:25650440

  20. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma

    PubMed Central

    Dunleavy, Kieron; Pittaluga, Stefania; Czuczman, Myron S.; Dave, Sandeep S.; Wright, George; Grant, Nicole; Shovlin, Margaret; Jaffe, Elaine S.; Janik, John E.; Staudt, Louis M.

    2009-01-01

    Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell–like (GCB) and activated B cell–like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor–kappa B (NF-κB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-κB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-κB through blocking IκBα degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.ClinicalTrials.gov under identifier NCT00057902. PMID:19380866

  1. Racial patterns of patients with primary mediastinal large B-cell lymphoma: SEER analysis.

    PubMed

    Liu, Pan-Pan; Wang, Ke-Feng; Xia, Yi; Bi, Xi-Wen; Sun, Peng; Wang, Yu; Li, Zhi-Ming; Jiang, Wen-Qi

    2016-07-01

    The aim of this study is to investigate the incidence and clinical outcomes of primary mediastinal large B-cell lymphoma (PMBL).Here we did a retrospective analysis using the surveillance, epidemiology, and end results (SEER) database to analyze the incidences and survival of patients with PMBL diagnosed during 2001-2012 among major ethnic groups.During 2001-2012, a total of 426 PMBL patients were identified, including 336 whites, 46 blacks, and 44 others. The incidence rates of female to male ratios in white, black, and other were 1.4938, 1.1202, and 1.7303 respectively, suggesting that the female-prominent disease occurrence was seen only in whites and others, but not in black population. Compared to white, the other had a worse 5-year overall survival (OS); however, factors including age, race, socioeconomic status, and stage associated with OS showed no significant difference among ethnic groups; thus, biology factors should be explored to explain the racial difference in OS.In conclusion, our findings revealed diversities in demographic features and prognosis among different racial groups. PMID:27399089

  2. Antitumor activity of fucoidan against diffuse large B cell lymphoma in vitro and in vivo.

    PubMed

    Yang, Guang; Zhang, Qianqiao; Kong, Yuanyuan; Xie, Bingqian; Gao, Minjie; Tao, Yi; Xu, Hongwei; Zhan, Fenghuang; Dai, Bojie; Shi, Jumei; Wu, Xiaosong

    2015-11-01

    Fucoidan is one of the major sulfated polysaccharides isolated from brown seaweeds. In this study, we determined the anti-cancer activity of fucoidan on diffuse large B cell lymphoma (DLBCL) cells both in vitro and in vivo. Fucoidan inhibited the growth of DLBCL cells in a dose- and time-dependent manner, and fucoidan treatment provoked G0/G1 cell cycle arrest, which was accompanied by p21 up-regulation and cyclin D1, Cdk4, and Cdk6 down-regulation. Fucoidan also induced caspase-dependent cell apoptosis in DLBCL cell lines and primary DLBCL cell. In addition, fucoidan treatment caused the loss of mitochondrial membrane potential and the release of cytochrome c and apoptosis-inducing factor from the mitochondria into the cytosol. Fucoidan also potentiated the activities of carfilzomib in killing DLBCL cells. Oral administration of fucoidan effectively inhibited tumor growth in xenograft mouse models. Our findings reveal the novel function of fucoidan as an anti-DLBCL agent, which can be used in the clinical treatment of DLBCL.

  3. ACR Appropriateness Criteria® Diffuse Large B-Cell Lymphoma.

    PubMed

    Dabaja, Bouthaina S; Advani, Ranjana; Hodgson, David C; Dhakal, Sughosh; Flowers, Christopher R; Ha, Chul S; Hoppe, Bradford S; Mendenhall, Nancy P; Metzger, Monika L; Plastaras, John P; Roberts, Kenneth B; Shapiro, Ronald; Smith, Sonali M; Terezakis, Stephanie A; Winkfield, Karen M; Younes, Anas; Constine, Louis S

    2015-12-01

    The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID:26583344

  4. Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties.

    PubMed

    Sarkozy, Clémentine; Coiffier, Bertrand

    2013-04-01

    Half of patients with diffuse large B-cell lymphoma (DLBCL) are more than 65 years old. These elderly patients frequently have other diseases, some of them severe, which may alter their ability to receive standard curative therapy. However, these associated diseases are heterogeneous and only a few contraindicate chemotherapy treatments. We reviewed all potential difficulties, such as the evaluation of comorbidities, the heterogeneous functional status of this population, and the consequences of the aging process that might be associated with treating these patients, and now propose solutions. As standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy may cure the majority of patients, it must always be the first proposed option. With this approach, elderly patients with DLBCL treated with a curative intent can reach a complete remission and have a similar outcome as younger patients. Reduced dose intensity must be applied for very elderly patients or those unfit for full-dose anthracycline. The critical question for a physician is why these patients cannot be treated with the standard regimen, namely R-CHOP. PMID:23339126

  5. Telomerase reverse transcriptase expression elevated by avian leukosis virus integration in B cell lymphomas

    PubMed Central

    Yang, Feng; Xian, Rena R.; Li, Yingying; Polony, Tatjana S.; Beemon, Karen L.

    2007-01-01

    Simple retroviruses induce tumors by integrating into the host genome, activating cellular oncogenes and microRNAs, or inactivating tumor suppressor genes. The identification of these genes elucidates molecular mechanisms of tumorigenesis. In this study, we identified avian leukosis virus (ALV) proviral integration sites in rapid-onset B cell lymphomas arising <12 weeks after infection of chicken embryos. By using inverse PCR, 28 unique viral integration sites were identified in rapid-onset tumors. Integrations in the telomerase reverse transcriptase (TERT) promoter/enhancer region were observed in four different tumors, suggesting that this is a common integration site. These provirus integrations ranged from 217 to 2,584 bp upstream of the TERT transcription initiation site and were all in the opposite transcriptional orientation to TERT. Southern blots of tumor samples demonstrated that these integrations are clonal and therefore occurred early in the process of tumorigenesis. Real-time RT-PCR showed overexpression of TERT mRNA in tumors harboring viral integrations in the TERT promoter. Telomerase activity was also up-regulated in these tumors; however, telomere-length alterations were not detected. Furthermore, viral LTR sequences directly enhanced the expression of luciferase reporters containing the TERT promoter sequences. This study documents retroviral up-regulation of cellular TERT by insertional activation to initiate or enhance tumor progression. PMID:18024587

  6. Clinical development of radioimmunotherapy for B-cell non-Hodgkin's lymphoma

    SciTech Connect

    Meredith, Ruby F. . E-mail: rmeredith@uabmc.edu; Knox, Susan J.

    2006-10-01

    Over the past several decades, several biomolecules have been investigated for their ability to deliver radiation to cancer cells, but antibodies have been the carriers of choice in systemic targeted radionuclide therapy (STaRT). Two radioimmunotherapy agents that target the CD20 antigen, {sup 131}I-tositumomab and {sup 9}Y-ibritumomab tiuxetan, have been approved by the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL), and clinical trials have shown that they are effective as monotherapies in the salvage setting, producing response rates that are often higher and durations of response that are often longer than those with chemotherapy. Escalated doses of these agents can be supported with stem cell transplantation and can produce high rates of complete response and greater survival in patients with relapsed NHL. The quality and duration of responses are greater with radioimmunotherapy when it is used earlier in the course of treatment.

  7. Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-09-12

    Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma

  8. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas.

    PubMed

    Senff, Nancy J; Noordijk, Evert M; Kim, Youn H; Bagot, Martine; Berti, Emilio; Cerroni, Lorenzo; Dummer, Reinhard; Duvic, Madeleine; Hoppe, Richard T; Pimpinelli, Nicola; Rosen, Steven T; Vermeer, Maarten H; Whittaker, Sean; Willemze, Rein

    2008-09-01

    Primary cutaneous B-cell lymphomas (CBCL) represent approximately 20% to 25% of all primary cutaneous lymphomas. With the advent of the World Health Organization-European Organization for Research and Treatment of Cancer (EORTC) Consensus Classification for Cutaneous Lymphomas in 2005, uniform terminology and classification for this rare group of neoplasms were introduced. However, staging procedures and treatment strategies still vary between different cutaneous lymphoma centers, which may be because consensus recommendations for the management of CBCL have never been published. Based on an extensive literature search and discussions within the EORTC Cutaneous Lymphoma Group and the International Society for Cutaneous Lymphomas, the present report aims to provide uniform recommendations for the management of the 3 main groups of CBCL. Because no systematic reviews or (randomized) controlled trials were available, these recommendations are mainly based on retrospective studies and small cohort studies. Despite these limitations, there was consensus among the members of the multidisciplinary expert panel that these recommendations reflect the state-of-the-art management as currently practiced in major cutaneous lymphoma centers. They may therefore contribute to uniform staging and treatment and form the basis for future clinical trials in patients with a CBCL.

  9. CD38 and interleukin 6 gene polymorphism in egyptians with diffuse large B-cell lymphoma (DLBCL).

    PubMed

    Talaat, Roba M; Abdel-Aziz, Amal M; El-Maadawy, Eman A; Abdel-Bary, Naser

    2015-01-01

    Given the importance of understanding the genetic variations involved in the pathogenesis of non-Hodgkin's lymphoma (NHL), this pilot study was designed to investigate the impact of CD38 (184C/G; rs6449182) and IL-6 (-174 G/C; rs1800795) gene polymorphism on susceptibility of Egyptians to diffuse large B cell lymphoma (DLBCL); major types of NHL. To the best of our knowledge, this study is the first one that examines CD38 polymorphism in the NHL. Genotyping polymorphism is performed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for CD38 and Mutagenically separated PCR (MS-PCR) for IL-6 in 100 Egyptian NHL patients with DLBCL subtype and 119 normal controls. The serum level of IL-6 was measured using Enzyme-linked immunosorbent assay (ELISA). CD38 (184C/G) genotype is significantly increased in NHL patients (p < 0.01), while the GG genotype is significantly increased in controls (p < 0.05). Only two genotypes were found (GG and GC) in IL-6 (-174), no CC in our NHL patients and only one case in the controls. Insignificant change in IL-6 (-174 G/C) genotypes was recorded. Significantly increased serum IL-6 (p < 0.05) was positively correlated (r = 0.17; p < 0.05) with the disease. Taken together, our data stressed the importance of CD38 gene polymorphism in developing DLBCL. Our pilot study indicates that CD38 (184) CG genotype might play a role in DLBCL susceptibility in Egyptians. Additional prospective studies on larger population are needed to confirm our findings.

  10. Primary non-Hodgkin's lymphoma of the salivary gland: a spectrum of lymphoepithelial sialadenitis, low-grade B-cell lymphoma of mucosa-associated lymphoid tissue with transformation to high-grade lymphoma.

    PubMed

    Agale, Shubhangi Vinayak; D'Costa, Grace Francis; Hastak, Meenal Shirish; Shedge, Rakesh Tukaram

    2010-01-01

    Lymphoid infiltrates of the salivary gland can be either reactive or neoplastic. The reactive lesion, lymphoepithelial sialadenitis (LESA) may be associated with Sjogren's syndrome (SS) or may occur as an isolated salivary gland enlargement. Patients with LESA/SS have a particularly high risk of subsequently developing lymphoma, which is a low-grade mucosa-associated lymphoid tissue (MALT) type lymphoma of the salivary gland. We document a rare case of primary non-Hodgkin's lymphoma of the parotid gland arising in the background of LESA and with a rare example of transformation from low grade to high-grade B cell lymphoma of MALT type. PMID:20551561

  11. Portraying the Expression Landscapes of B-Cell Lymphoma-Intuitive Detection of Outlier Samples and of Molecular Subtypes

    PubMed Central

    Hopp, Lydia; Lembcke, Kathrin; Binder, Hans; Wirth, Henry

    2013-01-01

    We present an analytic framework based on Self-Organizing Map (SOM) machine learning to study large scale patient data sets. The potency of the approach is demonstrated in a case study using gene expression data of more than 200 mature aggressive B-cell lymphoma patients. The method portrays each sample with individual resolution, characterizes the subtypes, disentangles the expression patterns into distinct modules, extracts their functional context using enrichment techniques and enables investigation of the similarity relations between the samples. The method also allows to detect and to correct outliers caused by contaminations. Based on our analysis, we propose a refined classification of B-cell Lymphoma into four molecular subtypes which are characterized by differential functional and clinical characteristics. PMID:24833231

  12. MEF2B mutations lead to deregulated expression of the BCL6 oncogene in Diffuse Large B cell Lymphoma

    PubMed Central

    Ying, Carol Y.; Dominguez-Sola, David; Fabi, Melissa; Lorenz, Ivo C.; Hussein, Shafinaz; Bansal, Mukesh; Califano, Andrea; Pasqualucci, Laura; Basso, Katia; Dalla-Favera, Riccardo

    2014-01-01

    The MEF2B gene encodes a transcriptional activator and is found mutated in ∼11% of diffuse large B cell lymphomas (DLBCLs) and ∼12% of follicular lymphomas. Here, we show that MEF2B directly activates the transcription of the proto-oncogene BCL6 in normal germinal-center B cells and is required for DLBCL proliferation. MEF2B mutations enhance MEF2B transcriptional activity either by disrupting its interaction with the co-repressor CABIN1, or by rendering it insensitive to phosphorylation- and sumoylation-mediated inhibitory signaling events. Consequently, Bcl-6 transcriptional activity is deregulated in DLBCL harboring MEF2B mutations. Thus, somatic mutations of MEF2B may contribute to lymphomagenesis by deregulating the expression of the BCL6 oncogene, and MEF2B may represent an alternative target to block Bcl-6 activity in DLBCLs. PMID:23974956

  13. High concentrations of glucose suppress etoposide-induced cell death of B-cell lymphoma through BCL-6.

    PubMed

    Shao, Yan; Ling, Chang Chun; Liu, Xu Qing

    2014-07-18

    Glucose is potentially a factor in the resistance to chemotherapy of B-cell lymphomas. In this study we investigated the expression of the glucose induced transcription factor Bcl-6 and the underlying mechanism by which it suppresses B-cell lymphoma cell death. Glucose was found to prevent etoposide-induced tumor cell death. BCL-6 expression was induced by glucose but down-regulated by etoposide. BCL-6 expression was regulated by the interaction of VDUP1 and p53. The molecular mechanism by which glucose prevented etoposide-induced tumor cell death was shown to involve the BCL-6 mediated caspase pathway. Our data suggest that glucose-induced BCL-6 overexpression could abrogate the etoposide chemotherapy effect on tumor cell death. PMID:24878528

  14. A B-cell lymphoma diagnosed in "floater" tissue: implications of the diagnosis and resolution of a laboratory error.

    PubMed

    Mosse, Claudio A; Stumph, Jennifer R; Best, D Hunter; Vnencak-Jones, Cindy L

    2009-09-01

    Contamination of a paraffin-embedded tissue block with another patient's tissue can lead to an incorrect diagnosis. We report the use of short tandem repeats for the analysis of DNA extracted from microdissected tissue from unstained slides prepared from a decalcified block from a 33-year-old woman who was previously diagnosed with a low-grade B-cell lymphoma. This diagnosis was based on a single fragment of tissue found among bone fragments taken during orthopedic surgery at a referring hospital. Our results confirm that the B-cell lymphoma tissue was not derived from our patient. Furthermore, we suggest that in cases for which the definitive identification of a tissue contaminant can resolve clinically, therapeutically, and prognostically significant questions, short tandem repeat analysis of DNA derived from microdissected surgical pathology samples should be considered to minimize errors and enhance the quality of care. PMID:19745614

  15. A 75-Year-Old Female with Dyspnea: An Unusual Presentation of Diffuse Large B-Cell Lymphoma

    PubMed Central

    Mukarram, Osama; Abusaada, Khalid

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a common variant of non-Hodgkin lymphoma (NHL). It usually presents as a rapidly enlarging mass. Numerous presentations involving the gastrointestinal tract, bone, and the central nervous system have been reported in the past including both primary and secondary involvement of organs. A 75-year-old lady was found to have a pericardial effusion while being evaluated for shortness of breath. A therapeutic pericardial tap was positive for pan-B cell markers. The patient's detailed radiological studies failed to show a primary tumor. We report this unusual presentation of DLBCL as a pericardial effusion without a primary source in a patient with mild shortness of breath.

  16. Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

    PubMed

    Uccini, Stefania; Al-Jadiry, Mazin F; Scarpino, Stefania; Ferraro, Daniela; Alsaadawi, Adel R; Al-Darraji, Amir F; Moleti, Maria Luisa; Testi, Anna Maria; Al-Hadad, Salma A; Ruco, Luigi

    2015-05-01

    Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations. PMID:25704629

  17. Molecular cloning and nucleotide sequence of a transforming gene detected by transfection of chicken B-cell lymphoma DNA

    NASA Astrophysics Data System (ADS)

    Goubin, Gerard; Goldman, Debra S.; Luce, Judith; Neiman, Paul E.; Cooper, Geoffrey M.

    1983-03-01

    A transforming gene detected by transfection of chicken B-cell lymphoma DNA has been isolated by molecular cloning. It is homologous to a conserved family of sequences present in normal chicken and human DNAs but is not related to transforming genes of acutely transforming retroviruses. The nucleotide sequence of the cloned transforming gene suggests that it encodes a protein that is partially homologous to the amino terminus of transferrin and related proteins although only about one tenth the size of transferrin.

  18. CGCI Investigators Reveal Comprehensive Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) Genomes | Office of Cancer Genomics

    Cancer.gov

    Researchers from British Columbia Cancer Agency used whole genome sequencing to analyze 40 DLBCL cases and 13 cell lines in order to fill in the gaps of the complex landscape of DLBCL genomes. Their analysis, “Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing,” was published online in Blood on May 22. The authors are Ryan Morin, Marco Marra, and colleagues.  

  19. Monocytoid B-cell lymphoma in patients with Sjögren's syndrome: a clinicopathologic study of 13 patients.

    PubMed

    Shin, S S; Sheibani, K; Fishleder, A; Ben-Ezra, J; Bailey, A; Koo, C H; Burke, J S; Tubbs, R; Rappaport, H

    1991-05-01

    A recent clinicopathologic study of a series of patients with monocytoid B-cell lymphoma (MBCL) indicated that there is a frequent association between MBCL and Sjögren's syndrome (SS) and raised the possibility of a relationship between these two disease entities. To further investigate the possible relationship of MBCL and SS, we studied pathologic and clinical characteristics of 13 patients with MBCL who had clinically documented SS. In all patients, the lymphoma had the characteristic morphologic features of MBCL, and immunologic and molecular hybridization studies confirmed the B-cell nature of the lymphoma. Twelve of the 13 patients were female, with a median age of 66 years at diagnosis. Eleven had localized disease and presented with either salivary gland or cervical lymph node enlargement; one patient presented with a breast mass, and another with generalized lymphadenopathy and hepatosplenomegaly. In five of 13 patients, the MBCL was associated with or progressed to large cell lymphoma. In two patients, there was bilateral involvement of the parotid gland; one had a synchronous high-grade lymphoma in both parotid glands. In two patients, bone marrow biopsies showed involvement by MBCL. Eleven patients are alive 2 to 55 months after the diagnosis of MBCL. One patient died with the disease 8 months after the initial diagnosis. Another patient died of an unrelated cause without evidence of disease 16 months after the diagnosis of MBCL. We conclude that there is a more than fortuitous association between MBCL and SS. This concept is consistent with previously reported observations of reactive monocytoid B cells in patients with benign lymphoepithelial lesions of salivary glands, which may result from selective homing of reactive monocytoid B lymphocytes to the benign lymphoepithelial lesions and their subsequent neoplastic transformation.

  20. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease.

    PubMed

    Chapuy, Bjoern; Cheng, Hongwei; Watahiki, Akira; Ducar, Matthew D; Tan, Yuxiang; Chen, Linfeng; Roemer, Margaretha G M; Ouyang, Jing; Christie, Amanda L; Zhang, Liye; Gusenleitner, Daniel; Abo, Ryan P; Farinha, Pedro; von Bonin, Frederike; Thorner, Aaron R; Sun, Heather H; Gascoyne, Randy D; Pinkus, Geraldine S; van Hummelen, Paul; Wulf, Gerald G; Aster, Jon C; Weinstock, David M; Monti, Stefano; Rodig, Scott J; Wang, Yuzhuo; Shipp, Margaret A

    2016-05-01

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition.

  1. Immunoproliferative Small Intestinal Disease Associated with Overwhelming Polymicrobial Gastrointestinal Infection with Transformation to Diffuse Large B-cell Lymphoma.

    PubMed

    Ewers, Evan C; Sheffler, Robert L; Wang, James; Ngauy, Viseth

    2016-05-01

    Immunoproliferative small intestinal disease (IPSID) is an extra-nodal B-cell lymphoma most commonly described in the Mediterranean, Africa, and Asia. It is associated with poverty and poor sanitation, and is rarely encountered in developed countries. A 26-year-old previously healthy, Marshallese male was transferred to our facility with a 6-month history of watery diarrhea, weakness, and cachexia refractory to multiple short courses of oral antibiotics. Stool cultures grew Campylobacter jejuni and Vibrio fluvialis. Endoscopic evaluation showed histologic evidence of Helicobacter pylori gastritis and gross evidence of whipworm infection found in the colon. Mesenteric lymph node biopsy cultures grew Escherichia coli. Histopathology and immunohistochemical stains of the small intestine were consistent with IPSID. He subsequently transformed to diffuse large B-cell lymphoma (DLBCL) with tonsillar involvement despite treatment with rituximab and an extended course of antibiotics. Systemic chemotherapy with six cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone, and lenalidomide, resulted in remission of his diffuse B cell lymphoma. This case is illustrative of IPSID developing in a previously healthy individual due to overwhelming polymicrobial gastrointestinal infection by C. jejuni and other enteric pathogens with subsequent transformation to an aggressive DLBCL. IPSID should be considered in residents of developing countries presenting with refractory chronic diarrhea, weight loss, and mesenteric lymphadenopathy. PMID:26903604

  2. Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP

    PubMed Central

    Wang, Jing; Zhou, Min; Xu, Jing-Yan; Yang, Yong-Gong; Zhang, Qi-Guo; Zhou, Rong-Fu; Chen, Bing; Ouyang, Jian

    2016-01-01

    Abstract This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43–4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05–3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19–0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33–0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era. PMID:27661033

  3. Serum nuclear magnetic resonance-based metabolomics and outcome in diffuse large B-cell lymphoma patients - a pilot study.

    PubMed

    Stenson, Martin; Pedersen, Anders; Hasselblom, Sverker; Nilsson-Ehle, Herman; Karlsson, Bengt Göran; Pinto, Rui; Andersson, Per-Ola

    2016-08-01

    The prognosis for diffuse large B-cell lymphoma (DLBCL) patients with early relapse or refractory disease is dismal. To determine if clinical outcome correlated to diverse serum metabolomic profiles, we used (1)H nuclear magnetic resonance (NMR) spectroscopy and compared two groups of DLBCL patients treated with immunochemotherapy: i) refractory/early relapse (REF/REL; n=27) and ii) long-term progression-free (CURED; n = 60). A supervised multivariate analysis showed a separation between the groups. Among discriminating metabolites higher in the REF/REL group were the amino acids lysine and arginine, the degradation product cadaverine and a compound in oxidative stress (2-hydroxybutyrate). In contrast, the amino acids aspartate, valine and ornithine, and a metabolite in the glutathione cycle, pyroglutamate, were higher in CURED patients. Together, our data indicate that NMR-based serum metabolomics can identify a signature for DLBCL patients with high-risk of failing immunochemotherapy, prompting for larger validating studies which could lead to more individualized treatment of this disease. PMID:26887805

  4. A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520.

    PubMed

    Puvvada, Soham D; Li, Hongli; Rimsza, Lisa M; Bernstein, Steven H; Fisher, Richard I; LeBlanc, Michael; Schmelz, Monika; Glinsmann-Gibson, Betty; Miller, Thomas P; Maddox, Anne-Marie; Friedberg, Jonathan W; Smith, Sonali M; Persky, Daniel O

    2016-10-01

    Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.

  5. Colonic diffuse large B-cell lymphoma in a liver transplant patient with historically very low tacrolimus levels.

    PubMed

    Moore, Christopher M; Lamzabi, Ihab; Bartels, Anne K; Jakate, Shriram; Van Thiel, David H

    2012-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) comprise a wide spectrum of hematologic malignancies that are found increasingly in orthotopic liver transplant (OLT) patients given the rising frequency of these surgeries and their long-term success. PTLDs are highly correlated with both the Epstein-Barr virus (EBV) infection and the degree of immunosuppression involved. Herein is reported a case of a 53-year-old male with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed symptoms of weakness and poor appetite 4 years later while on tacrolimus 3 mg b.i.d. with historically very low plasma levels. He was found to be anemic and colonoscopy revealed a 4.5 cm cecal diffuse large B-cell lymphoma (DLBCL). Further workup revealed mesenteric lymph node enlargement consistent and nodal DLBCL dissemination. He was treated with cyclophosphamide-hydroxyldaunorubicin-oncovin-prednisone-rituximab (CHOP-R) chemotherapy and his tacrolimus dose was lowered. Additionally, he manifested PTLD-associated cryoglobulinemia leading to acute kidney injury. After a prolonged hospitalization he was discharged with close followup. PMID:23259146

  6. T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells.

    PubMed

    Azzaoui, Imane; Uhel, Fabrice; Rossille, Delphine; Pangault, Celine; Dulong, Joelle; Le Priol, Jerome; Lamy, Thierry; Houot, Roch; Le Gouill, Steven; Cartron, Guillaume; Godmer, Pascal; Bouabdallah, Krimo; Milpied, Noel; Damaj, Gandhi; Tarte, Karin; Fest, Thierry; Roussel, Mikael

    2016-08-25

    In diffuse large B-cell lymphoma (DLBCL), the number of circulating monocytes and neutrophils represents an independent prognostic factor. These cell subsets include monocytic and granulocytic myeloid-derived suppressor cells (M- and G-MDSCs) defined by their ability to suppress T-cell responses. MDSCs are a heterogeneous population described in inflammatory and infectious diseases and in numerous tumors including multiple myeloma, chronic lymphocytic leukemia, and DLBCL. However, their mechanisms of action remain unclear. We broadly assessed the presence and mechanisms of suppression of MDSC subsets in DLBCL. First, a myeloid suppressive signature was identified by gene expression profiling in DLBCL peripheral blood. Accordingly, we identified, in a cohort of 66 DLBCL patients, an increase in circulating G-MDSC (Lin(neg)HLA-DR(neg)CD33(pos)CD11b(pos)) and M-MDSC (CD14(pos)HLA-DR(low)) counts. Interestingly, only M-MDSC number was correlated with the International Prognostic Index, event-free survival, and number of circulating Tregs. Furthermore, T-cell proliferation was restored after monocyte depletion. Myeloid-dependent T-cell suppression was attributed to a release of interleukin-10 and S100A12 and increased PD-L1 expression. In summary, we identified expanded MDSC subsets in DLBCL, as well as new mechanisms of immunosuppression in DLBCL. PMID:27338100

  7. Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP.

    PubMed

    Wang, Jing; Zhou, Min; Xu, Jing-Yan; Yang, Yong-Gong; Zhang, Qi-Guo; Zhou, Rong-Fu; Chen, Bing; Ouyang, Jian

    2016-09-01

    This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43-4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05-3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19-0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33-0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era. PMID:27661033

  8. Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T Cells for B-cell Leukemia/Lymphoma

    ClinicalTrials.gov

    2016-08-22

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  9. Primary Diffuse Large B-Cell Lymphoma Localized to the Lacrimal Sac: A Case Presentation and Review of the Literature

    PubMed Central

    Yim, Brandom; Gabig, Theodore G.

    2016-01-01

    We report a rare case of diffuse large B-cell lymphoma (DLBCL) of the lacrimal sac in a 50-year-old male. The incidence of primary ocular lymphoma is low and it is considered a rare disease. Moreover, reports of ocular DLBCL are uncommon and the disease remains poorly characterized. Our patient presented for management of osteomyelitis and was incidentally found to have a painless swelling and cyst around his right eye. A PET/CT scan revealed hypermetabolic activity within the lacrimal sac and a subsequent excisional biopsy of the mass yielded histopathology consistent with DLBCL. Consequently, the patient underwent treatment with R-CHOP therapy. The patient responded well to chemotherapy with a substantial shrinkage in tumor burden and the disease remained localized. Herein, we present a rare case of primary ocular lymphoma, highlight the importance of early diagnosis, and review current treatment modalities.

  10. Acute adrenal insufficiency secondary to bilateral adrenal B-cell lymphoma: a case report and review of the literature

    PubMed Central

    De Miguel Sánchez, Carlos; Ruiz, Luis; González, Jose Luis; Hernández, Jose Luis

    2016-01-01

    Primary adrenal lymphoma is an extremely rare entity which constitutes less than 1% of extranodal lymphomas. Most cases present with bilateral adrenal masses and without extraadrenal involvement, which can lead to symptoms of adrenal insufficiency. The prognosis is usually poor and chemotherapy is the first-line treatment option. We report here on a 78-year-old man admitted to our Internal Medicine Department because of constitutional symptoms and high fever spikes. He was diagnosed with adrenal insufficiency and a CT-scan revealed bilateral adrenal masses of about 6 cm in diameter. A percutaneous biopsy was performed and the histological exam was consistent with diffuse large B cell lymphoma. A review of the literature of this unusual entity was also carried out. PMID:27170834

  11. Primary Diffuse Large B-Cell Lymphoma Localized to the Lacrimal Sac: A Case Presentation and Review of the Literature

    PubMed Central

    Yim, Brandom; Gabig, Theodore G.

    2016-01-01

    We report a rare case of diffuse large B-cell lymphoma (DLBCL) of the lacrimal sac in a 50-year-old male. The incidence of primary ocular lymphoma is low and it is considered a rare disease. Moreover, reports of ocular DLBCL are uncommon and the disease remains poorly characterized. Our patient presented for management of osteomyelitis and was incidentally found to have a painless swelling and cyst around his right eye. A PET/CT scan revealed hypermetabolic activity within the lacrimal sac and a subsequent excisional biopsy of the mass yielded histopathology consistent with DLBCL. Consequently, the patient underwent treatment with R-CHOP therapy. The patient responded well to chemotherapy with a substantial shrinkage in tumor burden and the disease remained localized. Herein, we present a rare case of primary ocular lymphoma, highlight the importance of early diagnosis, and review current treatment modalities. PMID:27672460

  12. Primary Diffuse Large B-Cell Lymphoma Localized to the Lacrimal Sac: A Case Presentation and Review of the Literature.

    PubMed

    Zarrabi, Kevin; Desai, Ved; Yim, Brandom; Gabig, Theodore G

    2016-01-01

    We report a rare case of diffuse large B-cell lymphoma (DLBCL) of the lacrimal sac in a 50-year-old male. The incidence of primary ocular lymphoma is low and it is considered a rare disease. Moreover, reports of ocular DLBCL are uncommon and the disease remains poorly characterized. Our patient presented for management of osteomyelitis and was incidentally found to have a painless swelling and cyst around his right eye. A PET/CT scan revealed hypermetabolic activity within the lacrimal sac and a subsequent excisional biopsy of the mass yielded histopathology consistent with DLBCL. Consequently, the patient underwent treatment with R-CHOP therapy. The patient responded well to chemotherapy with a substantial shrinkage in tumor burden and the disease remained localized. Herein, we present a rare case of primary ocular lymphoma, highlight the importance of early diagnosis, and review current treatment modalities. PMID:27672460

  13. Testicular ischemia due to intravascular large B-cell lymphoma: a novel presentation in an immunosuppressed individual.

    PubMed

    Tranchida, Paul; Bayerl, Michael; Voelpel, Mary Jo; Palutke, Margarita

    2003-10-01

    A 56-year-old man presented with fever, disorientation, and testicular pain. He was receiving azathioprine immunosuppression for autoimmune hepatitis. Orchiectomy identified occlusion of spermatic cord vessels by intravascular large B-cell lymphoma (IVLBL) and ischemic changes in the testis. Tumor cells were positive for CD 10, CD 20, CD 30, and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) and early region RNA (EBER). He was treated with the cessation of azathioprine, chemotherapy, anti-CD 20 immunotherapy, and radiotherapy. Twenty months after diagnosis, he is alive with no evidence of lymphoma or hepatitis. This is the first report of IVLBL presenting with testicular ischemia. It highlights the importance of prompt diagnosis and intervention to achieve durable response. That this lymphoma arose in the setting of immunosuppressive therapy introduces additional complexity relating to pathogenesis, clinical behavior, and treatment.

  14. Diffuse large B-cell lymphoma of the orbit: A tertiary eye care center experience in Saudi Arabia☆

    PubMed Central

    Alkatan, Hind M.; Alaraj, Ahmad M.; Al-Ayoubi, Ayman

    2011-01-01

    Primary Diffuse Large B-cell Lymphoma (DLBCL) represents the 2nd most common lymphoma occurring in the orbit, after Mucosal Associated Lymphoid Tissue (MALT) lymphoma. A total of 5 cases of ocular adnexal DLBCL were diagnosed over 25 years of experience at our tertiary eye care center. Two cases involved the lacrimal sac and one case involved the lacrimal gland. In this paper we are presenting the remaining 2 non-lacrimal cases of DLBCL. The first case is a 32 year old male who was referred with a slowly growing, painless mass involving the left medial canthal area as a case of dacryocystitis. The mass was found to be extending into the orbit inferiorly with upward displacement of the left globe. The second case is a 65 year-old lady who presented with unilateral proptosis as a result of a right orbital mass extending to the orbital apex. Histopathologic examination and immunohistochemical analysis of the incisional biopsy in both cases confirmed the diagnosis of Diffuse Large B-cell Lymphoma (DLBCL). PMID:23960998

  15. miR-4284 and miR-4484 as Putative Biomarkers for Diffuse Large B-Cell Lymphoma.

    PubMed

    Tamaddon, Gholamhossein; Geramizadeh, Bita; Karimi, Mohammad Hossein; Mowla, Seyed Javad; Abroun, Said

    2016-07-01

    Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. MicroRNAs (miRNAs) are endogenous small RNA, which can regulate gene expression at the post-transcriptional level. MiRNA profiling has shown a great potential as novel diagnostic and prognostic biomarkers. The present study was performed at the Nemazee Teaching Hospital (Shiraz, Iran) from 2011 to 2013. The aim of this study was to assess the deregulation of miRNAs profiles in DLBL against hyperplasic reactive lymph node as a normal. This could serve as a biomarker for DLBL. The miRCURY LNA™ microarray was used on the total RNA, which was extracted from formalin-fixed paraffin-embedded tissue of 24 de novo diffuse large B-cell lymphoma patients and 14 normal lymph nodes. The greatest changes were detected in miR-4284 and miR-4484 level in patient's lymphoma samples. These miRNAs can act as a diagnostic biomarker for DLBL. PMID:27365556

  16. BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.

    PubMed

    Hogg, Simon J; Newbold, Andrea; Vervoort, Stephin J; Cluse, Leonie A; Martin, Benjamin P; Gregory, Gareth P; Lefebure, Marcus; Vidacs, Eva; Tothill, Richard W; Bradner, James E; Shortt, Jake; Johnstone, Ricky W

    2016-09-01

    Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030-41. ©2016 AACR. PMID:27406984

  17. Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.

    PubMed

    Dai, Haiping; Ehrentraut, Stefan; Nagel, Stefan; Eberth, Sonja; Pommerenke, Claudia; Dirks, Wilhelm G; Geffers, Robert; Kalavalapalli, Srilaxmi; Kaufmann, Maren; Meyer, Corrina; Faehnrich, Silke; Chen, Suning; Drexler, Hans G; MacLeod, Roderick A F

    2015-01-01

    Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings

  18. Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.

    PubMed

    Dai, Haiping; Ehrentraut, Stefan; Nagel, Stefan; Eberth, Sonja; Pommerenke, Claudia; Dirks, Wilhelm G; Geffers, Robert; Kalavalapalli, Srilaxmi; Kaufmann, Maren; Meyer, Corrina; Faehnrich, Silke; Chen, Suning; Drexler, Hans G; MacLeod, Roderick A F

    2015-01-01

    Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings

  19. Benefit of Consolidative Radiation Therapy for Primary Bone Diffuse Large B-Cell Lymphoma

    SciTech Connect

    Tao, Randa; Allen, Pamela K.; Rodriguez, Alma; Shihadeh, Ferial; Pinnix, Chelsea C.; Arzu, Isadora; Reed, Valerie K.; Oki, Yasuhiro; Westin, Jason R.; Fayad, Luis E.; Medeiros, L. Jeffrey; Dabaja, Bouthaina

    2015-05-01

    Purpose: Outcomes for patients with diffuse large B-cell lymphoma (DLBCL) differ according to the site of presentation. With effective chemotherapy, the need for consolidative radiation therapy (RT) is controversial. We investigated the influence of primary bone presentation and receipt of consolidative RT on progression-free survival (PFS) and overall survival (OS) in patients with DLBCL. Methods and Materials: We identified 102 patients with primary bone DLBCL treated consecutively from 1988 through 2013 and extracted clinical, pathologic, and treatment characteristics from the medical records. Survival outcomes were calculated by the Kaplan-Meier method, with factors affecting survival determined by log-rank tests. Univariate and multivariate analyses were done with a Cox regression model. Results: The median age was 55 years (range, 16-87 years). The most common site of presentation was in the long bones. Sixty-five patients (63%) received R-CHOP–based chemotherapy, and 74 (72%) received rituximab. RT was given to 67 patients (66%), 47 with stage I to II and 20 with stage III to IV disease. The median RT dose was 44 Gy (range, 24.5-50 Gy). At a median follow-up time of 82 months, the 5-year PFS and OS rates were 80% and 82%, respectively. Receipt of RT was associated with improved 5-year PFS (88% RT vs 63% no RT, P=.0069) and OS (91% vs 68%, P=.0064). On multivariate analysis, the addition of RT significantly improved PFS (hazard ratio [HR] = 0.14, P=.014) with a trend toward an OS benefit (HR=0.30, P=.053). No significant difference in PFS or OS was found between patients treated with 30 to 35 Gy versus ≥36 Gy (P=.71 PFS and P=.31 OS). Conclusion: Patients with primary bone lymphoma treated with standard chemotherapy followed by RT can have excellent outcomes. The use of consolidative RT was associated with significant benefits in both PFS and OS.

  20. Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines

    PubMed Central

    Nagel, Stefan; Eberth, Sonja; Pommerenke, Claudia; Dirks, Wilhelm G.; Geffers, Robert; Kalavalapalli, Srilaxmi; Kaufmann, Maren; Meyer, Corrina; Faehnrich, Silke; Chen, Suning; Drexler, Hans G.; MacLeod, Roderick A. F.

    2015-01-01

    Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2–10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings

  1. The contribution of HGAL/GCET2 in immunohistological algorithms: a comparative study in 424 cases of nodal diffuse large B-cell lymphoma.

    PubMed

    Gualco, Gabriela; Bacchi, Lívia M; Domeny-Duarte, Pollyanna; Natkunam, Yasodha; Bacchi, Carlos E

    2012-11-01

    Diffuse large B-cell lymphoma can be subclassified into at least two molecular subgroups by gene expression profiling: germinal center B-cell like and activated B-cell like diffuse large B-cell lymphoma. Several immunohistological algorithms have been proposed as surrogates to gene expression profiling at the level of protein expression, but their reliability has been an issue of controversy. Furthermore, the proportion of misclassified cases of germinal center B-cell subgroup by immunohistochemistry, in all reported algorithms, is higher compared with germinal center B-cell cases defined by gene expression profiling. We analyzed 424 cases of nodal diffuse large B-cell lymphoma with the panel of markers included in the three previously described algorithms: Hans, Choi, and Tally. To test whether the sensitivity of detecting germinal center B-cell cases could be improved, the germinal center B-cell marker HGAL/GCET2 was also added to all three algorithms. Our results show that the inclusion of HGAL/GCET2 significantly increased the detection of germinal center B-cell cases in all three algorithms (P<0.001). The proportions of germinal center B-cell cases in the original algorithms were 27%, 34%, and 19% for Hans, Choi, and Tally, respectively. In the modified algorithms, with the inclusion of HGAL/GCET2, the frequencies of germinal center B-cell cases were increased to 38%, 48%, and 35%, respectively. Therefore, HGAL/GCET2 protein expression may function as a marker for germinal center B-cell type diffuse large B-cell lymphoma. Consideration should be given to the inclusion of HGAL/GCET2 analysis in algorithms to better predict the cell of origin. These findings bear further validation, from comparison to gene expression profiles and from clinical/therapeutic data.

  2. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment

    PubMed Central

    Nicolae, Alina; Pittaluga, Stefania; Abdullah, Shahed; Steinberg, Seth M.; Pham, Thu Anh; Davies-Hill, Theresa; Xi, Liqiang; Raffeld, Mark

    2015-01-01

    Few studies have reported Epstein-Barr virus–positive (EBV+) large B-cell lymphomas (LBCLs) in young patients without immunodeficiency. We identified 46 such cases in patients ≤45 years of age and analyzed the clinical and pathological characteristics. EBV+ LBCLs affected predominantly males (male:female = 3.6:1), with a median age of 23 years (range, 4-45 years). All patients presented with lymphadenopathy and 11% also had extranodal disease. Morphologically, 3 patterns were identified: T-cell/histiocyte-rich large B-cell lymphoma-like (n = 36), gray zone lymphoma (n = 7), and diffuse LBCL-not otherwise specified (n = 3). Tumor cells (EBV+ in >90% of cells) expressed B-cell antigens, were often CD30 and PD-L1 positive, and showed a nongerminal center immunophenotype. A total of 93% expressed EBV latency type II and 7% latency type III. Indoleamine 2,3-dioxygenase was expressed on background accessory cells. The most common treatment regimen was rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (58%), with local radiation therapy added in 21%. With a median follow-up of 22 months, 82% of patients are in clinical remission and only 8% died of disease. Younger patients achieved a significantly higher overall survival than prior series of EBV+ LBCLs reported in the elderly (P < .0001). In conclusion, EBV+ LBCLs are not restricted to the elderly. Young patients present with nodal disease and have a good prognosis. PMID:25999451

  3. Diffuse Large B-Cell Lymphoma in an Adolescent Male Presenting as Ureteral Stricture

    PubMed Central

    Jaeger, Christopher D.; McAlvany, Kelly L.; Zingula, Shannon N.; Kramer, Stephen A.; Granberg, Candace F.

    2014-01-01

    Lymphoma may affect the ureter in cases of retroperitoneal involvement. We present a case of an adolescent male found to have non-Hodgkin lymphoma initially presenting as ureteral stricture evident on imaging. He was treated and responded to multiagent chemotherapy with resolution of both the lymphoma and the ureteral stricture. Although rare, non-Hodgkin lymphoma should be included in the differential diagnosis of pediatric patients with noncalculous, idiopathic ureteral strictures. PMID:25093138

  4. Primary bladder lymphoma, diffuse large B-cell type: Case report and literature review of 26 cases.

    PubMed

    Simpson, W Greg; Lopez, Armando; Babbar, Paurush; Payne, Lynnetta Faith

    2015-01-01

    Primary lymphoma of the urinary bladder is exceedingly rare, representing 0.2% of all extranodal non-Hodgkin's lymphoma. Although Matsuno et al. and others state the most common type is mucosa-associated lymphoid tissue (MALT) lymphoma, 20% of all the primary lymphomas of the urinary bladder are considered to be high grade neoplasms; the majority being diffuse large B-cell lymphoma (DLBCL). This is a case report of a 48-year-old man that presented with hematuria, frequency, nocturia, and flank pain that was found to have high grade DLBCL. Twenty-six other cases of both low and high grade primary bladder lymphomas were selected in order to provide a thorough comparison of different treatment modalities. Of the cases reviewed, bladder lymphoma was more common in females (2:1). The average age at diagnosis was 63.9 years old (low grade: 68.7 years old, high grade: 58.8 years old). The most common low-grade neoplasm was MALT lymphoma (85.7%). For the low-grade malignancies, the most successful treatments were simple therapies (2 transurethral resection of a bladder tumour [TURBT], 1 antibiotics), solitary chemotherapy, and combination TURBT/chemo; all 3 of which achieved 100% clinical remission (CR) in the cases reviewed. The most common high grade neoplasm was DLBCL (76.9%). The most successful therapies used to treat high grade lesions were solitary chemotherapy (cyclophosphamide, duanorubacin, vincristine, prednisolone [CHOP] or ritoximab, CHOP [R-CHOP]) and combination therapies (2 radiation/CHOP, 2 surgery/CHOP). In the agreement with the current literature, this review has shown that simple therapies (TURBT) are equally as effective as aggressive treatments (chemotherapy, radiation) and should therefore be used as first line treatment in low grade tumors. For high grade malignancies, chemotherapy (R-CHOP or CHOP) alone or combination therapy (CHOP/surgery or CHOP/radiation) is recommended. PMID:25837971

  5. [Lymphoma of Ocular and Periocular Tissues - Clinicopathological Correlations].

    PubMed

    Schmack, I; Grossniklaus, H E; Hartmann, S

    2016-07-01

    Lymphomas of the ocular adnexa and intraocular tissue include a wide range of lymphoproliferative neoplastic disorders. They are predominantly extranodal non-Hodgkin lymphomas (NHL). The World Health Organization (WHO) classification of lymphoid neoplasm and individual morphological, immunophenotypical, and molecular genetic features, indicate that they may be divided into B-cell (approximately 80 % of all NHL) and T-cell lymphomas (approximately 10-20 % of all NHL). The most common forms of ocular NHL are extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphoid tissue (MALT-type), follicular lymphoma (FL), diffuse large B-cell lymphoma, and mantel cell lymphoma. The clinical signs and symptoms are usually very unspecific and depend on the location, size, and extent of the underlying lymphoma subtype. Typical low grade lymphomas have an indolent clinical course and often remain unrecognized for many years. On the other hand, high grade NHLs, such as DLBCL or MCL, are frequently aggressive, with rapid tumour growth and poor prognosis, despite early detection. Histopathology is still the gold standard in the diagnosis of ocular lymphomas. Basic understanding of the principal pathophysiological and clinical aspects of the development and progression of orbital and ocular lymphomas seems to be mandatory for optimal diagnosis and treatment and for improving survival and prognosis. Both residents in training and board certified ophthalmologists should be aware of these problems. PMID:27468099

  6. Epitope-driven DNA vaccine design employing immunoinformatics against B-cell lymphoma: a biotech's challenge.

    PubMed

    Iurescia, Sandra; Fioretti, Daniela; Fazio, Vito Michele; Rinaldi, Monica

    2012-01-01

    DNA vaccination has been widely explored to develop new, alternative and efficient vaccines for cancer immunotherapy. DNA vaccines offer several benefits such as specific targeting, use of multiple genes to enhance immunity and reduced risk compared to conventional vaccines. Rapid developments in molecular biology and immunoinformatics enable rational design approaches. These technologies allow construction of DNA vaccines encoding selected tumor antigens together with molecules to direct and amplify the desired effector pathways, as well as highly targeted vaccines aimed at specific epitopes. Reliable predictions of immunogenic T cell epitope peptides are crucial for rational vaccine design and represent a key problem in immunoinformatics. Computational approaches have been developed to facilitate the process of epitope detection and show potential applications to the immunotherapeutic treatment of cancer. In this review a number of different epitope prediction methods are briefly illustrated and effective use of these resources to support experimental studies is described. Epitope-driven vaccine design employs these bioinformatics algorithms to identify potential targets of vaccines against cancer. In this paper the selection of T cell epitopes to develop epitope-based vaccines, the need for CD4(+) T cell help for improved vaccines and the assessment of vaccine performance against tumor are reviewed. We focused on two applications, namely prediction of novel T cell epitopes and epitope enhancement by sequence modification, and combined rationale design with bioinformatics for creation of new synthetic mini-genes. This review describes the development of epitope-based DNA vaccines and their antitumor effects in preclinical research against B-cell lymphoma, corroborating the usefulness of this platform as a potential tool for cancer therapy. Achievements in the field of DNA vaccines allow to overcome hurdles to clinical translation. In a scenario where the vaccine

  7. Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era

    PubMed Central

    Gisselbrecht, Christian; Glass, Bertram; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Ketterer, Nicolas; Shpilberg, Ofer; Hagberg, Hans; Ma, David; Brière, Josette; Moskowitz, Craig H.; Schmitz, Norbert

    2010-01-01

    Purpose Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients and Methods Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. Results The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001). Conclusion In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP. PMID:20660832

  8. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma.

    PubMed

    Nakamura, Nobuhiko; Hara, Takeshi; Shibata, Yuhei; Matsumoto, Takuro; Nakamura, Hiroshi; Ninomiya, Soranobu; Kito, Yusuke; Kitagawa, Junichi; Kanemura, Nobuhiro; Goto, Naoe; Shiraki, Makoto; Miyazaki, Tatsuhiko; Takeuchi, Tamotsu; Shimizu, Masahito; Tsurumi, Hisashi

    2015-12-01

    Sarcopenia reportedly predicts poor outcomes in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, because previous studies only involved elderly patients, it is difficult to generalize these results to all patients with DLBCL. We retrospectively analyzed 207 patients with DLBCL who received the R-CHOP or R-THP-COP regimen between June 2004 and May 2014. Sarcopenia was measured by the analysis of CT images at the L3 level before treatment. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm(2)/m(2)). Median age at diagnosis in the 121 males and 86 females was 67 years (range, 19-86 years). The sex-specific cutoffs for the L3 SMI were determined by receiver operator curve (ROC) analysis. Sarcopenic patients were older than non-sarcopenic patients, with a median age of 70 and 65 years, respectively (p < 0.001). Other International Prognostic Index factors were not significantly different when comparing sarcopenic and non-sarcopenic patients. With a median follow-up of 50.4 months, the 3-year overall survival (OS) was 70 % in the sarcopenic group and 85 % in the non-sarcopenic group (p = 0.0260). In a subgroup analysis by gender, there was a significant difference in the OS when comparing sarcopenic and non-sarcopenic patients in males but not in females (p = 0.0003, p = 0.4440, respectively). Sarcopenia is an independent prognostic factor in male patients with DLBCL. PMID:26385388

  9. Diffuse large B-cell lymphoma of the breast: prognostic factors and treatment outcomes

    PubMed Central

    Sun, Yao; Joks, Monika; Xu, Li-Ming; Chen, Xiu-Li; Qian, Dong; You, Jin-Qiang; Yuan, Zhi-Yong

    2016-01-01

    Background The breast is a rare site of extranodal involvement of diffuse large B-cell lymphoma (DLBCL). We aimed to assess the clinical characteristics, prognostic factors, and treatment outcomes of breast DLBCL. Patients and methods We retrospectively analyzed 113 patients (from our institution and the literature) between 1973 and 2014. The primary end point was overall survival (OS). Kaplan–Meier OS curves were compared with the log-rank test. Cox regression analysis was applied to determine the prognostic factors for OS, progression-free survival (PFS), local control (LC), and cause-specific survival (CSS). Results A total of 113 patients were included in the study: 42 cases from our hospital and 71 cases from 12 publications. The median age at diagnosis was 58 years. With a median follow-up time of 39.2 months, the estimated 5-year OS, PFS, LC, and CSS were 71.4%, 58.8%, 75.6%, and 74.9%, respectively. In multivariate analysis, more than four cycles of chemotherapy, having localized cancer, lumpectomy with or without axillary lymph node (ALN) dissection, and low to low-to-intermediate International Prognostic Index were favorable factors for OS. For PFS, significant prognostic factors were rituximab use, B symptoms, and tumor size. As for the local group, lumpectomy with or without ALN dissection and more than four cycles of chemotherapy were favorable factors for OS. Tumor size >4 cm and nonuse of rituximab were adverse factors for PFS. Twenty-one patients (18.6%) developed local relapse and 33 (29.2%) developed systemic relapse. Eight patients had central nervous system relapse (7.3%). Conclusion Our results reveal that local and extended staging criteria can reflect the different prognosis and treatment outcomes of breast DLBCL. Rituximab use, lumpectomy, and more than four cycles of chemotherapy are recommended as a treatment regimen. However, further study is warranted to validate our data. PMID:27103833

  10. HLA-G and MHC Class II Protein Expression in Diffuse Large B-Cell Lymphoma.

    PubMed

    Jesionek-Kupnicka, Dorota; Bojo, Marcin; Prochorec-Sobieszek, Monika; Szumera-Ciećkiewicz, Anna; Jabłońska, Joanna; Kalinka-Warzocha, Ewa; Kordek, Radzisław; Młynarski, Wojciech; Robak, Tadeusz; Warzocha, Krzysztof; Lech-Maranda, Ewa

    2016-06-01

    The expression of human leukocyte antigen-G (HLA-G) and HLA class II protein was studied by immunohistochemical staining of lymph nodes from 148 patients with diffuse large B-cell lymphoma (DLBCL) and related to the clinical course of the disease. Negative HLA-G expression was associated with a lower probability of achieving a complete remission (p = 0.04). Patients with negative HLA-G expression tended towards a lower 3-year overall survival (OS) rate compared to those with positive expression of HLA-G (p = 0.08). When restricting the analysis to patients receiving chemotherapy with rituximab, the estimated 3-year OS rate of patients with positive HLA-G expression was 73.3 % compared with 47.5 % (p = 0.03) in those with negative expression. Patients with negative HLA class II expression presented a lower 3-year OS rate compared to subjects with positive expression (p = 0.04). The loss of HLA class II expression (p = 0.05) and belonging to the intermediate high/high IPI risk group (p = 0.001) independently increased the risk of death. HLA class II expression also retained its prognostic value in patients receiving rituximab; the 3-year OS rate was 65.3 % in patients with positive HLA class II expression versus 29.6 % (p = 0.04) in subjects that had loss of HLA class II expression. To our knowledge, for the first time, the expression of HLA-G protein in DLBCL and its association with the clinical course of the disease was demonstrated. Moreover, the link between losing HLA class II protein expression and poor survival of patients treated with immunochemotherapy was confirmed.

  11. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma.

    PubMed

    Nakamura, Nobuhiko; Hara, Takeshi; Shibata, Yuhei; Matsumoto, Takuro; Nakamura, Hiroshi; Ninomiya, Soranobu; Kito, Yusuke; Kitagawa, Junichi; Kanemura, Nobuhiro; Goto, Naoe; Shiraki, Makoto; Miyazaki, Tatsuhiko; Takeuchi, Tamotsu; Shimizu, Masahito; Tsurumi, Hisashi

    2015-12-01

    Sarcopenia reportedly predicts poor outcomes in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, because previous studies only involved elderly patients, it is difficult to generalize these results to all patients with DLBCL. We retrospectively analyzed 207 patients with DLBCL who received the R-CHOP or R-THP-COP regimen between June 2004 and May 2014. Sarcopenia was measured by the analysis of CT images at the L3 level before treatment. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm(2)/m(2)). Median age at diagnosis in the 121 males and 86 females was 67 years (range, 19-86 years). The sex-specific cutoffs for the L3 SMI were determined by receiver operator curve (ROC) analysis. Sarcopenic patients were older than non-sarcopenic patients, with a median age of 70 and 65 years, respectively (p < 0.001). Other International Prognostic Index factors were not significantly different when comparing sarcopenic and non-sarcopenic patients. With a median follow-up of 50.4 months, the 3-year overall survival (OS) was 70 % in the sarcopenic group and 85 % in the non-sarcopenic group (p = 0.0260). In a subgroup analysis by gender, there was a significant difference in the OS when comparing sarcopenic and non-sarcopenic patients in males but not in females (p = 0.0003, p = 0.4440, respectively). Sarcopenia is an independent prognostic factor in male patients with DLBCL.

  12. A two-scale model for correlation between B cell VDJ usage in zebrafish

    NASA Astrophysics Data System (ADS)

    Pan, Keyao; Deem, Michael

    2011-03-01

    The zebrafish (Danio rerio) is one of the model animals for study of immunology. The dynamics of the adaptive immune system in zebrafish is similar to that in higher animals. In this work, we built a two-scale model to simulate the dynamics of B cells in primary and secondary immune reactions in zebrafish and to explain the reported correlation between VDJ usage of B cell repertoires in distinct zebrafish. The first scale of the model consists of a generalized NK model to simulate the B cell maturation process in the 10-day primary immune response. The second scale uses a delay ordinary differential equation system to model the immune responses in the 6-month lifespan of zebrafish. The generalized NK model shows that mature B cells specific to one antigen mostly possess a single VDJ recombination. The probability that mature B cells in two zebrafish have the same VDJ recombination increases with the B cell population size or the B cell selection intensity and decreases with the B cell hypermutation rate. The ODE model shows a distribution of correlation in the VDJ usage of the B cell repertoires in two six-month-old zebrafish that is highly similar to that from experiment. This work presents a simple theory to explain the experimentally observed correlation in VDJ usage of distinct zebrafish B cell repertoires after an immune response.

  13. Detection of MYD88 L265P in patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia and other B-cell non-Hodgkin lymphomas

    PubMed Central

    Shin, Sang-Yong; Kim, Hyun-Young; Park, Chang-Hun; Kim, Hee-Jin; Kim, Jong-Won; Kim, Seok Jin; Kim, Won Seog

    2016-01-01

    Background Recent studies have identified a high prevalence of the MYD88 L265P mutation in lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) cases, whereas low frequencies have been observed in other B cell non-Hodgkin lymphomas (NHLs). Methods We evaluated the sensitivity of the mutant enrichment 3'-modified oligonucleotide (MEMO)-PCR technique, a new detection method. We examined the MYD88 L265P mutation in a series of Korean patients with LPL/WM and other B cell NHLs in bone marrow aspirates, using the MEMO-PCR technique. Results The sensitivity of MEMO-PCR was estimated to be approximately 10-16.7%. MYD88 L265P was detected in 21 of 28 LPL cases (75%) and only three of 69 B cell NHL cases (4.3%). Conclusion Although MEMO-PCR had relatively low sensitivity, we confirmed the high prevalence of the MYD88 L265P mutation in Korean LPL patients. Our study suggests the diagnostic value of MYD88 L265P for differentiating B-cell NHLs.

  14. Activation of the Endoplasmic Reticulum Stress-Associated Transcription Factor X Box-Binding Protein-1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive B-Cell Lymphomas with Prognostic Implications

    PubMed Central

    Balague, Olga; Mozos, Ana; Martinez, Daniel; Hernandez, Luis; Colomo, Lluis; Mate, Jose Luis; Teruya-Feldstein, Julie; Lin, Oscar; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio

    2009-01-01

    X box-binding protein 1 (Xbp-1) is a transcription factor that is required for the terminal differentiation of B lymphocytes into plasma cells. The Xbp-1 gene is activated in response to endoplasmic reticulum stress signals, which generate a 50-kDa nuclear protein that acts as a potent transactivator and regulates the expression of genes related to the unfolded protein response. Activated Xbp-1 is essential for cell survival in plasma-cell tumors but its role in B-cell lymphomas is unknown. We analyzed the expression of activated Xbp-1 in reactive lymphoid tissues, 411 lymphomas and plasma-cell neoplasms, and 24 B-cell lines. In reactive tissues, Xbp-1 was only found in nuclear extracts. Nuclear expression of Xbp-1 was observed in occasional reactive plasma cells and in a subpopulation of Irf-4+/Bcl-6−/Pax-5− B cells in the light zones of reactive germinal centers, probably representing cells committed to plasma-cell differentiation. None of the low-grade lymphomas showed evidence of Xbp-1 activation; however, Xbp-1 activation was found in 28% of diffuse large B-cell lymphomas, independent of germinal or postgerminal center phenotype, as well as in 48% of plasmablastic lymphomas and 69% of plasma-cell neoplasms. Diffuse large B-cell lymphomas with nuclear Xbp-1 expression had a significantly worse response to therapy and shorter overall survival compared with negative tumors. These findings suggest that Xbp-1 activation may play a role in the pathogenesis of aggressive B-cell lymphomas. PMID:19389935

  15. Differential expression of viral agents in lymphoma tissues of patients with ABC diffuse large B-cell lymphoma from high and low endemic infectious disease regions

    PubMed Central

    Högfeldt, Therese; Jaing, Crystal; Loughlin, Kevin Mc; Thissen, James; Gardner, Shea; Bahnassy, Abeer A.; Gharizadeh, Baback; Lundahl, Joachim; Österborg, Anders; Porwit, Anna; Zekri, Abdel-Rahman N.; Khaled, Hussein M.; Mellstedt, Håkan; Moshfegh, Ali

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma (NHL) in adults, accounts for approximately 30–40% of newly diagnosed lymphomas worldwide. Environmental factors, such as viruses and bacteria, may contribute to cancer development through chronic inflammation and the integration of oncogenes, and have previously been indicated in cervical cancer, hepatocellular carcinoma, gastric cancer and lymphoproliferative disorders. In the present study, the presence of microbial agents was analyzed in the lymphoma tissue of patients with activated B-cell like (ABC) DLBCL. The present study compared two groups of patients from geographically varied regions that possess a difference in the prevalence of viral and other microbial agents. The patient populations were from Sweden (a low endemic infectious disease region) and Egypt (a high endemic infectious disease region). A differential expression of several viruses in lymphoma tissues was noted when comparing Swedish and Egyptian patients. JC polyomavirus (JCV) was detected in Swedish and Egyptian patients and, uniquely, the complete hepatitis B virus (HBV) genome was detected only in Egyptian lymphoma patients. None of these viruses were detected in control lymph tissues from Sweden or Egypt. In total, 38% of the Egyptian patients were found to have HBV surface antigens (HBsAgs) in their serum; however, HBsAgs were not found in any of the Swedish patients. The percentage of serum HBsAgs in Egyptian patients with ABC DLBCL was significantly increased compared with the general Egyptian population (P<0.05). The present study may support a notion that viral agents, including JCV and HBV, may be involved in the tumorigenesis of DLBCL in regions of high infectious disease. PMID:27698858

  16. Differential expression of viral agents in lymphoma tissues of patients with ABC diffuse large B-cell lymphoma from high and low endemic infectious disease regions

    PubMed Central

    Högfeldt, Therese; Jaing, Crystal; Loughlin, Kevin Mc; Thissen, James; Gardner, Shea; Bahnassy, Abeer A.; Gharizadeh, Baback; Lundahl, Joachim; Österborg, Anders; Porwit, Anna; Zekri, Abdel-Rahman N.; Khaled, Hussein M.; Mellstedt, Håkan; Moshfegh, Ali

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma (NHL) in adults, accounts for approximately 30–40% of newly diagnosed lymphomas worldwide. Environmental factors, such as viruses and bacteria, may contribute to cancer development through chronic inflammation and the integration of oncogenes, and have previously been indicated in cervical cancer, hepatocellular carcinoma, gastric cancer and lymphoproliferative disorders. In the present study, the presence of microbial agents was analyzed in the lymphoma tissue of patients with activated B-cell like (ABC) DLBCL. The present study compared two groups of patients from geographically varied regions that possess a difference in the prevalence of viral and other microbial agents. The patient populations were from Sweden (a low endemic infectious disease region) and Egypt (a high endemic infectious disease region). A differential expression of several viruses in lymphoma tissues was noted when comparing Swedish and Egyptian patients. JC polyomavirus (JCV) was detected in Swedish and Egyptian patients and, uniquely, the complete hepatitis B virus (HBV) genome was detected only in Egyptian lymphoma patients. None of these viruses were detected in control lymph tissues from Sweden or Egypt. In total, 38% of the Egyptian patients were found to have HBV surface antigens (HBsAgs) in their serum; however, HBsAgs were not found in any of the Swedish patients. The percentage of serum HBsAgs in Egyptian patients with ABC DLBCL was significantly increased compared with the general Egyptian population (P<0.05). The present study may support a notion that viral agents, including JCV and HBV, may be involved in the tumorigenesis of DLBCL in regions of high infectious disease.

  17. STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

    PubMed

    Mizowaki, Takashi; Sasayama, Takashi; Tanaka, Kazuhiro; Mizukawa, Katsu; Takata, Kumi; Nakamizo, Satoshi; Tanaka, Hirotomo; Nagashima, Hiroaki; Nishihara, Masamitsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

    2015-09-01

    Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

  18. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis

    PubMed Central

    Pangault, Céline; Amé-Thomas, Patricia; Ruminy, Philippe; Rossille, Delphine; Caron, Gersende; Baia, Maryse; De Vos, John; Roussel, Mikael; Monvoisin, Céline; Lamy, Thierry; Tilly, Hervé; Gaulard, Philippe; Tarte, Karin; Fest, Thierry

    2010-01-01

    Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained on whole biopsy samples, have been associated with patient survival. In this study we performed gene expression profiling of purified B-cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 nonredundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an IL-4-centered pathway associated with an activation of STAT6 that favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (TFH), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6pos B cells were located at the vicinity of cells expressing the PD-1 TFH marker. Moreover, purified FL-derived TFH, expressed IL4 at very high levels compared to purified tonsil-derived TFH or non-TFH microenvironment. Altogether, our study demonstrated that tumor-infiltrating TFH specifically express functional IL-4 in FL, creating an IL-4-dependent TFH-B cell axis. This crosstalk could sustain FL pathogenesis and represent a new potential therapeutic target. PMID:20944673

  19. Primary cardiac diffuse large B-cell lymphoma in immunocompetent patients: clinical, histologic, immunophenotypic, and genotypic features of 3 cases.

    PubMed

    Soon, Gwyneth; Ow, Guan Wei; Chan, Hian Li; Ng, Siok Bian; Wang, Shi

    2016-10-01

    Primary cardiac lymphoma (PCL) is a rare extranodal lymphoma that involves only the heart and/or pericardium. Primary cardiac lymphoma is much less common in immunocompetent patients compared with those who are immunosuppressed. Patients with PCL have variable clinical manifestations that may lead to misdiagnosis and delay in treatment. Modern radiologic imaging now allows for earlier detection of these tumors. This study describes the clinical, histologic/cytologic, immunophenotypic, and molecular genetic findings for 3 immunocompetent patients with primary cardiac diffuse large B-cell lymphoma. All 3 patients had different initial clinical presentations. The neoplastic cells in all 3 cases were large in size, morphologically resembling diffuse large B-cell lymphoma. Neoplastic cells in 2 cases had non-germinal center (GC)-like (non-GC-like) and 1 case had GC-like immunophenotype. Neoplastic cells in all 3 cases showed C-MYC and BCL2 immunohistochemical protein coexpression. Neoplastic cells in 1 case showed double-hit MYC and BCL2 gene rearrangements, whereas another 1 case showed MYC gene rearrangement without BCL2 gene rearrangement. Epstein-Barr virus-encoded RNA was negative in the neoplastic cells in all 3 cases. All 3 patients received rituximab-based chemotherapy. Two patients subsequently had disease relapse at other extranodal sites at 10 and 24 months, respectively, whereas 1 patient was alive without disease at 9 months after diagnosis. If there is sufficient diagnostic tissue in these rare tumors, molecular studies should ideally be performed for prognostication and further patient management. PMID:27649953

  20. DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

    PubMed Central

    Amin, Rada; Mourcin, Frédéric; Uhel, Fabrice; Pangault, Céline; Ruminy, Philippe; Dupré, Loic; Guirriec, Marion; Marchand, Tony; Fest, Thierry; Lamy, Thierry

    2015-01-01

    Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM+ FL B cells activated a stronger BCR signaling network than IgG+ FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM+ FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN–dependent adhesion of highly mannosylated IgM+ FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN–expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets. PMID:26272216

  1. DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma

    PubMed Central

    Schmid, Corina A.; Robinson, Mark D.; Scheifinger, Nicole A.; Müller, Sebastian; Cogliatti, Sergio; Tzankov, Alexandar

    2015-01-01

    The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton’s tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling. PMID:25847947

  2. Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma.

    PubMed

    Popov, Sergey W; Moldenhauer, Gerhard; Wotschke, Beate; Brüderlein, Silke; Barth, Thomas F; Dorsch, Karola; Ritz, Olga; Möller, Peter; Leithäuser, Frank

    2007-07-15

    Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL. PMID:17638864

  3. Primary diffuse large B-cell lymphoma of the corpora cavernosa presented as a perineal mass

    PubMed Central

    Carlos, González-Satué; Ivanna, Valverde Vilamala; Gustavo, Tapia Melendo; Joan, Areal Calama; Javier, Sanchez Macias; Luis, Ibarz Servio

    2012-01-01

    Primary male genital lymphomas may appear rarely in testis, and exceptionally in the penis and prostate, but there is not previous evidence of a lymphoma arising from the corpora cavernosa. We report the first case in the literature of a primary diffuse cell B lymphoma of the corpora cavernosa presented with low urinary tract symptoms, perineal pain and palpable mass. Diagnosis was based on trucut biopsy, histopathological studies and computed tomographic images. PMID:22919138

  4. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort.

    PubMed

    Evens, Andrew M; Kanakry, Jennifer A; Sehn, Laurie H; Kritharis, Athena; Feldman, Tatyana; Kroll, Aimee; Gascoyne, Randy D; Abramson, Jeremy S; Petrich, Adam M; Hernandez-Ilizaliturri, Francisco J; Al-Mansour, Zeina; Adeimy, Camille; Hemminger, Jessica; Bartlett, Nancy L; Mato, Anthony; Caimi, Paolo F; Advani, Ranjana H; Klein, Andreas K; Nabhan, Chadi; Smith, Sonali M; Fabregas, Jesus C; Lossos, Izidore S; Press, Oliver W; Fenske, Timothy S; Friedberg, Jonathan W; Vose, Julie M; Blum, Kristie A

    2015-09-01

    Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous

  5. Useful Strategy of Pulmonary Microvascular Cytology in the Early Diagnosis of Intravascular Large B-cell Lymphoma in a Patient with Hypoxemia: A Case Report and Literature Review.

    PubMed

    Yamakawa, Hideaki; Yoshida, Masahiro; Yabe, Masami; Baba, Emiri; Ishikawa, Takeo; Takagi, Masamichi; Katagi, Hiroaki; Kuwano, Kazuyoshi

    2015-01-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma characterized by the presence of tumor cells within blood vessels, and it is considered to be a subtype of diffuse large B-cell lymphoma. We report a case of IVLBCL presenting as progressive hypoxemia. In this case, a definitive diagnosis could not be achieved by repeated transbronchial lung biopsy, a bone marrow biopsy, and a random skin biopsy, and the ultimate diagnosis was made on the basis of a pulmonary microvascular cytology (PMC) examination. Therefore, PMC is considered to be a useful strategy for the diagnosis of IVLBCL, particularly in this critically ill patient suffering from hypoxemia.

  6. p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

    PubMed Central

    Sáez, Al; Sánchez, E; Sánchez-Beato, M; Cruz, M A; Chacón, I; Muñoz, E; Camacho, F I; Martínez-Montero, J C; Mollejo, M; Garcia, J F; Piris, M A

    1999-01-01

    Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27KIP1 staining. We analysed p27KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27KIP1 was found in lymphomas of this type. The overall correlation between p27KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins. © 1999 Cancer Research Campaign PMID:10424746

  7. Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma presenting in nasal cavity: a case report and review of literature

    PubMed Central

    Chen, Ji; Feng, Xiaoli; Dong, Mei

    2015-01-01

    Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin’s lymphoma (NHL) with distinct morphologic and immunohistochemical features. We reported a 57-year-old female with ALK-positive DLBCL in her left nasal cavity. Histologically, the tumor cells were characterized by plasmablastic morphology and tested positive for ALK in a cytoplasmic granular staining pattern. The neoplastic cells were positive for CD38, CD4, MUM1, CD138 and Vimentin. However, they failed to express CD56, CD30, as well as mature B cells markers, such as CD79a, CD20 and T cells markers such as CD2, CD3, CD5, CD7 and CD8. The patient achieved complete response after four cycles of CHOEP (cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide) treatment. Then she received radiotherapy of the originally involved area. This case represented a rare ALK-positive DLBCL in the nasal region. PMID:25973114

  8. In Situ Hepatitis C NS3 Protein Detection Is Associated with High Grade Features in Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas

    PubMed Central

    Rabiega, Pascaline; Molina, Thierry J.; Charlotte, Frédéric; Lazure, Thierry; Davi, Frédéric; Settegrana, Catherine; Berger, Françoise; Alric, Laurent; Cacoub, Patrice; Terrier, Benjamin; Suarez, Felipe; Sibon, David; Dupuis, Jehan; Feray, Cyrille; Tilly, Hervé; Pol, Stanislas; Deau Fischer, Bénédicte; Roulland, Sandrine; Thieblemont, Catherine; Leblond, Véronique; Carrat, Fabrice; Hermine, Olivier; Besson, Caroline

    2016-01-01

    Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the "ANRS HC-13 LymphoC" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas. PMID:27257992

  9. B cell non-Hodgkin's lymphoma in a girl with the DiGeorge anomaly

    PubMed Central

    Ramos, J.; Lopez-Laso, E.; Ruiz-Contreras, J.; Giancaspro, E.; Madero, S.

    1999-01-01

    The DiGeorge anomaly (DGA) is occasionally associated with cellular immunodeficiency. We report a female infant diagnosed with complete DGA, who developed fatal, high grade, non-Hodgkin's lymphoma that expressed Epstein-Barr virus (EBV). Non-Hodgkin's lymphoma should be considered in children with DGA.

 PMID:10519724

  10. Effect of unintentional cyclophosphamide underdosing on diffuse large B-cell lymphoma response to chemotherapy: a retrospective review

    PubMed Central

    Al-Ahmadi, Majed; Lazo-Langner, Alejandro; Mangel, Joy; Phm, Ally Dhalla BSc; Liu, Kevin; Minuk, Leonard

    2016-01-01

    Background: Between March 2012 and March 2013, a miscommunication in labelling between the drug compounder supplier and cancer centre pharmacies resulted in accidental overdilution of cyclophosphamide and gemcitabine used by several cancer centres in Canada. At our centre, 177 hematology patients were affected, among whom the largest subset of patients was those with diffuse large B-cell lymphoma. In this study, we evaluated the effect of such underdosing on disease response. Methods: We conducted a retrospective cohort study involving all patients with diffuse large B-cell lymphoma who received at least 1 chemotherapy cycle containing diluted cyclophosphamide at our centre and compared them with a historical group of patients matched by stage and age. The primary outcome was event-free survival (a composite of disease progression or death). Secondary outcomes included complete remission and overall response rate. Groups were compared using unpaired Student t, χ2 or Fisher exact tests, as appropriate. Survival analysis was done using the Kaplan-Meier method. Results: Event-free survival was no different between groups (log-rank p = 0.99). At a median follow-up of 548 days, progression or death occurred in 21 of 77 patients in the case group (27.3%) and in 24 of 74 patients in the control group (32.4%) (p = 0.5). At the end of treatment, complete remission was achieved in 41 patients in the case group (53.2%) and 43 patients in the control group (57.3%) (p = 0.6), whereas overall response rate was 71.4% in the case group and 66.7% in the control group (p = 0.5). Interpretation: Compared with a historical control group, we found no differences in event-free survival or response rates among patients with diffuse large B-cell lymphoma who received 1 or more doses of accidentally diluted cyclophosphamide-containing chemotherapy. PMID:27398369

  11. The Role of Autologous Stem Cell Transplantation in the Treatment of Diffuse Large B-Cell Lymphoma

    PubMed Central

    Gunnellini, Marco; Emili, Rita; Coaccioli, Stefano; Liberati, Anna Marina

    2012-01-01

    Diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) accounting for approximately 30% of new lymphoma diagnoses in adult patients. Complete remissions (CRs) can be achieved in 45% to 55% of patients and cure in approximately 30–35% with anthracycline-containing combination chemotherapy. The ageadjusted IPI (aaIPI) has been widely employed, particularly to “tailor” more intensive therapy such as high-dose therapy (HDT) with autologous hemopoietic stem cell rescue (ASCT). IPI, however, has failed to reliably predict response to specific therapies. A subgroup of young patients with poor prognosis exists. To clarify the role of HDT/ASCT combined with rituximab in the front line therapy a longer follow-up and randomized studies are needed. The benefit of HDT/ASCT for refractory or relapsed DLBCL is restricted to patients with immunochemosensitive disease. Currently, clinical and biological research is focused to improve the curability of this setting of patients, mainly young. PMID:22312366

  12. Fever and arthralgia as the initial symptoms of primary bone marrow diffuse large B-cell lymphoma: A case report

    PubMed Central

    REN, SAISAI; TAO, YANLING; JIA, LU; CHENG, PANPAN; ZHANG, JILEI; ZHANG, HAO

    2016-01-01

    Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is rare, and only a few cases have been reported. Fever and arthralgia as the initial symptom are extremely rare; however, awareness must be made of this presentation. The current study describes the clinical and pathological findings of a 41-year-old man affected by fever and arthralgia. Blood tests revealed leukopenia and anemia. Multiple bone marrow biopsies were conducted and confirmed the diagnosis of primary bone marrow DLBCL. Primary bone marrow DLBCL is a rare and frequently misdiagnosed subset of non-Hodgkin's lymphoma. The current case demonstrates that utility of bone marrow biopsy for diagnosis should not be ignored, and that repeated bone marrow punctures in multiple locations may be necessary. PMID:27123129

  13. Evidence that the malignant lymphoma of Sjögren's syndrome is a monoclonal B-cell neoplasm.

    PubMed

    Zulman, J; Jaffe, R; Talal, N

    1978-11-30

    We studied the malignant lymphomas that developed in patients with Sjögren's syndrome and the antecedent benign salivary-gland lesions to determine their cellular characteristics. We used an immunoperoxidase technic that identified intracellular gamma, alpha and mu heavy chains and kappa and lambda light chains. In six of nine patients, the lymphomas were composed of cells containing intracytoplasmic immunoglobulin that was exclusively IgMK. The benign lymphoepithelial salivary-gland lesions preceding these malignant tumors consisted of approximately equal numbers of lymphoid cells containing either kappa or lambda light chains. Thus, in some patients with Sjögren's syndrome, there may be a progression in the lympho-proliferative lesions from a polyclonal infiltrate to a monoclonal neoplasm. Intracytoplasmic immunoglobulin identifies six of the nine cases as being B-cell in origin.

  14. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma

    PubMed Central

    Nielsen, Torsten Holm; Yu, Stephen; Alcaide, Miguel; Chong, Lauren; MacDonald, David; Tosikyan, Axel; Kukreti, Vishal; Kezouh, Abbas; Petrogiannis-Haliotis, Tina; Albuquerque, Marco; Fornika, Daniel; Alamouti, Sepideh; Froment, Remi; Greenwood, Celia M. T.; Oros, Kathleen Klein; Camglioglu, Errol; Sharma, Ayushi; Christodoulopoulos, Rosa; Rousseau, Caroline; Johnson, Nathalie; Crump, Michael; Morin, Ryan D.; Mann, Koren K.

    2016-01-01

    The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to “not reached”). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692). PMID:27166360

  15. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma.

    PubMed

    Scuto, Anna; Kujawski, Maciej; Kowolik, Claudia; Krymskaya, Ludmila; Wang, Lin; Weiss, Lawrence M; Digiusto, David; Yu, Hua; Forman, Stephen; Jove, Richard

    2011-05-01

    Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy.

  16. Epstein Barr virus in relation to apoptosis markers and patients' outcome in pediatric B-cell non-Hodgkin lymphoma.

    PubMed

    Chabay, P; Lara, J; Lorenzetti, M; Cambra, P; Acosta Haab, G; Aversa, L; De Matteo, E; Preciado, M V

    2011-08-28

    In this study, we investigated Epstein Barr virus (EBV) presence, associated to proliferation and apoptosis proteins in pediatric B-cell Non-Hodgkin lymphoma (B-NHL). EBERs, Ki67, active caspase 3, Bax and Bcl2 were analyzed on B-NHL tissue from 40 patients. Forty percent showed EBV expression, significantly higher among patients ⩽10years (P=0.027), and associated with immunosuppression (P=0.020), but not associated apotosis markers. However, EBV was associated with a worse event-free survival (P=0.016), particularly under immunosuppression. Even though EBV did not seem to alter apoptotic pathways, it exhibited survival disadvantage and could be an important cofactor in B-cell lymphomagenesis in younger children. PMID:21546156

  17. STK38 is a Critical Upstream Regulator of MYC’s Oncogenic Activity in Human B-cell lymphoma

    PubMed Central

    Bisikirska, Brygida C.; Adam, Stacey J.; Alvarez, Mariano J.; Rajbhandari, Presha; Cox, Rachel; Lefebvre, Celine; Wang, Kai; Rieckhof, Gabrielle E.; Felsher, Dean W.; Califano, Andrea

    2013-01-01

    The MYC proto-oncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. While MYC constitutes a formidable therapeutic target, it also plays an essential role in normal physiology, thus creating the need for context--specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase-activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor (BCR) activation, while its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC addicted tumors in vivo thus providing a novel viable target for treating these malignancies. PMID:23178486

  18. High-resolution genomic profiling reveals clonal evolution and competition in gastrointestinal marginal zone B-cell lymphoma and its large cell variant.

    PubMed

    Flossbach, Lucia; Holzmann, Karlheinz; Mattfeldt, Torsten; Buck, Michaela; Lanz, Karin; Held, Michael; Möller, Peter; Barth, Thomas F E

    2013-02-01

    We studied marginal zone B-cell lymphomas of the gastrointestinal tract including seven small cell lymphomas, eight large cell areas of composite lymphomas and 13 large cell variants using SNP array profiling. We found an increase of genomic complexity with lymphoma progression from small to large cytology, and identified gains of prominent (proto) oncogenes such as REL, BCL11A, ETS1, PTPN1, PTEN and KRAS which were found exclusively in the large cell variants. Copy numbers of ADAM3A, SCAPER and SIRPB1 were varying between the three different modes of presentation, hence suggestive for aberrations associated with progression from small to large cell lymphoma. The number of aberrations was slightly higher in the large cell part of composite lymphomas than in large cell lymphomas, suggesting that clonal selection takes place and that composite lymphomas are in a transition state. To further investigate this, we comparatively analyzed samples of two morphologically different regions of the same small cell tumor with a BIRC3-MALT1 translocation, as well as material acquired at two different time points from one composite lymphoma. We found genomic heterogeneity in both cases, supporting the theory of competing subclones in the evolution and progression of extranodal marginal zone B-cell lymphoma.

  19. Perivertebral B-cell lymphoma in a Queensland koala (Phascolarctos cinereus adustus) with paralytic symptoms in the hind limbs.

    PubMed

    Kido, Nobuhide; Edamura, Kazuya; Inoue, Naomi; Shibuya, Hisashi; Sato, Tsuneo; Kondo, Masako; Shindo, Izumi

    2012-08-01

    A male Queensland koala (Phascolarctos cinereus adustus) at Kanazawa Zoological Gardens (Kanagawa, Japan) exhibited paralytic symptoms in the hind limbs. Computed tomography and magnetic resonance imaging revealed a mass on the left ventral side of the 11th to 13th thoracic vertebrae, and the presence of myelitis or edema in the spinal cord. The koala was under anesthesia during the examination and suddenly developed ventricular fibrillation and died. Necropsy revealed a firm flat ovoid hemorrhagic mass on the vertebrae. Following a microscopic examination including immunohistochemistry, the perivertebral mass was diagnosed as B cell lymphoma. Therefore, neoplastic cell infiltration into the spinal cord may cause paralytic symptoms in the hind limbs.

  20. Mycobacterium haemophilum as the Initial Presentation of a B-Cell Lymphoma in a Liver Transplant Patient

    PubMed Central

    Doherty, T.; Lynn, M.; Cavazza, A.; Sames, E.; Hughes, R.

    2014-01-01

    A 66-year-old woman presented with pustular lesions of her face, trunk, and limbs and an acute arthritis of the knees and elbows. She had a complex medical background and had been on immunosuppressants for three years after a liver transplant. Tissue samples from her skin lesions and synovial fluid showed acid-fast bacilli. Mycobacterium haemophilum, an atypical mycobacteria, was later grown on culture. During her treatment with combination antibiotic therapy, she developed a pronounced generalised lymphadenopathy. Histology showed features of a diffuse B-cell lymphoma, a posttransplant lymphoproliferative disorder (PTLD). PMID:24523979

  1. Integrating understanding of epidemiology and genomics in B-cell non-Hodgkin lymphoma as a pathway to novel management strategies.

    PubMed

    Glass, Samantha; Phan, Anh; Williams, Jessica N; Flowers, Christopher R; Koff, Jean L

    2016-03-01

    Non-Hodgkin lymphomas include a biologically and clinically heterogeneous group of cancers distinguished by genetics, histology, and treatment outcomes. New discoveries regarding the genomic alterations and epidemiological exposures associated with these lymphomas have enhanced our understanding of factors that contribute to lymphomagenesis for specific subtypes. We explore the impact of normal B-cell biology engineered for recognizing a wide variety of antigens on the development of specific lymphoma subtypes, review lymphoma genetics, and examine the epidemiology of B-cell NHLs including recent investigations of risk factors for particular lymphoma subtypes based on large pooled analyses. Burkitt lymphoma, an aggressive form of B-cell NHL involving translocation of the MYC gene and an immunoglobulin gene has been associated with a history of eczema, hepatitis C, and occupation as a cleaner. Increased risk of diffuse large B-cell lymphoma has been associated with increased young adult body mass index, history of B-cell-activating autoimmune diseases, hepatitis C, and several single nucleotide variants involving the human leukocyte antigen (HLA) region of chromosome 6 and non-HLA loci near EXOC2, PVT1, MYC, and NCOA1. Tumor sequencing studies suggest that multiple pathways are involved in the development of DLBCL. Additional studies of epidemiological exposures, genome wide associations, and tumor sequencing in follicular, lymphoplasmacytic, marginal zone, and mantle cell lymphoma demonstrate overlapping areas of increased risk factors and unique factors for specific subtypes. Integrating these findings is important for constructing comprehensive models of NHL pathogenesis, which could yield novel targets for therapy and strategies for lymphoma prevention in certain populations. PMID:27115168

  2. The utility of lactate dehydrogen