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Sample records for gastric b-cell lymphoma

  1. 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

  2. B-cell clonality and infection with Helicobacter pylori: implications for development of gastric lymphoma.

    PubMed Central

    Sorrentino, D; Ferraccioli, G F; DeVita, S; Avellini, C; Beltrami, C A; Labombarda, A; Bernardis, V; De Biase, F; Trevisi, A; Pivetta, B; Boiocchi, M; Bartoli, E

    1996-01-01

    BACKGROUND: Although Helicobacter pylori has been implicated in the pathogenesis of gastric mucosa associated lymphoid tissue (MALT) and MALT lymphoma, it is not known how it may trigger these lesions and whether there is an identifiable pre-neoplastic stage. AIMS: To investigate the relation between MALT, H pylori infection, and B-cell clonality (a potential marker of pre-neoplastic lesions). PATIENTS: 141 subjects with simple dyspepsia. METHODS: Gastric biopsy specimens from all patients were examined for MALT and H pylori. Of these, 25 consecutive MALT positive specimens were scored for features of MALT lymphoma and VDJ clonality studied by polymerase chain reaction. RESULTS: Overall, prevalence was 62% for H pylori and 46% for MALT. VDJ clonality was frequent in the sub-group studied (nine of 25), mostly associated with lymphoid follicles (eight of nine or 89%), and with a high scoring for MALT lymphoma. VDJ clonality was equally frequent in patients with and without H pylori (seven of 20 and two of five or 35% and 40% respectively). CONCLUSIONS: B-cell clonality is unexpectedly common in subjects with simple dyspepsia and MALT raising clinical management questions. These findings also suggest that the cascade MALT formation--B-cell clonality--MALT lymphoma may not be uniquely associated with H pylori infection. PMID:8984020

  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. 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

  5. PET/CT findings in a case with FDG-avid disseminated lacrimal gland MALToma with sequential development of large B-cell lymphoma and gastric MALToma.

    PubMed

    Yildirim-Poyraz, Nilufer; Ozdemir, Elif; Basturk, Abdulkadir; Kilicarslan, Aydan; Turkolmez, Seyda

    2015-02-01

    Primary orbital lymphomas are rare; the major histopathologic type is extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MALToma. We present a case of a 79-year-old female patient with FDG-avid lacrimal gland MALToma with nodal and pulmonary involvement (stage IVE). Nasopharynx and gastric involvement were detected on restaging F-FDG PET/CT after rituximab therapy, and it was found to have a site of transformation to diffuse large B-cell lymphoma (DLBCL) in the nasopharynx. Gastric MALT lymphoma was also confirmed histopathologically, and she then underwent combination chemotherapy regimen, resulting in regression after 3 courses. PMID:24873799

  6. Spontaneous regression and recurrence of primary low-grade B-cell gastric lymphoma on the gastric stump 15 and 20 years after gastroresection.

    PubMed

    Pentimone, F; Moncini, C; Pastine, F; Gerini, A; Lucchesi, Q

    2002-09-01

    The recurrence of primary gastric lymphoma (PGL) on the gastric stump after gastroresection is rare. We describe the case of an 84-year-old man who had recurrences 15 and 20 years after a Billroth I gastrectomy. The concordance of the three gastric biopsies showing a low grade B-cell lymphocytic lymphoma of the mucosa-associated tissue, demonstrated the recurrence of the disease. The patient has serological evidence of Helicobacter pylori infection but the eradication therapy had no effect on the evolution of the disease. The case suggests that PGL is really a particular entity in the non-Hodgkin's lymphoma group, characterized by a long spontaneous natural history, with long lasting spontaneous remissions and recurrences. PMID:12094145

  7. 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

  8. Regression of gastric large B-Cell lymphoma accompanied by a florid lymphoma-like T-cell reaction: immunomodulatory effect of Ganoderma lucidum (Lingzhi)?

    PubMed

    Cheuk, Wah; Chan, John K C; Nuovo, Gerard; Chan, May K M; Fok, Manson

    2007-04-01

    Complete regression of high-grade lymphoma is extremely rare. We report 1 such case that might have been conceivably mediated by Ganoderma lucidum (Lingzhi), an immunomodulatory herbal medicine. A 47-year-old man presented with epigastric pain. Endoscopy revealed a large gastric ulcer, which on biopsy was diagnostic of large B-cell lymphoma. At gastrectomy 11 days later, no evidence was found of large B-cell lymphoma despite thorough sampling. Instead, there was a dense and permeative infiltrate of CD3(+) CD8(+) cytotoxic small T lymphocytes spanning the whole thickness of the gastric wall. In situ reverse transcription polymerase chain reaction for T-cell receptor beta-chain family did not detect a monoclonal T-cell population. We postulate that the cytotoxic T cells may represent an active host-immune response against the large B-cell lymphoma that resulted in a complete regression. On questioning, the patient had taken megadoses of Ganoderma lucidum, which might have triggered the successful immune reaction. PMID:17478779

  9. Risk factors and patterns of lymph node involvement in primary gastric large B-cell lymphoma: implications for target definition

    PubMed Central

    Zhang, Ximei; Wang, Peiguo; Zhao, Lujun; Yuan, Zhiyong; Wang, Ping

    2016-01-01

    Background The aim of this study was to identify the appropriate radiation volume for primary gastric diffuse large B-cell lymphoma (PG-DLBCL). Methods We retrospectively analyzed the clinical and pathological findings of 68 patients treated with total gastrectomy and D2 lymphadenectomy. Results There were 23, 14, and 29 patients with stage I, stage II, and stage IIE disease, respectively, and 30 patients had lymph node involvement. Primary tumor location, as well as the depth of invasion, was significantly associated with lymph node involvement. When the tumor was limited to the muscularis, the involved lymph nodes were found to be perigastric nodes. For tumors invading beyond the muscularis, regional lymph nodes were involved. Conclusion The optimal radiation volume for patients with PG-DLBCL is largely dependent on the primary location and depth of invasion. Larger series and longer follow-up are needed to further delineate the radiation volumes for PG-DLBCL. PMID:27536138

  10. 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

  11. Retrospective analysis of primary gastric diffuse large B cell lymphoma in the rituximab era: a multicenter study of 95 patients in Japan.

    PubMed

    Tanaka, Tsutomu; Shimada, Kazuyuki; Yamamoto, Kazuhito; Hirooka, Yoshiki; Niwa, Yasumasa; Sugiura, Isamu; Kitamura, Kunio; Kosugi, Hiroshi; Kinoshita, Tomohiro; Goto, Hidemi; Nakamura, Shigeo

    2012-03-01

    Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is common subtype of extranodal non-Hodgkin lymphoma. The optimal treatment strategy for PG-DLBCL in the rituximab era still remains unknown. To evaluate clinical outcomes of PG-DLBCL in the rituximab era, we conducted a retrospective, multicenter analysis of 95 patients with PG-DLBCL. In 58 patients with localized disease, 3-year progression-free survival (PFS) and overall survival (OS) were 91% and 91% for patients with six cycles of rituximab plus CHOP (R-CHOP) and 92% and 95% for patients with three to four cycles of R-CHOP plus radiotherapy (Log-rank test, P = 0.595 and P = 0.278, respectively). In 37 patients with advanced disease, 3-year PFS and 3-year OS were 43% and 64% for patients with R-CHOP chemotherapy with or without radiotherapy. On multivariate analysis, advanced stage and elevated serum LDH levels were independent predictors of survival in patients with PG-DLBCL. One patient with localized disease relapsed in lymph node, and eight patients with advanced disease relapsed in lymph node (n = 3), stomach (n = 2), central nervous system (CNS; n = 2), and duodenum (n = 1). Intriguingly, CNS relapse developed within 6 months after initial series of treatment (4.9 and 5.8 months, respectively), and stomach relapse developed in later phase (27.2 and 32.9 months, respectively). Clinical outcomes of PG-DLBCL were extremely favorable for localized-stage patients in the rituximab era, although these might be poor for advanced-stage patients even in the rituximab era. Further prospective analyses are warranted. PMID:21822617

  12. 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

  13. Primary Gastric Burkitt’s Lymphoma

    PubMed Central

    Mitra, Swarupa; Mehta, Anurag; Gupta, Sunil Kumar; Sharma, Anila; Louis, A. Robert; Sharma, Manoj Kumar; Saxena, Upasna; Simson, David K.; Dewan, Abhinav

    2014-01-01

    The primary gastrointestinal non-Hodgkin’s lymphoma, although rare, is among the most common extra-nodal lymphomas, considering that gastric lymphomas are more common than intestinal lymphomas. Burkitt’s lymphoma (BL) is an aggressive form of B-cell lymphoma that is typically endemic in Africa, while non-endemic cases are found in the rest of the world. Primary gastric BL is extremely rare and only around 50 cases have been reported worldwide. Here we present the case of a young HIV-negative male, who was referred to our department with a stage IV gastric BL. He was planned for palliative chemotherapy, but after the first cycle of chemotherapy he succumbed to the progression of the disease. PMID:25568743

  14. CD43 expression in B cell lymphoma.

    PubMed Central

    Treasure, J.; Lane, A.; Jones, D. B.; Wright, D. H.

    1992-01-01

    AIMS: To determine the expression of CD43 in frozen sections in a range of B cell lymphomas. METHODS: The monoclonal antibody WR14, clustered provisionally in the Fourth Leucocyte Typing Workshop as a CD43 reagent, was investigated by epitope blocking studies on formalin fixed reactive lymph node tissue, using the established CD43 antibody MT1, to validate its use as a CD43 reagent. CD43 expression was studied in 131 immunophenotypically defined B cell lymphomas, including lymphocytic lymphoma (Lc, n = 13), centrocytic lymphoma (Cc, n = 14), and a range of follicle centre cell lymphomas (FCC) including centroblastic/centrocytic follicular (CbCcF, n = 48), centroblastic diffuse (CbD, n = 39), centroblastic/centrocytic diffuse (CbCcD, n = 4), centroblastic follicular and diffuse (Cb FD, n = 3) and centroblastic/centrocytic follicular and diffuse (CbCc FD, n = 1). Nine lymphomas of mucosa associated lymphoid tissue (MALT) were also examined. RESULTS: Epitope blocking studies showed that WR14 is a CD43 reagent that binds to an epitope identical with or close to that recognised by MT1. Eleven of 13 (84%) cases of Lc and 11 of 14 (78%) cases of Cc expressed CD43; 87 of 95 (91%) cases of FCC did not. All eight low grade lymphomas of MALT were negative. One high grade lymphoma, transformed from a low grade MALT lymphoma, was positive for CD43. The expression of CD43 by tumours of B cell lineage was associated with the expression of CD5 (p < 0.001) although either antigen could occasionally be found in the absence of the other. CONCLUSION: CD43 reagents can be used in conjunction with CD5 antibodies for the immunophenotypic discrimination of follicle centre cell lymphomas from non-follicle centre cell lymphomas. Images PMID:1280654

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

    ClinicalTrials.gov

    2016-09-01

    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

  16. 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

  17. 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

  18. Oblimersen Sodium and Rituximab in Treating Patients With Recurrent B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2014-05-13

    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 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; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. Primary Diffuse Large B-cell Lymphoma involving the Mandible.

    PubMed

    Alshahrani, Faleh Ali A; Aljabab, Abdulsalam S; Motabi, Ibraheem Hm; Alrashed, Abdullah; Anil, Sukumaran

    2015-10-01

    Lymphomas of the oral cavity are rare and typically present as intraosseous lesions that are most commonly diffuse large B-cell type. Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma histologically characterized by diffuse proliferation of large neoplastic B-lymphoid cells with a nuclear size equal to or exceeding normal histiocytic nuclei. A case of DLBCL of the mandible in an 18 years old male patient is presented. This report discusses this rare malignancy, including clinical presentation, histopathologic features, immunologic profile, treatment and prognosis. Though lymphoma of mandible is rare, it must be considered in differential diagnosis of swellings arising in the region. PMID:26581467

  20. NHL (diffuse large B-cell lymphoma)

    PubMed Central

    2010-01-01

    Introduction Non-Hodgkin’s lymphoma (NHL) is the sixth most common cancer in the UK; 9443 new cases were diagnosed in the UK in 2002, and it caused 4418 UK deaths in 2003. Incidence rates show distinct geographical variation, with age-standardised incidence rates ranging from 17 per 100,000 in northern America to 4 per 100,000 in south-central Asia. NHL occurs more commonly in males than in females, and the age-standardised UK incidence increased by 10.3% between 1993 and 2002. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line treatments for aggressive, or for relapsed aggressive, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogeneic stem-cell support, chemotherapy (conventional dose salvage, high-dose plus autologous transplant stem-cell support, conventional dose in people with chemosensitive disease), CHOP 14, CHOP 21, CHOP 21 with radiotherapy, CHOP 21 with rituximab, ACVBP, MACOP-B, m-BACOD, PACEBOM, and ProMACE-CytaBOM. PMID:21406125

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

    ClinicalTrials.gov

    2016-06-14

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

    ClinicalTrials.gov

    2016-06-15

    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

  3. 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

  4. Composite diffuse large B-cell lymphoma and follicular B-cell lymphoma - case report and review of literature.

    PubMed

    Turbatu, Andrei; Stoian, Marilena; Brezean, Iulian; Stoica, Victor Constantin Ion; Colita, Andrei; Dobrea, Camelia; State, Nicoleta; Ionescu, Cosmin; Ivanescu, Ana-Maria; Oprea, Madalina; Ghimici, Cecilia; Lupu, Anca Roxana

    2014-06-01

    Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. PMID:25705280

  5. Composite Diffuse Large B-Cell Lymphoma and Follicular B-Cell Lymphoma – Case Report and Review of Literature

    PubMed Central

    TURBATU, Andrei; STOIAN, Marilena; BREZEAN, Iulian; STOICA, Victor Constantin Ion; COLITA, Andrei; DOBREA, Camelia; STATE, Nicoleta; IONESCU, Cosmin; IVANESCU, Ana-Maria; OPREA, Madalina; GHIMICI, Cecilia; LUPU, Anca Roxana

    2014-01-01

    Composite lymphoma refers to the co-occurrence of two or more morphologically and immunophenotypically separate lymphomas in the same topographic site at the time of clinical presentation. It is an infrequent type of lymphoid neoplasm, present in lymphoid tissue and may be due to the existence of two genetically related neoplasms such as transformation of a single lymphoma into another more aggressive lymphoma or be due to the presence of two clonally unrelated lymphomas. This paper is presenting a case of diffuse non-Hodgkin large B-cell lymphoma with areas of low grade and high grade follicular non-Hodgkin B-cell lymphoma in a retroperitoneal lymph node and spleen of an 62 year old woman. Histopathological examination and immunohistochemistry features proved the diagnosis of composite lymphoma. PMID:25705280

  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. TOX expression in cutaneous B-cell lymphomas.

    PubMed

    Schrader, Anne M R; Jansen, Patty M; Willemze, Rein

    2016-08-01

    Thymocyte selection-associated high-mobility group box (TOX) is aberrantly expressed in cutaneous T-cell lymphomas. In a recent study, TOX expression was noted unexpectedly in the follicle center (germinal center) B-cells of reactive lymph nodes and tonsils, used as external controls. To evaluate whether TOX is also expressed by cutaneous B-cell lymphomas, TOX immunohistochemistry was performed on skin biopsies of 44 patients with primary and secondary cutaneous B-cell proliferations. TOX was expressed not only in the reactive follicle center cells of lymph nodes, tonsils, cutaneous lymphoid hyperplasia, and primary cutaneous marginal zone lymphomas, but also by the neoplastic follicle center cells of 16/17 patients with primary cutaneous follicle center lymphoma (PCFCL) and 7/7 patients with cutaneous manifestations of systemic follicular lymphoma (FL). Notably, TOX showed a very similar expression pattern as BCL6, a marker of germinal center B-cells. In 4/10 patients with a BCL6(+) primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) and in 2/2 patients with a secondary cutaneous BCL6(+) diffuse large B-cell lymphoma (DLBCL), TOX was expressed by more than 50 % of the neoplastic B-cells. In contrast, in 3/3 BCL6(-) PCDLBCL,LT, TOX was completely negative or weakly expressed by a minor proportion of the neoplastic B-cells. In conclusion, TOX is expressed not only by neoplastic T-cells, but also by both reactive and neoplastic follicle center (germinal center) B-cells and a proportion of BCL6(+) PCDLBCL,LT and secondary cutaneous BCL6(+) DLBCL. The functional significance of TOX expression in reactive and neoplastic B-cells remains to be elucidated. PMID:27180090

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

    ClinicalTrials.gov

    2016-09-13

    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. 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

  10. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology

    PubMed Central

    Sagaert, Xavier; Tousseyn, Thomas; Yantiss, Rhonda K

    2012-01-01

    The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms. PMID:23443141

  11. Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology.

    PubMed

    Sagaert, Xavier; Tousseyn, Thomas; Yantiss, Rhonda K

    2012-12-15

    The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms. PMID:23443141

  12. Fenretinide and Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2014-09-30

    Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse 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 Mantle Cell Lymphoma; Stage II Marginal Zone Lymphoma; Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse 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 Mantle Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic 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; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult

  13. Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management.

    PubMed

    Hu, Qinglong; Zhang, Yizhuo; Zhang, Xiaoyan; Fu, Kai

    2016-01-01

    Helicobacter pylori (H. pylori)-associated gastritis is one of the most common infectious diseases in the United States, China and worldwide. Gastric mucosa-associated tissue lymphoma (MALT lymphoma) is a rare mature B-cell neoplasm associated with H. pylori infection that is curable by antibiotics therapy alone. The pathological diagnosis of gastric MALT lymphoma can be reached by histological examination, immunohistochemical staining and B-cell clonality analysis. H. pylori eradication is the choice of therapy for early-stage gastric MALT lymphoma. High response rates and long-term survival have been reported in refractory and localized diseases treated with low-dose radiation therapy. Systemic chemotherapy is recommended for advanced-stage gastric MALT lymphoma and cases with large B-cell lymphoma transformation. Recent advances in the pathological diagnosis and management of gastric MALT lymphoma are reviewed in this article. PMID:27468353

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

    ClinicalTrials.gov

    2016-09-07

    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

  15. 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. PMID:22222636

  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. Diffuse large B-cell lymphoma of the prostate.

    PubMed

    Warrick, Joshua I; Owens, Scott R; Tomlins, Scott A

    2014-10-01

    In this article, we review prostatic lymphomas and discuss the differential diagnosis of high-grade malignant neoplasms of the prostate. We illustrate this with a case of a 46-year-old man seen with lower urinary tract obstruction who had diffuse involvement by a high-grade malignancy on prostate biopsy. Morphologic evaluation and immunohistochemistry were consistent with diffuse large B-cell lymphoma of the prostate. Workup with positron emission tomography-computed tomography demonstrated intensely hypermetabolic lymph nodes in the mediastinum, as well as widespread osseous involvement and involvement of the pancreatic tail, prostate, and urinary bladder, suggesting secondary prostatic involvement by a nodal lymphoma. Lymphomas of the prostate are uncommon in surgical pathology practice and usually represent secondary involvement from leukemia/lymphoma at a more typical site. Chronic lymphocytic leukemia/small lymphocytic lymphoma is the most common subtype. PMID:25268190

  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. 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

  2. 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

  3. 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

  4. 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

  5. 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

  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. Clonal relationships in recurrent B-cell lymphomas

    PubMed Central

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

    2016-01-01

    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

  8. 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

  9. Diffuse large B-cell lymphoma: A metabolic disorder?

    PubMed Central

    Tanios, Georges; Aranguren, Ines M.; Goldstein, Jack S.; Patel, Chirag B.

    2013-01-01

    Patient Male, 81 Final Diagnosis: Non-Hodgkin lymphoma Symptoms: General weakness • hypoglycemia • metabolic acidosis Medication: — Clinical Procedure: — Specialty: Hematology Objective: Challenging differential diagnosis Background: B cell lymphoma constitutes 80–85% of cases of Non Hodgkin’s lymphoma in the Untied States. Metabolic complications may arise from the disease itself or through its end organ involvement. Case Report: We describe a case of a diffuse large B cell lymphoma diagnosed by abdominal computed tomography after it initially presented as hypoglycemia not correctable by dextrose infusion that instead resulted in increased anion gap metabolic acidosis with elevated lactate levels. Conclusions: The case illustrates how lymphomas can present unusually with hypoglycemia and lactic acidosis, the latter being an ominous sign that can occur without liver involvement. In this regard, the case demonstrates the metabolic sequelae of lymphoma that should raise suspicion for an underlying process. This has implications for diagnosis, treatment, and patient survival. Attention should be paid especially in the primary care setting in order to minimize delays in diagnosis. PMID:24349605

  10. 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

  11. 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

  12. 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

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

    PubMed Central

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

    2015-01-01

    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

  14. Rituximab and chemotherapy in diffuse large B-cell lymphoma.

    PubMed

    Sonet, Anne; Bosly, André

    2009-06-01

    Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era. PMID:19496708

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

    ClinicalTrials.gov

    2016-07-26

    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

  16. 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

  17. [Diffuse large B-cell lymphoma developed newly after 9-year remission of a follicular lymphoma].

    PubMed

    Hirano, Taichi; Tsuji, Takahiro; Yamasaki, Hiroshi; Toyozumi, Yasuo; Arima, Nobuyuki; Tsuda, Hiroyuki

    2016-02-01

    Follicular lymphoma (FL) occasionally transforms into diffuse large B-cell lymphoma (DLBCL). This is generally associated with a poor prognosis, necessitating more potent chemotherapy as salvage treatment. However, de novo DLBCL, but not DLBCL transformed from FL, can be treated as primary DLBCL. We encountered a 63-year-old woman who developed DLBCL after a 9-year remission following treatment of FL. To differentiate DLBCL transformed from FL and de novo DLBCL, VDJ gene rearrangements in IgH were examined by PCR using biopsy specimens from both lymphomas. The results revealed the two lymphomas to be different clones. Thus, she was diagnosed with primary DLBCL. Therefore, routine chemotherapy and radiation therapy were conducted for the primary DLBCL with a limited stage, achieving complete remission. Treatment based on the clonality assessment of VDJ gene rearrangements is potentially useful for treating late relapse of B-cell lymphoma according to the pathological conditions of patients. PMID:26935635

  18. Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis.

    PubMed

    Nosotti, Lorenzo; Baiocchini, Andrea; Bonifati, Claudio; Visco-Comandini, Ubaldo; Mirisola, Concetta; Del Nonno, Franca

    2015-04-18

    Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance. PMID:25914782

  19. 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

  20. 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

  1. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  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. 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

  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. 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

  6. 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

  7. Comprehensive Assessment and Classification of High-Grade B-cell Lymphomas.

    PubMed

    Behdad, Amir; Bailey, Nathanael G

    2016-03-01

    High-grade B-cell lymphomas (HGBCLs) are a heterogeneous group of neoplasms that include subsets of diffuse large B-cell lymphoma, Burkitt lymphoma, and lymphomas with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Morphologically indistinguishable HGBCLs may demonstrate variable clinical courses and responses to therapy. The morphologic evaluation and classification of these neoplasms must be followed by further genetic and immunophenotypic work-up. These additional diagnostic modalities lead to a comprehensive stratification of HGBCL that determines the prognosis and optimal therapy. This article reviews the well-established and emerging biomarkers that are most relevant to the clinical management of HGBCL. PMID:26940267

  8. Breakthrough therapies in B-cell non-Hodgkin lymphoma.

    PubMed

    Cheah, C Y; Fowler, N H; Wang, M L

    2016-05-01

    The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas. This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell's signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric antigen receptor T cells. PMID:26802148

  9. 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

  10. 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. PMID:20382409

  11. 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

  12. Rare Case of Primary Gastric Burkitt Lymphoma in a Child.

    PubMed

    Kim, Soon Chul; Hwang, Jung Won; Lee, Min Kyung; Hwang, Pyoung Han

    2016-08-25

    Primary gastric tumors are very rare in children. Burkitt lymphoma is a common type of non-Hodgkin's lymphoma, and gastric Burkitt lymphoma usually occurs in the aged. When involving the gastrointestinal tract, primary gastric Burkitt lymphoma is very rare in younger childhood. Many gastric lymphomas including mucosa-associated lymphoid tissue lymphoma are associated with Helicobacter pylori infection or acute bleeding symptom. We report a seven-year-old boy who presented with only some vomiting and postprandial pain. His upper gastrointestinal endoscopy and biopsy revealed a large primary Burkitt lymphoma with no acute bleeding and no evidence of H. pylori infection. After chemotherapy, he remains in remission. PMID:27554215

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

    PubMed Central

    Zhou, Yi; Rosenblum, Marc K.; Dogan, Ahmet; Jungbluth, Achim A.; Chiu, April

    2016-01-01

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

  14. 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

  15. 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

  16. 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

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

    ClinicalTrials.gov

    2016-01-07

    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

  18. 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

  19. 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

  20. 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

  1. Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma.

    PubMed

    Pon, Julia R; Marra, Marco A

    2016-01-14

    Our understanding of the pathogenesis and heterogeneity of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) has been dramatically enhanced by recent attempts to profile molecular features of these lymphomas. In this article, we discuss ways in which testing for molecular features may impact DLBCL and FL management if clinical trials are designed to incorporate such tests. Specifically, we discuss how distinguishing lymphomas on the basis of cell-of-origin subtypes or the presence of other molecular features is prognostically and therapeutically significant. Conversely, we discuss how the molecular similarities of DLBCL and FL have provided insight into the potential of both DLBCL and FL cases to respond to agents targeting alterations they have in common. Through these examples, we demonstrate how the translation of our understanding of cancer biology into improvements in patient outcomes depends on analyzing the molecular correlates of treatment outcomes in clinical trials and in routinely treated patients. PMID:26447189

  2. [Primary bilateral adrenal T-cell lymphoma. A case report rarer than B-cell lymphoma].

    PubMed

    Sfaxi, M; Bouzouita, A; Bouasker, I; Kourda, N; Ben Slama, M R; Ben Jilani Baltaji, S; Chebil, M

    2008-06-01

    Primary adrenal lymphoma is a rare condition. Only 70 cases were described in the literature. Adrenal lymphoma is often bilateral and in most of the cases of B-cell type. T-cell lymphoma is exceptional. The prognosis is bad and patient can die early because of acute adrenal insufficiency. We report a case of a 70-year-old man who was admitted for acute adrenal insufficiency due to primary bilateral adrenal T-cell lymphoma. He had corticotherapy and surgical exploration for intra-abdominal sepsis. He died because of multivisceral deficiency. Clinical features and imaging are not specific. (18)F-FDG PET Scan is an excellent mean to detect malignant tumor of adrenal gland. Percutaneous needle biopsy is useful to determine histology. The standard treatment is chemotherapy. PMID:18455145

  3. 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

  4. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies.

    PubMed

    Shain, K H; Tao, J

    2014-08-01

    Specific niches within the lymphoma tumor microenvironment (TME) provide sanctuary for subpopulations of tumor cells through stromal cell-tumor cell interactions. These interactions notably dictate growth, response to therapy and resistance of residual malignant B cells to therapeutic agents. This minimal residual disease (MRD) remains a major challenge in the treatment of B-cell malignancies and contributes to subsequent disease relapse. B-cell receptor (BCR) signaling has emerged as essential mediator of B-cell homing, survival and environment-mediated drug resistance (EMDR). Central to EMDR are chemokine- and integrin-mediated interactions between lymphoma and the TME. Further, stromal cell-B cell adhesion confers a sustained BCR signaling leading to chemokine and integrin activation. Recently, the inhibitors of BCR signaling have garnered a substantial clinical interest because of their effectiveness in B-cell disorders. The efficacy of these agents is, at least in part, attributed to attenuation of BCR-dependent lymphoma-TME interactions. In this review, we discuss the pivotal role of BCR signaling in the integration of intrinsic and extrinsic determinants of TME-mediated lymphoma survival and drug resistance. PMID:24037527

  5. 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

  6. 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

    2016-07-12

    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

  7. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review.

    PubMed

    Asano, Naoki; Iijima, Katsunori; Koike, Tomoyuki; Imatani, Akira; Shimosegawa, Tooru

    2015-07-14

    Since Isaacson and Wright first reported on the extra-nodal marginal zone B-cell lymphoma of the stomach in 1983, following studies have clarified many aspects of this disease. We now know that the stomach is the most affected organ by this disease, and approximately 90% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are related to Helicobacter pylori (H. pylori) infection. This implies that approximately 10% of gastric MALT lymphomas occur independent of H. pylori infection. The pathogenesis of these H. pylori-negative gastric MALT lymphomas remains unclear. To date, there have been several speculations. One possibility is that genetic alterations result in nuclear factor-kappa B (NF-κB) activation. Among these alterations, t(11;18)(q21;q21) is more frequently observed in H. pylori-negative gastric MALT lymphomas, and such translocation results in the synthesis of fusion protein API2-MALT1, which causes canonical and noncanonical NF-κB activation. Another possibility is infection with bacteria other than H. pylori. This could explain why H. pylori eradication therapy can cure some proportions of H. pylori-negative gastric MALT lymphoma patients, although the bacteria responsible for MALT lymphomagenesis are yet to be defined. Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment. A certain proportion of H. pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence, H. pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H. pylori infection status. PMID:26185372

  8. Orbital MALT lymphoma, abdominal hodgkin lymphoma, and systemic diffuse large B-cell lymphoma develop sequentially in one patient.

    PubMed

    Matsuo, Toshihiko; Ichimura, Kouichi; Shinagawa, Katsuji

    2012-01-01

    In February 2002, a 42-year-old woman developed ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), MALT lymphoma, in the bilateral orbits involving lacrimal glands. She underwent 30 Gy external beam irradiation to the orbital lesions on both sides. She was well until November 2008 when she developed abdominal lymphadenopathy and transabdominal excisional biopsy showed mixed cellularity classical Hodgkin lymphoma at stage II. She underwent standard combination chemotherapy. In July 2010, she developed systemic lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma (DLBCL) by cervical lymph node biopsy. She underwent rituximab monotherapy and finally allogeneic hematopoietic stem cell transplantation in October 2010, but died of renal failure in February 2011. Amplification by polymerase chain reaction of the immunoglobulin heavy chain gene gave rise to dominant discrete fragments of the same size between the orbital lesion with MALT lymphoma in 2002 and the cervical lymph node lesion with DLBCL in 2010. The sequential development of MALT lymphoma, Hodgkin lymphoma, and DLBCL in the long-term course of this patient suggests the common origin of the neoplastic cells, changing their pathological faces in response to irradiation and combination chemotherapy. PMID:22706530

  9. A Case of Malignant Gastrointestinal Stromal Tumor Initially Misdiagnosed as Malignant B-Cell Lymphoma

    PubMed Central

    Suh, Byoung Jo

    2016-01-01

    Errors that occur in anatomic pathology influence the treatment strategy of patients with malignancy. There are four general types of error with three subtypes in the category of defective interpretation. The first subtype is a false-negative diagnosis or undercall of the extent or severity of the lesion, the second is a false-positive diagnosis, and the third is misclassification. We herein report a 65-year-old female patient with malignant gastrointestinal stromal tumor that was diagnosed after reevaluation of the lesion at our hospital – and treated with proximal gastrectomy – after initial diagnosis as malignant B-cell lymphoma on esophagogastroduodenoscopy biopsy of a small gastric fundic mass and subsequent treatment with six cycles of CHOP chemotherapy with aggravation of the mass at another hospital. PMID:27462236

  10. 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.

  11. 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

  12. B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and classical hodgkin lymphoma: diagnosis by fine-needle aspiration cytology.

    PubMed

    Lynnhtun, Kyaw; Varikatt, Winny; Pathmanathan, Nirmala

    2014-08-01

    A 58-year-old lady presented with mediastinal lymphadenopathy. A thoracoscopic ultrasound-guided fine-needle aspiration showed large atypical epithelioid cells arranged in cohesive sheets and dispersed as single cells with intact cytoplasm amid a background of lymphocytes and histiocytes. A cytological diagnosis of "a malignant neoplasm" was made, raising a broad list of differential diagnoses. A broad panel of immunocytochemical stains performed on the cell block was indicative of a lymphoproliferative disorder, but the immunophenotype was intermediate between diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). Diffuse and strong reactivity to CD20, CD79a, and PAX-5, and weak reactivity to CD30, was in favor of a DLBCL, or more precisely mediastinal (thymic) large B cell lymphoma (MLBL). However, there were negative staining for LCA, OCT-2, and BOB-1 as well as positive staining for EBV-encoded RNA, which were against a diagnosis of MLBL and raised the possibility of cHL. The absence of RS cells and the typical mileu, the negativity for CD15 and the strong positivity of CD20 and PAX-5 were against a diagnosis of cHL. On this basis, the diagnosis of "B-cell lymphoproliferative disorder with features intermediate between DLBCL and cHL" was rendered. The diagnosis was subsequently confirmed on excisional biopsy. This case report demonstrates broad differential diagnoses raised by this diagnostic entity and the importance of an adequate cell block for accurate designation. PMID:23630122

  13. 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

  14. 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

  15. EBV, HHV8 and HIV in B cell non Hodgkin lymphoma in Kampala, Uganda

    PubMed Central

    2010-01-01

    Background B cell non Hodgkin lymphomas account for the majority of lymphomas in Uganda. The commonest is endemic Burkitt lymphoma, followed by diffuse large-B-cell lymphoma (DLBCL). There has been an increase in incidence of malignant lymphoma since the onset of the HIV/AIDS pandemic. However, the possible linkages of HHV8 and EBV to the condition of impaired immunity present in AIDS are still not yet very clearly understood. Objectives 1. To describe the prevalence of Epstein-Barr virus, Human Herpes virus 8 and Human Immunodeficiency Virus-1 in B cell non Hodgkin lymphoma biopsy specimens in Kampala, Uganda. 2. To describe the histopathology of non Hodgkin lymphoma by HIV serology test result in Kampala, Uganda Method Tumour biopsies specimens from 119 patients with B cell non Hodgkin lymphoma were classified according to the WHO classification. Immunohistochemistry was used for detection of HHV8 and in situ hybridization with Epstein Barr virus encoded RNA (EBER) for EBV. Real time and nested PCR were used for the detection of HIV. The patients from whom the 1991-2000 NHL biopsies had been taken did not have HIV serology results therefore 145 patients biopsies where serology results were available were used to describe the association of HIV with non Hodgkin lymphoma type during 2008-2009. Results In this study, the majority (92%) of the Burkitt lymphomas and only 34.8% of the diffuse large B cell lymphomas were EBV positive. None of the precursor B lymphoblastic lymphomas or the mantle cell lymphomas showed EBV integration in the lymphoma cells. None of the Burkitt lymphoma biopsies had HIV by PCR. Of the 121 non Hodgkin B cell lymphoma patients with HIV test results, 19% had HIV. However, only 1(0.04%) case of Burkitt lymphoma had HIV. All the tumours were HHV8 negative. Conclusions The majority of the Burkitt lymphomas and two fifths of the diffuse large B cell lymphomas had EBV. All the tumours were HHV8 negative. Generally, the relationship of NHL and HIV

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Imaging findings for intravascular large B-cell lymphoma of the liver

    PubMed Central

    Bae, Jungmin; Park, Ha Young

    2015-01-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma that most commonly involves the central nervous system and skin. To our knowledge, no state-of-the art imaging findings have been reported for hepatic IVLBCL in the English literature. We report the first case of hepatic involvement of IVLBCL along with a literature review. PMID:26523272

  3. Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma

    PubMed Central

    Wilson, Wyndham H.; Bromberg, Jacoline E.C.; Stetler-Stevenson, Maryalice; Steinberg, Seth M.; Martin-Martin, Lourdes; Muñiz, Carmen; Sancho, Juan Manuel; Caballero, Maria Dolores; Davidis, Marjan A.; Brooimans, Rik A.; Sanchez-Gonzalez, Blanca; Salar, Antonio; González-Barca, Eva; Ribera, Jose Maria; Shovlin, Margaret; Filie, Armando; Dunleavy, Kieron; Mehrling, Thomas; Spina, Michele; Orfao, Alberto

    2014-01-01

    The benefit of intrathecal therapy and systemic rituximab on the outcome of diffuse large B-cell lymphoma at risk of central nervous system disease is controversial. Furthermore, the effect of intrathecal treatment and rituximab in diffuse large B-cell and Burkitt lymphoma with occult leptomeningeal disease detected by flow cytometry at diagnosis is unknown. Untreated diffuse large B-cell (n=246) and Burkitt (n=80) lymphoma at clinical risk of central nervous system disease and having had pre-treatment cerebrospinal fluid were analyzed by flow cytometry and cytology. Spinal fluid involvement was detected by flow cytometry alone (occult) in 33 (13%) diffuse large B-cell and 9 (11%) Burkitt lymphoma patients, and detected by cytology in 11 (4.5%) and 5 (6%) patients, respectively. Diffuse large B-cell lymphoma with occult spinal fluid involvement had poorer survival (P=0.0001) and freedom from central nervous system relapse (P<0.0001) compared to negative cases. Burkitt lymphoma with occult spinal fluid involvement had an inferior freedom from central nervous system relapse (P=0.026) but not survival. The amount of intrathecal chemotherapy was quantitatively associated with survival in diffuse large B-cell lymphoma with (P=0.02) and without (P=0.001) occult spinal fluid involvement. However, progression of systemic disease and not control of central nervous system disease was the principal cause of treatment failure. In diffuse large B-cell lymphoma, systemic rituximab was associated with improved freedom from central nervous system relapse (P=0.003) but not with survival. Our results suggest that patients at risk of central nervous system disease should be evaluated by flow cytometry and that intrathecal prophylaxis/therapy is beneficial. PMID:24727817

  4. 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

  5. Clinicopathological Analysis of B Cell Lymphomas, Unclassifiable; with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma in a Tertiary Care Hospital in Southern India.

    PubMed

    Selvi, Subramanian Kalaivani; Kar, Rakhee; Basu, Debdatta; Jacob, Sajini Elizabeth; Dubashi, Biswajit

    2016-06-01

    B-cell lymphomas, unclassifiable; with features intermediate between large B-cell lymphoma and Burkitt lymphoma (BCLu-DLBCL/BL) is a new entity included in the recent World Health Organization (WHO) classification of Tumours of the Hematopoietic and Lymphoid Tissues (2008) to overcome the problems of difficulty in classifying certain lymphomas having overlapping morphological, immunophenotypical and genetic features. To study the clinicopathological profile of BCLu-DLBCL/BL. Cross-sectional study over 3 year period in the Haematology section of Department of Pathology in a large teaching hospital in Southern India from January 2011 to December 2013. All the cases reported as BCLu-DLBCL/BL were collected and the clinical, morphological and immunohistochemical parameters were analyzed. Descriptive statistics. There were seven cases, four males and three females, of age ranging from 20 to 70 years. Five cases had extranodal involvement. Four cases had Burkitt morphology with strong Bcl2 positivity and absent CD10 expression. One case had the morphology and immunophenotype that of typical BL, along with strong positivity to Bcl2 suggesting a double hit hypothesis. Two cases had morphology and immunophenotype of BL with low Ki 67. Three patients on follow up had adverse outcome. BCLu-DLBCL/BL, a provisional category in WHO 2008 is useful in classifying the cases not meeting the criteria for classical BL or DLBCL. Each of these cases was interesting with different sites of involvement, different morphological features and immunophenotype with most of the patients on follow up ending with a grave prognosis. PMID:27065578

  6. 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

  7. A case of primary adrenal diffuse large B-cell lymphoma in HIV.

    PubMed

    Malik, Seema; Chapman, Cordelia B-P; Drew, Olivia

    2016-07-01

    Primary adrenal diffuse large B-cell lymphoma in HIV is a very rare, highly aggressive extra-nodal lymphoma. There is only one previous case reported in the literature. Our patient presented with isolated bilateral adrenal masses with no lymphadenopathy or visceral involvement, which made the diagnosis challenging. PMID:26113518

  8. [Gastric non-Hodgkin lymphoma associated with heavy metal exposures].

    PubMed

    Garavito Rentería, Jorge; Araujo Banchón, William Javier; Quesada Ríos, María Pía; Ponce de León, Diego

    2012-01-01

    Primary extranodal Non-Hodgkin lymphoma (NHL) is a non epithelial tumours that accounts for 40% of cases of NHL. Spread of nodal lymphomas to the gastrointestinal tract (GIT) is the most common location. Within the GIT is the stomach the most affected organ (60%). We report the case of 52-year- old man , mining company worker for over 10 years, which is derived to the Service of Gastroenterology with history of epigastric pain, nausea, vomiting and weight loss. Upper gastrointestinal endoscopic examination revealed an ulcerated lesion on greater curve of stomach and histopathological examination and subsequent immunohistochemical analysis showed diffuse large B cell gastric NHL. Also, the patient had multiple organ involvement in relation to chronic exposure to heavy metals, which was found in the mineralograma, with the highest concentration of uranium, thallium, arsenic, lead and mercury. The literature has described the association of chronic occupational exposure to uranium and arsenic with NHL presenting gastrointestinal involvement. Therefore, gastric commitment can not be considered as an isolated injury, but rather part of systemic involvement associated with elevated concentrations of metals. Mining is a key driver of income for Peru; however, there are no reports to date of the association of gastrointestinal NHL commitment regarding occupational exposure to heavy metals. PMID:23307094

  9. [Is it useful to perform a (67)gallium scintigraphy in the follow-up of patients with gastric lymphoma?].

    PubMed

    Ruiz Hernández, G; Pallardó-Calatayud, J; Ferrer Albiach, C; Balaguer-Martínez, J V; Romero-de-Avila, C; Castillo-Pallarés, F J

    2001-02-01

    Gastric (67)gallium uptake in patients with peptic ulcer has been described in many publications literature. We present the case of a jejunal (67)gallium uptake in a patient with a background of total gastrectomy due to a diffuse large B cell gastric lymphoma, associated to benign peptic ulcer which had been identified by endoscopy. We have not found any similar cases in regards to (67)gallium reported in the literature. This study aims to present a review of the causes of gastrointestinal uptake of (67)gallium and of the utility of the radiotracer in patients with gastric lymphoma. PMID:11181327

  10. 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

  11. 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. PMID:26937937

  12. 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

  13. Clinicopathological prognostic factors of 24 patients with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.

    PubMed

    Miyamoto, Ken-Ichi; Kobayashi, Yukio; Maeshima, Akiko Miyagi; Taniguchi, Hirokazu; Nomoto, Junko; Kitahara, Hideaki; Fukuhara, Suguru; Munakata, Wataru; Maruyama, Dai; Tobinai, Kensei

    2016-06-01

    B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (iBL/DLBCL), is a rare, but an aggressive subtype. In iBL/DLBCL, clinicopathological prognostic factors, including MYC and BCL2 translocations (double hit translocation, DHT) and the expression of both MYC and BCL2 (double hit score 2, DHS2), have not been studied thoroughly. We retrospectively analyzed the prognostic impact of clinicopathological factors, including MYC split, IGH/BCL2 fusion, MYC and BCL2 expressions, in 24 iBL/DLBCL patients (median age: 47 years). Fifteen patients (62 %) underwent intensive chemotherapy, and nine patients (38 %) underwent rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The 5-year progression-free (PFS) and overall survival (OS) rates of intensive chemotherapy and R-CHOP were 57 and 72 %, respectively. PFS was significantly shorter in patients with high IPI score (P < .0001), stage IV (P = .001), aged ≥60 years (P = .042), IGH/BCL2 fusion (P = .029), DHS2 (P = .015), and DHT (P = .03). OS was significantly shorter in patients with high IPI score (P < .0001) and aged ≥60 years (P = .008). In iBL/DLBCL, IGH/BCL2 fusion, DHS2, and DHT were pathological prognostic factors for poor PFS, while IPI remained as more predictive for PFS and OS. PMID:27095041

  14. 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

  15. B-cell receptor signaling as a driver of lymphoma development and evolution

    PubMed Central

    Niemann, Carsten U.; Wiestner, Adrian

    2014-01-01

    The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B-cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and displays chronic active BCR signaling resulting in constitutive activation of the NF-κB pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B-cell malignancies. Here, we review the role of the BCR in the pathogenesis of B-cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway. PMID:24060900

  16. Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: A Colombian perspective

    PubMed Central

    Yepes, Sally; Torres, Maria Mercedes; Saavedra, Carlos; Andrade, Rafael

    2012-01-01

    AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia. METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication. RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells. CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases. PMID:22363141

  17. The role of miRNAs and epigenetic mechanisms in primary gastric mucosa-associated lymphoid tissue lymphoma.

    PubMed

    Vasilatou, Diamantina; Sioulas, Athanasios D; Pappa, Vasiliki; Papanikolaou, Ioannis S; Triantafyllou, Konstantinos; Dimitriadis, George D; Papageorgiou, Sotirios G

    2016-07-01

    Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare low-grade B-cell non-Hodgkin lymphoma associated with Helicobacter pylori infection and the subsequent chronic inflammation. Significant progress in understanding the pathogenesis of the disease has already been made. However, the exact molecular pathways of lymphomagenesis remain unclear. Furthermore, difficulties regarding accurate diagnosis of gastric MALT lymphoma and its discrimination from gastritis or other lymphoma subtypes arise. Recent studies evaluate the role of miRNAs and epigenetic alterations on MALT lymphoma pathogenesis and prognosis. This review critically summarizes the most important data on the role of miRNAs and epigenetics in MALT lymphomas pathogenesis, prognosis and treatment. PMID:27079806

  18. CD20-negative diffuse large B-cell lymphomas: biology and emerging therapeutic options.

    PubMed

    Castillo, Jorge J; Chavez, Julio C; Hernandez-Ilizaliturri, Francisco J; Montes-Moreno, Santiago

    2015-06-01

    CD20-negative diffuse large B-cell lymphoma (DLBCL) is a rare and heterogeneous group of lymphoproliferative disorders. Known variants of CD20-negative DLBCL include plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus 8-associated multicentric Castleman disease and anaplastic lymphoma kinase-positive DLBCL. Given the lack of CD20 expression, atypical cellular morphology and aggressive clinical behavior characterized by chemotherapy resistance and inferior survival rates, CD20-negative DLBCL represents a challenge from the diagnostic and therapeutic perspectives. The goals of the present review are to summarize the current knowledge on the biology of the distinct variants of CD20-negative DLBCL, provide future therapeutic directions based on the limited preclinical and clinical data available, and increase awareness concerning these rare malignancies among pathologists and clinicians. PMID:25641215

  19. 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

  20. Epigenetic Heterogeneity of B-Cell Lymphoma: DNA Methylation, Gene Expression and Chromatin States.

    PubMed

    Hopp, Lydia; Löffler-Wirth, Henry; Binder, Hans

    2015-01-01

    Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells. These dysfunctions are governed by widespread epigenetic effects altering the promoter methylation of the involved genes, their activity status as moderated by histone modifications and also by chromatin remodeling. We identified four groups of genes showing characteristic expression and methylation signatures among Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma and multiple myeloma. These signatures are associated with epigenetic effects such as remodeling from transcriptionally inactive into active chromatin states, differential promoter methylation and the enrichment of targets of transcription factors such as EZH2 and SUZ12. PMID:26371046

  1. Epigenetic Heterogeneity of B-Cell Lymphoma: DNA Methylation, Gene Expression and Chromatin States

    PubMed Central

    Hopp, Lydia; Löffler-Wirth, Henry; Binder, Hans

    2015-01-01

    Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells. These dysfunctions are governed by widespread epigenetic effects altering the promoter methylation of the involved genes, their activity status as moderated by histone modifications and also by chromatin remodeling. We identified four groups of genes showing characteristic expression and methylation signatures among Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma and multiple myeloma. These signatures are associated with epigenetic effects such as remodeling from transcriptionally inactive into active chromatin states, differential promoter methylation and the enrichment of targets of transcription factors such as EZH2 and SUZ12. PMID:26371046

  2. 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

  3. Differentiating Between Burkitt Lymphoma and CD10+ Diffuse Large B-Cell Lymphoma

    PubMed Central

    McGowan, Paul; Nelles, Nicole; Wimmer, Jana; Williams, Dawn; Wen, Jianguo; Li, Marilyn; Ewton, April; Curry, Choladda; Zu, Youli; Sheehan, Andrea; Chang, Chung-Che (Jeff)

    2016-01-01

    The goal of this study was to evaluate routine flow cytometric (FC) immunophenotypic markers in differentiating between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL). We performed retrospective analysis of FC data from 55 patients. We evaluated 9 FC parameters: forward and side scatter (FSC and SSC); mean fluorescent intensity (MFI) for CD20, CD10, CD38, CD79b, CD43, and CD71; and the percentage of neoplastic cells positive for CD71 (%CD71). The FSC; MFIs of CD10, CD43, CD79b, and CD71; and %CD71 cells were significantly different between BL and CD10+ DLBCL (P < .05; Student t test). A 5-point scoring system (FSC, %CD71, and MFIs of CD43, CD79b, and CD71) was devised, and 6 (60%) of 10 BLs scored 3 or greater and 1 (10%) of 10 CD10+ DLBCLs scored 3 (P = .04; χ2). Our findings indicate that routine FC parameters can aid in differentiating BL from CD10+ DLBCL. PMID:22431545

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

    ClinicalTrials.gov

    2015-10-20

    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

  5. 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

  6. Primary diffuse large B-cell lymphoma associated with chronic osteomyelitis of the knee.

    PubMed

    Romero-Rojas, Alfredo E; Diaz-Perez, Julio A; Raju, Sharat; Messa-Botero, Oscar; Prieto-Bletan, Andres; Criollo-Palacios, Felipe

    2014-12-01

    Diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation is a recently adopted category of DLBCL, which describes an aggressive B-cell lymphoma raised in the setting of non-immune chronic inflammation. Primary presentation of this subtype of DLBCL in bone is extremely rare. Here, we present the case of a 27 year old woman with DLBCL of the right distal femur, identified after a three-year history of chronic osteomyelitis. In this report, we describe the clinical and histopathologic features of this unusual presentation of DLBCL and discuss aspects relevant to diagnosis and treatment of this entity. PMID:25199714

  7. Clonal evolution of B cells in transformation from low- to high-grade lymphoma

    PubMed Central

    Matolcsy, András; Schattner, Elaine J.; Knowles, Daniel M.; Casali, Paolo

    2015-01-01

    An outcome of low-grade B cell non-Hodgkins's lymphomas is the transformation to high-grade diffuse large B cell lymphomas (DLBL). To investigate the mechanisms of clonal evolution in the transformation to DLBL, we performed longitudinal molecular analyses of immunoglobulin (Ig), VHDJH gene sequences expressed in cases of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL) that transformed to DLBL. Among the neoplastic CLL and SLL cells and their respective high-grade transformants, there was no evidence for a clonotypic shift or acquired mutations in the expressed Ig VHDJH gene segments, as further confirmed by a specific and sensitive PCR-single strand polymorphism analysis. In contrast, among the FL cells there was a high degree of intraclonal diversification with highly divergent VHDJH gene sequences. Despite this intraclonal heterogeneity, the related DLBL expressed a collinear but unique VHDJH gene sequence. The intraclonal genealogical tree for the FL case demonstrated that the DLBL emerged in association with unique VHDJH gene mutational events. Among the intraclonal FL and related DLBL transformants, the nature and distribution of the Ig VHDJH gene mutations were consistent with antigenic selection. Thus, clonal evolution in the transformation from low- to high-grade B cell lymphoma may involve distinct pathways which vary according to the cellular origin and the type of the progenitor B cell tumor. PMID:10229093

  8. Imbalanced Matriptase Pericellular Proteolysis Contributes to the Pathogenesis of Malignant B-Cell Lymphomas

    PubMed Central

    Chou, Feng-Pai; Chen, Ya-Wen; Zhao, Xianfeng F.; Xu-Monette, Zijun Y.; Young, Ken H.; Gartenhaus, Ronald B.; Wang, Jehng-Kang; Kataoka, Hiroaki; Zuo, Annie H.; Barndt, Robert J.; Johnson, Michael; Lin, Chen-Yong

    2014-01-01

    Membrane-associated serine protease matriptase is widely expressed by epithelial/carcinoma cells in which its proteolytic activity is tightly controlled by the Kunitz-type protease inhibitor, hepatocyte growth factor activator inhibitor (HAI-1). We demonstrate that, although matriptase is not expressed in lymphoid hyperplasia, roughly half of the non-Hodgkin B-cell lymphomas analyzed express significant amounts of matriptase. Furthermore, a significant proportion of these tumors express matriptase in the absence of HAI-1. Aggressive Burkitt lymphoma was more likely than indolent follicular lymphoma to express matriptase alone (86% versus 36%). In the absence of significant HAI-1 expression, the lymphoma cells activate and shed active matriptase when the cells are stimulated with mildly acidic buffer or the hypoxia-mimicking agent, CoCl2. The shed active matriptase can initiate pericellular proteolytic cascades by activating urokinase-type plasminogen activator on the cell surface of monocytes, and it can activate prohepatocyte growth factor. In addition, matriptase knockdown suppressed proliferation and colony-forming ability of neoplastic B cells in culture and growth as tumor xenografts in mice. Furthermore, exogenous expression of HAI-1 significantly suppressed proliferation of neoplastic B cells. These studies suggest that dysregulated pericellular proteolysis as a result of unregulated matriptase expression with limited HAI-1 may contribute to the pathological characteristics of several human B-cell lymphomas through modulation of the tumor microenvironment and enhanced tumor growth. PMID:24070417

  9. Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia

    PubMed Central

    Greenwald, Rebecca J.; Tumang, Joseph R.; Sinha, Anupama; Currier, Nicolas; Cardiff, Robert D.; Rothstein, Thomas L.; Faller, Douglas V.; Denis, Gerald V.

    2010-01-01

    Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein–associated factor, 250 kDa (TAFII250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, “priming” transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain. PMID:14563639

  10. Targeted gene analysis: increased B-cell lymphoma 6 in preeclamptic placentas.

    PubMed

    Louwen, Frank; Muschol-Steinmetz, Cornelia; Friemel, Alexandra; Kämpf, Anne Kristina; Töttel, Eva; Reinhard, Joscha; Yuan, Juping

    2014-06-01

    Preeclampsia is a leading cause for maternal and perinatal mortality and morbidity. Microarray-based transcriptional profiling has been widely used for identifying genes responsible for preeclampsia. These studies deliver multiple pictures of gene signatures, implying the complicated pathophysiology. In the present work, we designed our own gene array containing genes involved in various signaling transduction pathways and analyzed placental samples from patients with preeclampsia and controls. We verify that genes associated with angiogenesis and migration pathways are mostly altered in preeclamptic placentas. Interestingly, several genes including B-cell lymphoma 6 have been identified to be linked to preeclampsia. Increased expression of B-cell lymphoma 6 is correlated with enhanced FLT1 and LEPTIN, the hallmarks of preeclampsia. Moreover, the protein level of B-cell lymphoma 6 is elevated in preeclamptic placentas and is predominantly localized in the nucleus of villous cytotrophoblasts lying directly underneath the syncytial layer, suggestive of an involvement in the function of villous trophoblasts. Altered B-cell lymphoma 6, a key oncogene in B-cell lymphomagenesis, may be involved in the pathogenesis of preeclampsia, and further investigations are required to decipher the molecular mechanisms. PMID:24767250

  11. Zosteriform Secondary Cutaneous Diffuse Large B-Cell Lymphoma on FDG PET/CT.

    PubMed

    Liao, Chiung-Wei; Yen, Kuo-Yang; Hsieh, Te-Chun; Kao, Chia-Hung

    2016-09-01

    We present a case of a woman who had erythematous papules on the abdomen accompanied with numbness and local heat sensation. She had received chemotherapy for advanced follicular lymphoma. F-FDG PET/CT demonstrated band-like hypermetabolic lesions seemingly involving dermatomes of lower abdominal wall, which was confirmed as secondary cutaneous diffuse large B-cell lymphoma via skin biopsy. PMID:27405036

  12. 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.

  13. 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. PMID:21087986

  14. 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

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

    PubMed Central

    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. PMID:27195036

  16. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

    PubMed Central

    Sungalee, Stéphanie; Mamessier, Emilie; Morgado, Ester; Grégoire, Emilie; Brohawn, Philip Z.; Morehouse, Christopher A.; Jouve, Nathalie; Monvoisin, Céline; Menard, Cédric; Debroas, Guilhaume; Faroudi, Mustapha; Mechin, Violaine; Navarro, Jean-Marc; Drevet, Charlotte; Eberle, Franziska C.; Chasson, Lionel; Baudimont, Fannie; Mancini, Stéphane J.; Tellier, Julie; Picquenot, Jean-Michel; Kelly, Rachel; Vineis, Paolo; Ruminy, Philippe; Chetaille, Bruno; Jaffe, Elaine S.; Schiff, Claudine; Hardwigsen, Jean; Tice, David A.; Higgs, Brandon W.; Tarte, Karin; Nadel, Bertrand; Roulland, Sandrine

    2014-01-01

    It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)+ memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation–induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)+ precursors and shapes the systemic presentation of FL patients. PMID:25384217

  17. [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

  18. 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

  19. Exophthalmos due to multicentric B-cell lymphoma in a goat

    PubMed Central

    Valentine, Beth A.; Stieger-Vanegas, Susanne; Brown, Steven R.; Tornquist, Susan J.; Young, Kyra

    2011-01-01

    Multicentric B-cell lymphoma with extensive retrobulbar involvement was diagnosed in a 6-year-old Nubian goat that was presented with conjunctival swelling and exophthalmos. Serologic testing for bovine leukemia virus (BLV) was negative. Postmortem computed tomography aided in identification of the extent of soft tissue and bone lesions. PMID:22654143

  20. EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis

    PubMed Central

    Smonskey, Matthew; Lasorsa, Elena; Rosario, Spencer; Kirk, Jason S.; Hernandez-Ilizaliturri, Francisco J.; Ellis, Leigh

    2016-01-01

    Reactivation of apoptotic pathways is an attractive strategy for patients with treatment-resistant B-cell lymphoma. The tumor suppressor, p53 is central for apoptotic response to multiple DNA damaging agents used to treat aggressive B-cell lymphomas, including etoposide. It has been demonstrated that etoposide induced DNA damage and therapeutic efficacy is enhanced by combination with inhibitors of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). Further, EZH2 was identified to regulate cell fate decisions in response to DNA damage. Using B-cell lymphoma cell lines resistant to etoposide induced cell death; we show that p53 is dramatically down regulated and MDMX, a negative regulator of p53, is significantly up regulated. However, these cell lines remain responsive to etoposide mediated DNA damage and exhibit cell cycle inhibition and induction of senescence. Furthermore, chemical inhibition of EZH2 directs DNA damage to a predominant p53 dependent apoptotic response associated with loss of MDMX and BCL-XL. These data provide confirmation of EZH2 in determining cell fate following DNA damage and propose a novel therapeutic strategy for patients with aggressive treatment-resistant B-cell lymphoma. PMID:26973857

  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. Mutation of chromatin modifiers; an emerging hallmark of germinal center B-cell lymphomas

    PubMed Central

    Lunning, M A; Green, M R

    2015-01-01

    Subtypes of non-Hodgkin's lymphomas align with different stages of B-cell development. Germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt's lymphoma (BL) each share molecular similarities with normal GCB cells. Recent next-generation sequencing studies have gained insight into the genetic etiology of these malignancies and revealed a high frequency of mutations within genes encoding proteins that modifying chromatin. These include activating and inactivating mutations of genes that perform post-translational modification of histones and organize chromatin structure. Here, we discuss the function of histone acetyltransferases (CREBBP, EP300), histone methyltransferases (KDM2C/D, EZH2) and regulators of higher order chromatin structure (HIST1H1C/D/E, ARID1A and SMARCA4) that have been reported to be mutated in ⩾5% of DLBCL, FL or BL. Mutations of these genes are an emerging hallmark of lymphomas with GCB-cell origins, and likely represent the next generation of therapeutic targets for these malignancies. PMID:26473533

  3. Endobronchial recurrence of gastric mucosa-associated lymphoid tissue lymphoma.

    PubMed

    McCollum, Charles R; VanAsselberg, Chad B; Cook-Glen, Celeste L; Bhagat, Rajesh; Abraham, George E

    2012-10-01

    Mucosa-associated lymphoid tissue (MALT) lymphoma is a diagnostic challenge when arising from bronchiolar submucosal tissue. The case herein describes a man with a lung mass and a remote history of gastric MALT lymphoma. After undergoing a bronchoscopic examination and tissue sampling, he was diagnosed with pulmonary recurrence of gastric MALT lymphoma. The diagnosis of MALT lymphoma in the lung can be challenging. Radiographic findings are typically nonspecific, and tissue biopsy by surgical means is often required. The diagnosis of bronchus-associated lymphoid tissue lymphoma has been previously demonstrated bronchoscopically when a needle aspiration is performed. This case supports the position that bronchoscopy with needle aspiration, and flow cytometry should be performed in all patients in whom pulmonary MALT lymphoma is suspected. PMID:23207539

  4. Pulmonary lymphoma of large B-cell type mimicking Wegener's granulomatosis.

    PubMed

    Miyahara, N; Eda, R; Umemori, Y; Murakami, T; Kunichika, N; Makihata, K; Aoe, K; Murakami, K; Takeyama, H; Harada, M

    2001-08-01

    A 27-year-old man with a primary pulmonary lymphoma of large B-cell type is described. Symptoms involved both the upper and lower respiratory tract. A chest roentgenogram showed a dense mass with cavitation. Transbronchial biopsy specimens revealed no atypical cells, rather they demonstrated granulomatous infiltration and vasculitis consistent with but not conclusively diagnostic of Wegener's granulomatosis. The pulmonary mass became smaller after sulfamethoxazole-trimethoprim therapy. These features suggested Wegener's granulomatosis. However, an open biopsy specimen was diagnostic for diffuse lymphoma of large B-cell type. High-grade pulmonary lymphoma should be considered in the differential diagnosis of patients with clinical and pathologic features suggesting Wegener's granulomatosis. PMID:11518126

  5. Intravascular large B-cell lymphoma complicated by invasive pulmonary aspergillosis: a rare presentation

    PubMed Central

    Mahasneh, Tamadur; Harrington, Zinta; Williamson, Jonathan; Alkhawaja, Darweesh; Duflou, Jo; Shin, Joo-Shik

    2014-01-01

    We describe a patient with persisting fevers, a progressive pulmonary infiltrate, and high levels of serum lactate dehydrogenase. No underlying cause for these changes was found prior to her death despite extensive investigations. Postmortem tissue revealed invasive pulmonary aspergillosis and subsequent brain examination revealed vascular changes in keeping with intravascular large B-cell lymphoma (IVLBCL). On review, subtle yet extensive lymphomatous infiltrates involved the vasculature of multiple other organs, including the lungs. Aspergillosis is a relatively rare presenting feature of lymphoproliferative disorders, and IVLBCL is a rare subtype of diffuse large B-cell non-Hodgkin's lymphoma with, to our knowledge, very few case reports to date. Lymphoma should be considered in patients presenting with pneumonitis with bilateral lung infiltrates on imaging, with a high serum level of lactate dehydrogenase. PMID:25473570

  6. Cutaneous Spindle-Cell B-Cell Lymphomas: Most are Neoplasms of Follicular Center Cell Origin.

    PubMed

    Charli-Joseph, Yann; Cerroni, Lorenzo; LeBoit, Philip E

    2015-06-01

    Cutaneous lymphomas of both B cells and less commonly T cells can exceptionally exhibit spindle-cell morphology. Less than 30 spindle-cell B-cell lymphomas of the skin have been described, mostly before the adoption of detailed immunohistochemistry, and thus initially interpreted as variants of diffuse large B-cell lymphoma (DLBCL). Furthermore, some authors suggest that cutaneous spindle-cell B-cell lymphomas (cSCBCLs) may behave more aggressively than their conventional morphologic counterparts and may thus merit more aggressive treatment. Herein we describe the largest case series of cSCBCL analyzed to date to characterize their clinicopathologic and immunohistochemical features and clarify their subtype according to the current WHO/EORTC classification scheme. Twenty-four cSCBCLs arose in 18 male and 6 female individuals with a mean age of 55 years, mostly on the head (12/24), trunk (8/24), and lower extremities (4/24). Histopathologic features were similar for all cases. Neoplasms involved the entire dermis and focally the subcutis. The neoplastic infiltrates comprised a mixture of medium-sized, visually prominent spindled cells (15%; up to 85% of the infiltrate) arranged in a fascicular pattern around nodular aggregates and admixed in a random manner between centrocyte/centroblast-like cells within these nodular collections. Immunohistochemical support for a follicular center cell origin was present in 22/24 cases, 1 was consistent with DLBCL-leg type and 1 defied precise classification, best fitting with intermediate-grade DLBCL-other. Our findings reinforce the concept that most cSCBCLs are variants of low-grade B-cell lymphomas of follicle center cell origin and not intermediate-grade variants of DLBCL. PMID:25634743

  7. Laparoscopic resection of synchronous gastric cancer and primary small intestinal lymphoma: a case report.

    PubMed

    Chen, Ding-Wei; Pan, Yu; Yan, Jia-Fei; Mou, Yi-Ping

    2014-05-28

    Synchronous gastric cancer and primary small intestinal lymphoma are extremely rare. A 49-year-old woman was referred to our hospital with a history of upper abdominal pain for two weeks and was diagnosed with synchronous cancer. During hospitalization, the patient underwent laparoscopic distal gastrectomy + resection of bilateral ovaries + partial resection of both small intestine and descending colon. Pathological examination revealed a synchronous cancer consisting of early gastric cancer with poorly differentiated adenocarcinoma located in mucosa, with lymph node metastasis (3+/29) (T1N1M0, stage IB); and diffuse large B cell lymphoma of small intestine involving descending colon and bilateral ovaries, with lymph node metastasis (2+/5) (Ann Arbor IIE). The patient recovered well, without any obvious complications and was discharged on post-operative day 7. The patient received six cycles of chemotherapy after operation. She has been doing well with no evidence of recurrence for 13 mo. PMID:24876758

  8. Primary colorectal lymphoma comprising both components of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma combined with cytomegalovirus colitis.

    PubMed

    Katsumata, Ryo; Matsumoto, Hiroshi; Motoyasu, Osawa; Murao, Takahisa; Ishii, Manabu; Fujita, Minoru; Tokunaga, Hirotoshi; Akiyama, Takashi; Wada, Hideho; Sugihara, Takashi; Shiotani, Akiko; Haruma, Ken

    2016-04-01

    A 16-year-old girl presented to our hospital with diarrhea and abdominal pain. The macroscopic findings of colonoscopy revealed multiple submucosal tumors and multiple ulcers, which were localized in the sigmoid colon, and diffuse granular mucosa which extended to the total colon. The pathological diagnosis was malignant lymphoma comprising both components of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, because the large lymphoma cells were CD20+, CD10-, and CD5-. Furthermore, immunohistochemical analysis of colorectal biopsy samples from multiple ulcers revealed cytomegalovirus (CMV)-positive cells. The patient was diagnosed with primary colorectal lymphoma comprising both components of DLBCL and MALT lymphoma combined with CMV colitis. She received anti-viral medication and chemotherapy. PMID:27015999

  9. Splenic B cell lymphoma with circulating villous lymphocytes: differential diagnosis of B cell leukaemias with large spleens.

    PubMed Central

    Melo, J V; Hegde, U; Parreira, A; Thompson, I; Lampert, I A; Catovsky, D

    1987-01-01

    The clinical, haematological, morphological and histological features of a series of 22 patients presenting with splenic lymphoma with circulating villous lymphocytes were assessed and compared with those of patients with other forms of chronic B cell leukaemia in an attempt to differentiate this condition from hairy cell leukaemia, prolymphocytic leukaemia, and chronic lymphocytic leukaemia, with which this condition has many features in common. The disease was twice as common in men than in women, with a mean (SD) age at diagnosis of 72 (9) years, and the most consistent presenting feature was massive enlargement of the spleen, which showed white and red pulp disease with a plasmacytic component. Small monoclonal bands were found in 60% of cases. Images Fig 1 Fig 2 Fig 3 Fig 4 PMID:3497180

  10. Therapeutic implication of concomitant chromosomal aberrations in patients with aggressive B-cell lymphomas.

    PubMed

    Marullo, Rossella; Rutherford, Sarah C; Leonard, John P; Cerchietti, Leandro

    2016-09-01

    A subset of diffuse large B-cell lymphomas (DLBCL) harbors concomitant rearrangements of MYC, BCL2 and BCL6 and is characterized by clinical aggressiveness and intrinsic refractoriness to standard chemo-immunotherapy. Commonly identified as "double or triple hit" lymphomas, these diseases represent a therapeutic challenge to chemotherapy-based regimens and likely require a more targeted approach. Herein we summarize the unique biological behavior of double and triple hit lymphomas focusing on the coordinated network of pathways that enable cancer cells to tolerate the oncogenic stress imposed by the co-expression of MYC, BCL2 and BCL6. We discuss how these enabling pathways contribute to the chemo-refractoriness of these tumors. We propose to exploit lymphoma cells' addiction to these oncogenic networks to design combinatorial treatments for this aggressive disease based on the modulation of epigenetically-silenced pathways and decreasing expression and activity of these oncogenic drivers. PMID:27419806

  11. ATMIN is required for maintenance of genomic stability and suppression of B cell lymphoma.

    PubMed

    Loizou, Joanna I; Sancho, Rocio; Kanu, Nnennaya; Bolland, Daniel J; Yang, Fengtang; Rada, Cristina; Corcoran, Anne E; Behrens, Axel

    2011-05-17

    Defective V(D)J rearrangement of immunoglobulin heavy or light chain (IgH or IgL) or class switch recombination (CSR) can initiate chromosomal translocations. The DNA-damage kinase ATM is required for the suppression of chromosomal translocations but ATM regulation is incompletely understood. Here, we show that mice lacking the ATM cofactor ATMIN in B cells (ATMIN(ΔB/ΔB)) have impaired ATM signaling and develop B cell lymphomas. Notably, ATMIN(ΔB/ΔB) cells exhibited defective peripheral V(D)J rearrangement and CSR, resulting in translocations involving the Igh and Igl loci, indicating that ATMIN is required for efficient repair of DNA breaks generated during somatic recombination. Thus, our results identify a role for ATMIN in regulating the maintenance of genomic stability and tumor suppression in B cells. PMID:21575860

  12. CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma.

    PubMed

    Däbritz, J Henry M; Yu, Yong; Milanovic, Maja; Schönlein, Martin; Rosenfeldt, Mathias T; Dörr, Jan R; Kaufmann, Andreas M; Dörken, Bernd; Schmitt, Clemens A

    2016-05-01

    The CD20-targeting monoclonal antibody rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its coadministration with conventional anticancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which rituximab exerts its antilymphoma activity are only partially understood. We show here that rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biologic properties, in established B-cell lymphoma cell lines as well as primary transformed B cells. In addition, rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound adriamycin (a.k.a. doxorubicin), and, to a lesser extent, by the antimicrotubule agent vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response signaling cascade triggered by adriamycin. As the underlying prosenescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to rituximab, and, in turn, the ROS scavenger N-acetylcysteine to largely abrogate rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a rituximab-containing treatment regimen, provide important mechanistic insights into the biologic complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy. Mol Cancer Ther; 15(5); 1074-81. ©2016 AACR. PMID:26880268

  13. 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

  14. 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

  15. 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

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

    PubMed Central

    McKenna, MK; Gachuki, BW; Alhakeem, SS; Oben, KN; Rangnekar, VM; Gupta, RC; 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

  17. MicroRNA Profiling of Primary Cutaneous Large B-Cell Lymphomas

    PubMed Central

    Koens, Lianne; Qin, Yongjun; Leung, Wai Y.; Corver, Willem E.; Jansen, Patty M.; Willemze, Rein; Vermeer, Maarten H.; Tensen, Cornelis P.

    2013-01-01

    Aberrant expression of microRNAs is widely accepted to be pathogenetically involved in nodal diffuse large B-cell lymphomas (DLBCLs). However, the microRNAs profiles of primary cutaneous large B-cell lymphomas (PCLBCLs) are not yet described. Its two main subtypes, i.e., primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) and primary cutaneous follicle center lymphoma (PCFCL) are characterized by an activated B-cell (ABC)-genotype and a germinal center B-cell (GCB)-genotype, respectively. We performed high-throughput sequencing analysis on frozen tumor biopsies from 19 cases of PCFCL and PCLBCL-LT to establish microRNA profiles. Cluster analysis of the complete microRNome could not distinguish between the two subtypes, but 16 single microRNAs were found to be differentially expressed. Single microRNA RT-qPCR was conducted on formalin-fixed paraffin-embedded tumor biopsies of 20 additional cases, confirming higher expression of miR-9-5p, miR-31-5p, miR-129-2-3p and miR-214-3p in PCFCL as compared to PCLBCL-LT. MicroRNAs previously described to be higher expressed in ABC-type as compared to GCB-type nodal DLBCL were not differentially expressed between PCFCL and PCLBCL-LT. In conclusion, PCFCL and PCLBCL-LT differ in their microRNA profiles. In contrast to their gene expression profile, they only show slight resemblance with the microRNA profiles found in GCB- and ABC-type nodal DLBCL. PMID:24358187

  18. MicroRNA profiling of primary cutaneous large B-cell lymphomas.

    PubMed

    Koens, Lianne; Qin, Yongjun; Leung, Wai Y; Corver, Willem E; Jansen, Patty M; Willemze, Rein; Vermeer, Maarten H; Tensen, Cornelis P

    2013-01-01

    Aberrant expression of microRNAs is widely accepted to be pathogenetically involved in nodal diffuse large B-cell lymphomas (DLBCLs). However, the microRNAs profiles of primary cutaneous large B-cell lymphomas (PCLBCLs) are not yet described. Its two main subtypes, i.e., primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) and primary cutaneous follicle center lymphoma (PCFCL) are characterized by an activated B-cell (ABC)-genotype and a germinal center B-cell (GCB)-genotype, respectively. We performed high-throughput sequencing analysis on frozen tumor biopsies from 19 cases of PCFCL and PCLBCL-LT to establish microRNA profiles. Cluster analysis of the complete microRNome could not distinguish between the two subtypes, but 16 single microRNAs were found to be differentially expressed. Single microRNA RT-qPCR was conducted on formalin-fixed paraffin-embedded tumor biopsies of 20 additional cases, confirming higher expression of miR-9-5p, miR-31-5p, miR-129-2-3p and miR-214-3p in PCFCL as compared to PCLBCL-LT. MicroRNAs previously described to be higher expressed in ABC-type as compared to GCB-type nodal DLBCL were not differentially expressed between PCFCL and PCLBCL-LT. In conclusion, PCFCL and PCLBCL-LT differ in their microRNA profiles. In contrast to their gene expression profile, they only show slight resemblance with the microRNA profiles found in GCB- and ABC-type nodal DLBCL. PMID:24358187

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

    PubMed

    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

  20. 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

  1. A tumor-related lymphoid progenitor population supports hierarchical tumor organization in canine B-cell lymphoma

    PubMed Central

    Ito, Daisuke; Endicott, Melissa M.; Jubala, Cristan M.; Helm, Karen M.; Burnett, Robert C.; Husbands, Brian D.; Borgatti, Antonella; Henson, Michael S.; Burgess, Kristine E.; Bell, Jerold S.; Kisseberth, William C.; Valli, Victor E.; Cutter, Gary R.; Avery, Anne C.; Hahn, Kevin A.; O’Brien, Timothy D.; Modiano, Jaime F.

    2016-01-01

    Background Tumors have heterogeneous properties, which could be explained by the existence of hierarchically and biologically distinct tumor cells such as tumor-initiating cells (TICs). This model is clinically important, as TICs are promising targets for cancer therapies. However, TICs in spontaneous B-cell lymphoma have not been conclusively identified. Hypothesis/Objectives Tumor cells with a progenitor phenotype exist in B-cell lymphoma, reflecting a hierarchical organization. Animals Twenty-eight client-owned dogs with previously untreated B-cell lymphoma and six healthy dogs. Methods This was a prospective study. Flow cytometry was used to identify lymphoid progenitor cells (LPCs) that co-expressed hematopoietic progenitor antigens CD34, CD117 (KIT), and CD133, with lymphoid differentiation markers CD21 and/or CD22 in B-cell lymphoma. The polymerase chain reaction for antigen receptor rearrangements was used to analyze clonality and relatedness of tumor populations. A xenograft model using NOD/SCID/IL-2Rγ−/− mice was adapted to expand and serially transplant primary canine B-cell lymphoma. Results LPCs were significantly expanded in lymph node samples from 28 dogs with B-cell lymphoma compared to six healthy dogs (p=0.0022). LPCs contained a clonal antigen receptor gene rearrangement identical to that of the bulk of tumor cells. Canine B-cell lymphoma xenografts in recipient mice that maintained LPCs in the tumors were recurrently observed. Conclusions and clinical importance These results suggest the presence of a hierarchy of tumor cells in canine B-cell lymphoma as has been demonstrated in other cancers. These findings have the potential to impact not only the understanding of lymphoma pathogenesis but also the development of lymphoma therapies by providing novel targets for therapy. PMID:21777289

  2. Clinical characteristics and prognostic factors of primary gastric lymphoma

    PubMed Central

    Wang, Yi-Gao; Zhao, Lin-Yong; Liu, Chuan-Qi; Pan, Si-Cheng; Chen, Xiao-Long; Liu, Kai; Zhang, Wei-Han; Yang, Kun; Chen, Xin-Zu; Zhang, Bo; Chen, Zhi-Xin; Chen, Jia-Ping; Zhou, Zong-Guang; Hu, Jian-Kun

    2016-01-01

    Abstract Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma. This retrospective study aimed to analyze the clinical characteristics, prognostic factors, and roles of different treatment modalities in patients with PGL. From January 2003 to November 2014, 165 patients who were diagnosed with PGL at West China Hospital were enrolled in this study. The clinical features, treatment, and follow-up information were analyzed. In this study, diffuse large B-cell lymphoma (DLBCL) (108, 65.5%) and mucosa-associated lymphoid tissue (MALT) lymphoma (52, 31.5%) were two predominant histological subtypes. One-year and 5-year overall survival (OS) rates of all patients were 95.2% and 79.5%, respectively; in whom 110 (66.7%) underwent surgery, 110 (66.7%) received chemotherapy, 12 (7.3%) received radiotherapy, and 10 (6.1%) received Helicobacter pylori eradication. And 75 patients (45.5%) were treated with at least 2 different types of therapies. Elevated lactic dehydrogenase (LDH) levels, poor performance status (PS), advanced stage, International Prognostic Index (IPI) score ≥3, conservative treatment, and high-grade histological subtype were associated with worse prognosis in univariate analysis. Cox regression analysis showed that LDH levels, PS, staging, and histological subtype were independent predictors of survival outcomes. In the DLBCL type, 5-year OS was significantly better in the surgically treated group (80.1%) than that of patients conservatively treated (49.8%) (P = 0.001). Surgical treatment had almost no impact on OS in the MALT type than conservative treatment (P = 0.597). The proportion of patients received conservative treatment increased from 4.5% in period 1 to 51.7% in period 4. High LDH levels, poor PS, advanced staging, and malignant pathological type at diagnosis are significantly associated with poor OS. Our data suggest that surgery is superior in prognosis over conservative treatment in the DLBCL type, but not

  3. 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. PMID:27101016

  4. 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

  5. Diffuse Large B-cell lymphoma: Prognostic markers and their impact on therapy.

    PubMed

    Jamil, Muhammad O; Mehta, Amitkumar

    2016-05-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL). DLBCL is clinically, pathologically and molecularly heterogeneous disease. Various clinical, pathological and molecular markers have been developed to characterize the disease. Based on these characterizations, new targeted agents are being investigated to optimize the treatment and improve the outcomes of DLBCL. Enhanced molecular understanding, invention of targeted agents and immunotherapy has opened the doors for improvement in the treatment of DLBCL. In this review, we will discuss various prognostic markers of DLBCL and their potential therapeutic implications. PMID:26808217

  6. 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

  7. Classical Hodgkin lymphoma primary refractory to brentuximab vedotin, with transformation to CD30-positive diffuse large B-cell lymphoma.

    PubMed

    Makita, Shinichi; Maeshima, Akiko Miyagi; Taniguchi, Hirokazu; Kitahara, Hideaki; Fukuhara, Suguru; Munakata, Wataru; Suzuki, Tatsuya; Maruyama, Dai; Kobayashi, Yukio; Tobinai, Kensei

    2016-09-01

    Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. It is highly effective for relapsed/refractory classical Hodgkin lymphoma (CHL), and has become a promising treatment option for these patients; however, approximately 25 % of patients are refractory to BV. Until now, the clinicopathologic features of CHL refractory to BV have not been well understood. Here, we report a patient with relapsed CHL with an unfavorable outcome, whose disease was primary refractory to BV and was histologically diagnosed as a transformation from mixed cellularity CHL to CD30-positive diffuse large B-cell lymphoma (DLBCL). The transformation to DLBCL showing high tumor density and high proliferative activity (Ki67 index >90 %) was possibly related to the primary refractory to BV and an aggressive clinical course, although the lymphoma was diffusely and strongly positive for CD30. PMID:27169615

  8. Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas

    PubMed Central

    Epperla, Narendranath; Fenske, Timothy S; Hari, Parameswaran N; Hamadani, Mehdi

    2015-01-01

    Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton’s tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT. PMID:26421260

  9. 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

  10. Recurrent endobronchial diffuse large B-cell lymphoma. Diagnosed by cryoprobe.

    PubMed

    Pajares, Virginia; Torrego, Alfons; Granell, Miquel; Szafranska, Justyna; Mozos, Anna; Puzo, Carmen

    2013-05-01

    The bronchial involvement of diffuse large B-cell lymphoma (DLBCL) is an exceptional finding. Histological diagnosis is done with lung tissue samples. In these cases, the need for immunohistochemistry studies in order to establish the diagnosis requires obtaining tissue samples of adequate size and quality. Sometimes, endoscopic explorations may be repeated to obtain further biopsies. We present the first documented case of recurrent endobronchial DLBCL that was diagnosed from a bronchial biopsy taken with a cryoprobe. PMID:22981515

  11. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells

    PubMed Central

    Katz, Samuel G.; LaBelle, James L.; Meng, Hailong; Valeriano, Regina P.; Fisher, Jill K.; Sun, Heather; Rodig, Scott J.; Kleinstein, Steven H.

    2014-01-01

    Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its α-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1–transgenic mice harboring Bim-deficient B cells. In response to immunization, EμCycD1CD19CREBimfl/fl mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM. PMID:24352880

  12. Recent Advances in Aggressive Large B-cell Lymphomas: A Comprehensive Review.

    PubMed

    Korkolopoulou, Penelope; Vassilakopoulos, Theodoros; Milionis, Vassilios; Ioannou, Maria

    2016-07-01

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with considerable heterogeneity reflected in the 2008 World Health Organization classification. In recent years, genome-wide assessment of genetic and epigenetic alterations has shed light upon distinct molecular subsets linked to dysregulation of specific genes or pathways. Besides fostering our knowledge regarding the molecular complexity of DLBCL types, these studies have unraveled previously unappreciated genetic lesions, which may be exploited for prognostic and therapeutic purposes. Following the last World Health Organization classification, we have witnessed the emergence of new variants of specific DLBCL entities, such as CD30 DLBCL, human immunodeficiency virus-related and age-related variants of plasmablastic lymphoma, and EBV DLBCL arising in young patients. In this review, we will present an update on the clinical, pathologic, and molecular features of DLBCL incorporating recently gained information with respect to their pathobiology and prognosis. We will emphasize the distinctive features of newly described or emerging variants and highlight advances in our understanding of entities presenting a diagnostic challenge, such as T-cell/histiocyte-rich large B-cell lmphoma and unclassifiable large B-cell lymphomas. Furthermore, we will discuss recent advances in the genomic characterization of DLBCL, as they may relate to prognostication and tailored therapeutic intervention. The information presented in this review derives from English language publications appearing in PubMed throughout December 2015. For a complete outline of this paper, please visit: http://links.lww.com/PAP/A12. PMID:27271843

  13. MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management

    PubMed Central

    Cai, Qingqing; Medeiros, L. Jeffrey; Xu, Xiaolu; Young, Ken H.

    2015-01-01

    MYC, a potent oncogene located at chromosome locus 8q24.21, was identified initially by its involvement in Burkitt lymphoma with t(8;14)(q24;q32). MYC encodes a helix-loop-helix transcription factor that accentuates many cellular functions including proliferation, growth and apoptosis. MYC alterations also have been identified in other mature B-cell neoplasms and are associated with aggressive clinical behavior. There are several regulatory factors and dysregulated signaling that lead to MYC up-regulation in B-cell lymphomas. One typical example is the failure of physiological repressors such as Bcl6 or BLIMP1 to suppress MYC over-expression. In addition, MYC alterations are often developed concurrently with other genetic alterations that counteract the proapoptotic function of MYC. In this review, we discuss the physiologic function of MYC and the role that MYC likely plays in the pathogenesis of B-cell lymphomas. We also summarize the role MYC plays in the diagnosis, prognostication and various strategies to detect MYC rearrangement and expression. PMID:26416427

  14. 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

    2016-03-01

    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. PMID:26458141

  15. 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

  16. Diffuse large B cell lymphoma of the cranial vault: two case reports.

    PubMed

    Tashiro, Ryosuke; Kanamori, Masayuki; Suzuki, Hiroyoshi; Utsunomiya, Akihiro; Meguro, Kuniaki; Uenohara, Hiroshi; Tominaga, Teiji

    2015-10-01

    Malignant lymphoma of the cranial vault is a rare entity and the tumor growth patterns are not well understood. Here we report two cases of malignant lymphoma involving the scalp and epidural space with slight changes in the intervening skull. A 63-year-old woman presented with a scalp mass in her right frontal area. Computed tomography (CT) and magnetic resonance (MR) imaging demonstrated mass lesions in the scalp and epidural space with slight osteolytic changes in the intervening skull. She underwent resection of the lesions. A 53-year-old man presented with a mass in his right frontal area. CT and MR imaging showed mass lesions in the scalp and epidural space without changes in the skull. He underwent resection of the lesions. The histopathological diagnosis was diffuse large B cell lymphoma in both cases. Microscopic examination of the intervening skull found that the bone marrow was diffusely replaced by lymphoma cells, and lymphoma cells extended to the extra- or intra-cranial space along the emissary veins without destruction of the cortical or trabecular bone. These histopathological findings explain the radiological findings and provide the clues to elucidate the mechanism of extension of cranial vault lymphoma. PMID:26177806

  17. 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

  18. 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

  19. Angiocrine Factors Deployed by Tumor Vascular Niche Induce B-Cell Lymphoma Invasiveness and Chemoresistance

    PubMed Central

    Cao, Zhongwei; Ding, Bi-Sen; Guo, Peipei; Lee, Sharrell B.; Butler, Jason M.; Casey, Stephanie C.; Simons, Michael; Tam, Wayne; Felsher, Dean W.; Shido, Koji; Rafii, Arash; Scandura, Joseph M.; Rafii, Shahin

    2014-01-01

    Summary Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is not understood how vascular niche-derived paracrine factors, known as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B-Cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch-ligand Jagged1 (Jag1) on neighboring tumor ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44+IGF1R+CSF1R+ LC phenotypes, including extra-nodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop could inhibit LC aggressiveness and enhance chemosensitivity. PMID:24651014

  20. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma

    PubMed Central

    Goldstein, Rebecca L.; Yang, Shao Ning; Taldone, Tony; Chang, Betty; Gerecitano, John; Elenitoba-Johnson, Kojo; Shaknovich, Rita; Tam, Wayne; Leonard, John P.; Chiosis, Gabriela; Cerchietti, Leandro; Melnick, Ari

    2015-01-01

    Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell–like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes. Functional assays revealed that teHSP90 facilitates BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components, including the kinases SYK and BTK. Consequently, treatment of BCR-dependent ABC DLBCL cells with PU-H71 attenuated BCR signaling, calcium flux, and NF-κB signaling, ultimately leading to growth arrest. Combined exposure of ABC DLBCL cell lines to PU-H71 and ibrutinib, a BCR pathway inhibitor, more potently suppressed BCR signaling than either drug alone. Correspondingly, PU-H71 combined with ibrutinib induced synergistic killing of lymphoma cell lines, primary human lymphoma specimens ex vivo, and lymphoma xenografts in vivo, without notable toxicity. Together, our results demonstrate that a pharmacoproteome-driven rational combination therapy has potential to provide more potent BCR-directed therapy for ABC DLCBL patients. PMID:26529251

  1. Composite B-cell and T-cell non-Hodgkin lymphoma of the tibia.

    PubMed

    Kaleem, Zahid; McGuire, Michael H; Caracioni, Adrian C; Leonard, Ronald L; Pathan, M Hanif; Lessmann, Ellen A; Chan, Wing C

    2005-02-01

    We report a unique case of de novo composite lymphoma in the tibia of a 35-year-old man who presented with increasingly frequent and intense pain in the right upper leg. He was otherwise healthy without significant medical history. A plain radiograph of the right leg showed a permeative lesion with alternating areas of radiolucency and radiodensity in the upper third of the tibia. Magnetic resonance imaging showed a large, heterogeneous enhancing lesion involving the medullary and cortical bone of the proximal tibia with cortical disruption and extension into the adjacent soft tissue. A biopsy showed sheets and clusters of large cells, punctuated by clusters of small, irregular lymphocytes. Flow cytometry and immunohistochemical analysis showed composite lymphoma: diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell non-Hodgkin lymphoma with predominantly small cell morphologic features. The DLBCL expressed CD19, CD20, CD79a, CD5, CD10, CD23, CD38, CD117, bcl-2, and bcl-6, with monotypic expression of immunoglobulin kappa light chain. The T cells expressed CD2, CD3, CD5, CD7, and CD8, with partial loss of CD4. Clonal rearrangement of T-cell receptor gamma chain gene was found. Neither the large B cells nor the small T cells expressed Epstein-Barr virus-encoded RNA. Physical examination and radiologic studies showed no evidence of lymphadenopathy, organomegaly, or other mass lesions in the body. No peripheral lymphocytosis or bone marrow involvement was present. PMID:15842045

  2. DNA repair genes are selectively mutated in diffuse large B cell lymphomas

    PubMed Central

    de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Sörqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundström, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

    2013-01-01

    DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis. PMID:23960188

  3. 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

  4. [Salvage gastrectomy and radiotherapy for R-CHOP-refractory gastric malignant lymphoma].

    PubMed

    Shibata, Shigeru; Akasaka, Harue; Wakiya, Taiichi; Yamanaka, Yuji; Narita, Junichi; Sutou, Takemichi; Iino, Chikara

    2014-11-01

    A man in his seventies presented with a stomach abnormality that was revealed upon physical examination.Following workup, he was diagnosed with gastric diffuse large B-cell lymphoma (DLBCL)StageII1 (Lugano staging system for gastrointestinal lymphoma) with low risk as defined by the International Prognostic Index criteria.The entire stomach showed an intense, abnormal FDG uptake by FDG-PET evaluation.He was treated with rituximab plus CHOP (R-CHOP).The patient's body weight decreased by 12 kg during the treatment period.Post -treatment evaluation by gastroscopy and FDG-PET following 5 courses of R-CHOP therapy revealed a residual lesion in the stomach.Total gastrectomy was performed for R-CHOP refractory gastric DLBCL.The pathological diagnosis was DLBCL, and the pathological therapeutic effect was Grade 1a.Lymphoma cells were detected at the duodenal margin of the resected specimen, and an FDG-PET scan showed abnormal FDG uptake in the duodenal stump necessitating salvage chemotherapy (DeVIC therapy)and radiotherapy.The patient's body weight increased by 5 kg after gastrectomy and there were no signs of relapse for 14 months after the operation.Salvage therapy including gastrectomy may be effective for chemotherapy-resistant gastric DLBCL. PMID:25731535

  5. 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.

  6. 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

  7. Immunoglobulin Gene Repertoire Diversification and Selection in the Stomach – From Gastritis to Gastric Lymphomas

    PubMed Central

    Michaeli, Miri; Tabibian-Keissar, Hilla; Schiby, Ginette; Shahaf, Gitit; Pickman, Yishai; Hazanov, Lena; Rosenblatt, Kinneret; Dunn-Walters, Deborah K.; Barshack, Iris; Mehr, Ramit

    2014-01-01

    Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL. PMID:24917868

  8. Orbital marginal zone B-cell lymphoma of Malt: Radiotherapy results and clinical behavior

    SciTech Connect

    Suh, Chang-Ok . E-mail: cosuh317@yumc.yonsei.ac.kr; Shim, Su Jung; Lee, Sang-wook; Yang, Woo Ick; Lee, Sang Yeul; Hahn, Jee Sook

    2006-05-01

    Purpose: To elucidate the clinical behavior and treatment outcome of low-grade primary orbital lymphoma arising from mucosa-associated lymphoid tissue (Malt). Methods and Materials: Forty-eight patients with pathologically confirmed marginal zone B-cell lymphoma of MALT were treated with radiotherapy (RT). Thirty-eight patients (79.1%) received thorough staging workup studies including bone marrow biopsy. Radiation doses ranged from 5.4 to 30.6 Gy (median, 30.6 Gy). Median follow-up period was 70 months. Results: Only 2 patients revealed extraorbital lymphoma involvement (bone marrow, skin). Forty-six of 52 eye lesions showed complete response to RT. Six lesions demonstrated a partial response and showed gradual regression during the follow-up period of 39-72 months. Three patients experienced local recurrences at 34, 48, and 52 months after RT, which seemed to be related to improper use of the lens shield. Salvage re-RT was successful. The 10-year actuarial relapse-free survival, cause-specific survival, and overall survival rates were 93.1%, 97.9%, and 86.9%, respectively. Conclusion: Most of the MALT lymphoma of the orbit was localized at diagnosis and extraorbital relapse rarely occurred. Therefore, extensive staging workup at the time of diagnosis and follow-up studies to detect distant relapse may not be obligatory. Low-dose RT alone with proper lens shielding is the optimum treatment modality for orbital MALT lymphoma.

  9. Markers of B-Cell Activation in Relation to Risk of Non-Hodgkin Lymphoma

    PubMed Central

    De Roos, Anneclaire J; Mirick, Dana K; Edlefsen, Kerstin L; LaCroix, Andrea Z; Kopecky, Kenneth J; Madeleine, Margaret; Magpantay, Larry; Martínez-Maza, Otoniel

    2012-01-01

    B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women’s Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis, in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers, for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8 to 5.5-fold increased risk of B-NHL. Additionally, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9–13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development, as early as 9 years before diagnosis. PMID:22846913

  10. 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

  11. [MALT B cell lymphoma with kidney damage and monoclonal gammopathy: a case study and literature review].

    PubMed

    Peces, R; Vega-Cabrera, C; Peces, C; Pobes, A; Fresno, M F

    2010-01-01

    We report a case of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) involving the left kidney and simultaneous onset of a monoclonal gammopathy IgM kappa. No predisposing local inflammatory condition was identified. Following left nephrectomy, the renal specimen showed the centrocyte like cells and lymphoid cells in the lymphoepithelial lesions were positive for CD20 and CD79α. The neoplastic cells expressed monotypic cytoplasmic IgM kappa. The demonstration of bone marrow cells of B-lineage expressing the same monoclonal protein as the tumor suggested bone marrow involvement, even in the absence of identical morphology. Despite chemotherapy and rituximab treatment, clinical follow-up showed right kidney extension with high-grade transformation, and finally systemic dissemination. This case illustrates that the kidney is among the sites that may be involved by MALT B-cell lymphomas in a primary or secondary fashion, and the need for expanded investigation of the possible dissemination. We review the literature on this unusual extranodal lymphoma. PMID:21113219

  12. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    PubMed

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  13. 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

  14. Cutaneous diffuse large B-cell lymphoma of the leg associated with chronic lymphedema.

    PubMed

    González-Vela, M Carmen; González-López, Marcos A; Val-Bernal, J Fernando; Fernández-Llaca, Héctor

    2008-02-01

    Development of malignant tumors is a rare but well known complication in chronic lymphedema (CL). We report herein a cutaneous diffuse large B-cell lymphoma of the leg associated with CL. An 89-year-old man presented with multiple cutaneous lesions on his right limb that showed a CL. Dermatological examination disclosed multiple violaceous, firm, slightly infiltrated nodules on the anterior aspect of the leg and the dorsum and sole of the foot. A biopsy of one nodule of the leg disclosed a diffuse large B-cell lymphoma, type of the legs. There was no evidence of lymphadenopathy on computed tomography (CT) scans of the chest, abdomen, and pelvis. A bone marrow aspiration and biopsy showed normal results. The patient was treated with local radiotherapy at a dose of 40 Gy, obtaining a highly significant, almost complete, clinical remission. A literature search identified 11 additional cases of primary cutaneous lymphoma associated with CL. An inadequate lymphatic drainage may make the lymphedematous region an immunologically vulnerable area, predisposing to neoplasia. PMID:18211492

  15. 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

  16. A case of primary pulmonary diffuse large B-cell lymphoma diagnosed by transbronchial biopsy.

    PubMed

    Yoshino, Naoyuki; 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

  17. 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

  18. B cell clonality in gastric lymphoid tissues of patients with Sjögren's syndrome.

    PubMed Central

    Ferraccioli, G F; Sorrentino, D; De Vita, S; Casatta, L; Labombarda, A; Avellini, C; Dolcetti, R; Di Luca, D; Beltrami, C A; Boiocchi, M; Bartoli, E

    1996-01-01

    OBJECTIVE: To determine the prevalence of mucosa associated lymphoid tissue (MALT) in the stomach and of a possible antigen driven proliferation, in patients with Sjögren's syndrome (SS). METHODS: Twenty one patients with primary SS and 80 dyspeptic controls underwent upper endoscopy. Lymphoid tissue and Helicobacter pylori were assessed by histopathological analysis. Epstein-Barr virus (EBV) or human herpes virus-6 (HHV-6) genome were studied by polymerase chain reaction (PCR) DNA amplification. Two PCR VDJ procedures were used to detect immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Organised MALT was found in 33.3% of the patients, compared with 21.5% of the controls (NS). H pylori infection was seen in 71% of patients and 63% of controls. Genomic EBV or HHV-6 was found in a minor portion of SS gastric tissues. B cell expansion was detected in nine of the 21 patients. Infectious agents in the stomach might have contributed to B cell clonality only in 55.5% of the cases. No strict relationship was found between lymphoid follicles and clonality. CONCLUSION: Lymphoid accumulation in the gastric mucosa is common in Sjögren's syndrome, but full evidence for an antigen driven B cell expansion could not be demonstrated. Only a portion of those with clonal B cell expansion had evidence of an infectious agent. Other unknown infectious agents or factors related to the underlying disease (autoantigen) and its tissue environment may have a further role as possible causes of B clonal expansion in the gastric mucosa. Images PMID:8660105

  19. Mature B-cell lymphoma and leukemia in children and adolescents-review of standard chemotherapy regimen and perspectives.

    PubMed

    Worch, Jennifer; Rohde, Marius; Burkhardt, Birgit

    2013-09-01

    Mature B-cell non-Hodgkin lymphoma (B-NHL) comprises more than 50% of all non-Hodgkin lymphoma (NHL) in children and adolescents. Many B-NHL subtypes frequently observed in adults are rarely diagnosed in children and adolescents. In this age group, Burkitt lymphoma (BL), Burkitt leukemia or FAB L3 leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBL), follicular lymphoma (FL), and aggressive mature B-NHL not further classifiable (B-NHL nfc) are the most common subtypes. Diverse clinical trials demonstrated similar results of current combination chemotherapy regimens succeeding in overall survival rates of more than 80%. However, treatment-related toxicity and the poor prognosis of relapse are serious concerns. Furthermore, specific histological B-NHL subtypes are rare in children and optimal treatment is not established. New treatment modalities are urgently needed for these patient groups. Rituximab, a monoclonal antibody that is already established in the treatment of adults with mature B-NHL, demonstrated promising results in pediatric patients. The definitive role of rituximab in the treatment of children and adolescents with B-NHL needs to be evaluated in prospective controlled clinical trials. This review provides a comprehensive overview of chemotherapy regimens and the perspectives for children and adolescents with mature B-cell lymphoma and leukemia. PMID:23570584

  20. 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

  1. B-cell lymphoma gene regulatory networks: biological consistency among inference methods

    PubMed Central

    de Matos Simoes, Ricardo; Dehmer, Matthias; Emmert-Streib, Frank

    2013-01-01

    Despite the development of numerous gene regulatory network (GRN) inference methods in the last years, their application, usage and the biological significance of the resulting GRN remains unclear for our general understanding of large-scale gene expression data in routine practice. In our study, we conduct a structural and a functional analysis of B-cell lymphoma GRNs that were inferred using 3 mutual information-based GRN inference methods: C3Net, BC3Net and Aracne. From a comparative analysis on the global level, we find that the inferred B-cell lymphoma GRNs show major differences. However, on the edge-level and the functional-level—that are more important for our biological understanding—the B-cell lymphoma GRNs were highly similar among each other. Also, the ranks of the degree centrality values and major hub genes in the inferred networks are highly conserved as well. Interestingly, the major hub genes of all GRNs are associated with the G-protein-coupled receptor pathway, cell-cell signaling and cell cycle. This implies that hub genes of the GRNs can be highly consistently inferred with C3Net, BC3Net, and Aracne, representing prominent targets for signaling pathways. Finally, we describe the functional and structural relationship between C3Net, BC3Net and Aracne gene regulatory networks. Our study shows that these GRNs that are inferred from large-scale gene expression data are promising for the identification of novel candidate interactions and pathways that play a key role in the underlying mechanisms driving cancer hallmarks. Overall, our comparative analysis reveals that these GRNs inferred with considerably different inference methods contain large amounts of consistent, method independent, biological information. PMID:24379827

  2. 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. PMID:27268263

  3. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection

    PubMed Central

    Arcaini, Luca; Rossi, Davide; Lucioni, Marco; Nicola, Marta; Bruscaggin, Alessio; Fiaccadori, Valeria; Riboni, Roberta; Ramponi, Antonio; Ferretti, Virginia V.; Cresta, Stefania; Casaluci, Gloria Margiotta; Bonfichi, Maurizio; Gotti, Manuel; Merli, Michele; Maffi, Aldo; Arra, Mariarosa; Varettoni, Marzia; Rattotti, Sara; Morello, Lucia; Guerrera, Maria Luisa; Sciarra, Roberta; Gaidano, Gianluca; Cazzola, Mario; Paulli, Marco

    2015-01-01

    Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%–56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%–77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome. PMID:25381127

  4. 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

  5. T cells, mast cells and microvascular density in diffuse large B cell lymphoma.

    PubMed

    Marinaccio, Christian; Ingravallo, Giuseppe; Gaudio, Francesco; Perrone, Tommasina; Ruggieri, Simona; Opinto, Giuseppina; Nico, Beatrice; Maiorano, Eugenio; Specchia, Giorgina; Ribatti, Domenico

    2016-08-01

    Diffuse large B cell lymphoma (DLBCL) is recognized as the most common form of non-Hodgkin lymphoma (NHL), accounting for about 40 % of all cases of NHL. Among the cellular components of the tumor inflammatory infiltrate, T cells and mast cells have been demonstrated to be correlated with tumor angiogenesis. In this report, we have investigated CD3 and tryptase expression and their relationship with microvascular density (MVD) in DLBCL patients. Moreover, we determined the significance of CD3 expression in bulky and non-bulky disease. CD3 expression was significantly lower in bulky disease patients when compared to non-bulky ones. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients. PMID:25957593

  6. 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

  7. Recent molecular and therapeutic advances in B-cell non-Hodgkin lymphoma in children.

    PubMed

    Giulino-Roth, Lisa; Goldman, Stanton

    2016-05-01

    Paediatric B-cell non-Hodgkin lymphoma (B-NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B-NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B-NHL with a focus on how this may help guide future rational targeted therapy. PMID:26996160

  8. Primary Gastrointestinal Diffuse Large B Cell Lymphoma Presenting with Cold Agglutinin Disease

    PubMed Central

    Eskazan, Ahmet Emre; Akmurad, Hamida; Ongoren, Seniz; Ozer, Ozden; Ferhanoglu, Burhan

    2011-01-01

    Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia (AIHA) generally caused by IgM autoantibodies which exhibit maximal reactivity at 4°C. CAD can be idiopathic or secondary to some diseases and/or conditions. Only a minority of cases of secondary AIHA in non-Hodgkin's lymphoma (NHL) are associated with cold antibodies. Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NHLs with a proportion of nearly 30% of all adult cases. 40% of patients with DLBCL have an extranodal disease or at least disease initially confined to extranodal sites. The most common extranodal site is the gastrointestinal tract. We present a patient with primary gastrointestinal DLBCL who presented with CAD and was treated with a CHOP-Rituximab regimen. PMID:21887126

  9. New insights into MicroRNAs involves in drug resistance in diffuse large B cell lymphoma

    PubMed Central

    Yu, Xin; Li, Zheng

    2015-01-01

    Diffuse large B cell lymphoma (DLBCL) accounts for nearly 40% of non-Hodgkin’s lymphoma cases. The combined chemotherapy of rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone (R-CHOP) is considered as the standard therapy for DLBCL; however, nearly half of the patients become refractory to the R-CHOP regimen. Early identification of drug resistance and therapeutic failures are crucial for the identification of high-risk patients. MicroRNAs (miRNAs) are a group of small and non-coding RNAs negatively regulating gene expression through binding to their target mRNAs. Recent studies demonstrated that miRNAs are involved in chemotherapeutic drug resistance in tumor. In our review, we summarize the current evidence on the role of miRNAs in the prediction and modulation of cellular response to rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone in DLBCL. PMID:26885255

  10. Numb Chin Syndrome as First Symptom of Diffuse Large B-Cell Lymphoma

    PubMed Central

    Carbone, Mario; Della Ferrera, Francesco; Carbone, Lucio; Gatti, Gaia; Carrozzo, Marco

    2014-01-01

    Numb chin syndrome is a rare sensory neuropathy of the mental nerve characterized by numbness, hypoesthesia, paraesthesia, and very rarely pain. Dental causes, especially iatrogenic ones, maxillofacial trauma, or malignant neoplasm are etiologic factors for this rare syndrome. Many malignant and metastatic neoplasms are causing this syndrome, like primary osteosarcoma, squamous cell carcinoma, and mandibular metastasis of primary carcinoma of breast, lung, thyroid, kidney, prostate, and nasopharynx. Haematological malignancies like acute lymphocytic leukaemia, Hodgkin and non-Hodgkin lymphoma, and myeloma can cause this neuropathy. The authors report a case of a 71-year-old woman in which the numb chin syndrome was the first symptom of the diffuse large B-cell lymphoma, which caused infiltration and reabsorption of the alveolar ridge and lower mandibular cortex. A biopsy of the mass was performed on fragments of tissue collected from the mandibular periosteum, medullary and cortical mandibular bone, and inferior alveolar nerve. PMID:25580308

  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. Motility and trafficking in B-cell non-Hodgkin's lymphoma (Review).

    PubMed

    Till, Kathleen J; Coupland, Sarah E; Pettitt, Andrew R

    2014-07-01

    B cell non-Hodgkin's lymphomas (B-NHLs) consist of a wide spectrum of entities and consequently have varied clinical courses. Like many other malignancies, each of the B-NHL depend on their microenvironment for growth and survival; therefore, understanding the factors involved in their tissue localisation is likely to have implications for therapies designed to treat B-NHL. This review summarises the chemokines, integrins and sphingosine-1 phosphate receptors involved in normal B cell location and distribution within the lymphoid tissues (lymph nodes, spleen and bone marrow). It also provides a précis of what is known about these factors in the disease state: i.e., in some subtypes of B-NHL. PMID:24788871

  13. Diffuse large B-cell lymphoma presenting in the leukemic phase

    PubMed Central

    Pires, Patricia Puccetti; Rays, Jairo; Catania, Marcos; Lima, Fabiana Roberto; Noronha, Thiago Rodrigo; Abdo, Andre Neder Ramires; Pereira, Juliana

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma comprising a heterogeneous group of disorders with variable histological and clinical behavior. Although other lymphomas may present in the leukemic phase more frequently, this appearance is unusually observed among DLBCL cases. Diagnosing lymphoma is not always easy, and the patient's clinical status quite often may hamper invasive procedures for diagnosis pushing the clinician to look for alternatives to reach the nearest possible accurate diagnosis. The authors report the case of a middle-aged man who presented the history of malaise, weight loss, and low-grade fever. The peripheral blood count showed leukocytosis with the presence of blasts and thrombocytopenia. The cytological morphology and immunophenotyping of the peripheral blood and bone marrow aspirate, as well as the bone marrow biopsy accompanied by a thorough immunohistochemical analysis, rendered the diagnosis of DLBCL in the leukemic phase. The patient was prescribed R-CHOP with a favorable outcome. Intra-abdominal lymph node biopsy was avoided because of the patient's critical medical condition. The authors highlight this rare form of presentation of DLBCL as well as the combination of peripheral blood, bone marrow aspirate, and bone marrow biopsy for reaching the diagnosis in cases were a lymph node sample is unavailable for the diagnostic work-up. PMID:27284540

  14. Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs.

    PubMed

    Ma, Ming; Zhao, Lianmei; Sun, Guogui; Zhang, Chao; Liu, Lihua; Du, Yanyan; Yang, Xingxiao; Shan, Baoen

    2016-05-01

    Interleukin-24 (IL-24) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells

  15. 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

  16. 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

  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. Precursor B-cell lymphoblastic lymphoma of oral cavity: A case report with its diagnostic workup

    PubMed Central

    Talreja, Komal Ladharam; Barpande, Suresh Ramchandra; Bhavthankar, Jyoti Dilip; Mandale, Mandakini S

    2016-01-01

    Lymphoblastic lymphoma (LBL), seen primarily in children or young adults, is a malignant neoplasia that originates from B or T lymphocyte precursors and rarely occurs in the oral cavity. In this localization, neither the clinical features nor the radiologic appearances are pathognomic and can pose significant diagnostic problems. Histopathologically, it presents as a round blue cell tumor. An early and accurate diagnosis of this entity is very important due to its high cure rate. We report a case of B-cell LBL involving oral cavity in a 10-year-old child. The purpose of this report is to explore the diagnostic workup. PMID:27194876

  19. Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma

    PubMed Central

    Cubedo, Elena; Gentles, Andrew J.; Huang, Chuanxin; Natkunam, Yasodha; Bhatt, Shruti; Lu, Xiaoqing; Jiang, Xiaoyu; Romero-Camarero, Isabel; Freud, Aharon; Zhao, Shuchun; Bacchi, Carlos E.; Martínez-Climent, Jose A.; Sánchez-García, Isidro; Melnick, Ari

    2012-01-01

    LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis. PMID:22517897

  20. CD79B limits response of diffuse large B cell lymphoma to ibrutinib.

    PubMed

    Kim, Joo Hyun; Kim, Won Seog; Ryu, Kyungju; Kim, Seok Jin; Park, Chaehwa

    2016-06-01

    Blockage of B cell receptor signaling with ibrutinib presents a promising clinical approach for treatment of B-cell malignancies. However, many patients show primary resistance to the drug or develop secondary resistance. In the current study, cDNA microarray and Western blot analyses revealed CD79B upregulation in the activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) that display differential resistance to ibrutinib. CD79B overexpression was sufficient to induce resistance to ibrutinib and enhanced AKT and MAPK activation, indicative of an alternative mechanism underlying resistance. Conversely, depletion of CD79B sensitized primary refractory cells to ibrutinib and led to reduced phosphorylation of AKT or MAPK. Combination of the AKT inhibitor or the MAPK inhibitor with ibrutinib resulted in circumvention of both primary and acquired resistance in ABC-DLBCL. Our data collectively indicate that CD79B overexpression leading to activation of AKT/MAPK is a potential mechanism underlying primary ibrutinib resistance in ABC-DLBCL, and support its utility as an effective biomarker to predict therapeutic response to ibrutinib. PMID:26699656

  1. 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

  2. Trends in incidence, treatment and survival of aggressive B-cell lymphoma in the Netherlands 1989–2010

    PubMed Central

    Issa, Djamila E.; van de Schans, Saskia A.M.; Chamuleau, Martine E.D.; Karim-Kos, Henrike E.; Wondergem, Marielle; Huijgens, Peter C.; Coebergh, Jan Willem W.; Zweegman, Sonja; Visser, Otto

    2015-01-01

    Only a small number of patients with aggressive B-cell lymphoma take part in clinical trials, and elderly patients in particular are under-represented. Therefore, we studied data of the population-based nationwide Netherlands Cancer Registry to determine trends in incidence, treatment and survival in an unselected patient population. We included all patients aged 15 years and older with newly diagnosed diffuse large B-cell lymphoma or Burkitt lymphoma in the period 1989–2010 and mantle cell lymphoma in the period 2001–2010, with follow up until February 2013. We examined incidence, first-line treatment and survival. We calculated annual percentage of change in incidence and carried out relative survival analyses. Incidence remained stable for diffuse large B-cell lymphoma (n=23,527), while for mantle cell lymphoma (n=1,634) and Burkitt lymphoma (n=724) incidence increased for men and remained stable for women. No increase in survival for patients with aggressive B-cell lymphoma was observed during the period 1989–1993 and the period 1994–1998 [5-year relative survival 42% (95%CI: 39%–45%) and 41% (38%–44%), respectively], but increased to 46% (43%–48%) in the period 1999–2004 and to 58% (56%–61%) in the period 2005–2010. The increase in survival was most prominent in patients under 65 years of age, while there was a smaller increase in patients over 75 years of age. However, when untreated patients were excluded, patients over 75 years of age had a similar increase in survival to younger patients. In the Netherlands, survival for patients with aggressive B-cell lymphoma increased over time, particularly in younger patients, but also in elderly patients when treatment had been initiated. The improvement in survival coincided with the introduction of rituximab therapy and stem cell transplantation into clinical practice. PMID:25512643

  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. 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

  5. Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10.

    PubMed

    Benjamin, D; Knobloch, T J; Dayton, M A

    1992-09-01

    A recent addition to the lymphokine network is human IL-10 (hIL-10). This novel lymphokine has striking homology to BCRF1 protein, the product of a previously uncharacterized open-reading frame in the Epstein-Barr virus (EBV) genome. To date, IL-10 expression has been described in several T clones induced with anti-CD3 and phorbol myristate acetate (PMA), in monocytes stimulated with lipopolysaccharide (LPS), and in murine B-cell lymphomas. We sought to determine whether human B cells express hIL-10 and, if so, its relationship to EBV and to other B-cell lymphokines. We studied 21 EBV-positive B-cell lines derived from patients with acquired immunodeficiency syndrome (AIDS) and Burkitt's lymphoma (n = 6), American Burkitt's (n = 3), African Burkitt's (n = 5), and normal lymphoblastoid cell lines (n = 7), in comparison with seven EBV-negative cell lines. All cell lines were activated with the tumor promoters PMA and teleocidin and were studied by Northern blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunoadsorbent assay (ELISA). We demonstrated that EBV-positive cell lines derived from patients with American Burkitt's lymphoma, and especially those from patients with AIDS, constitutively express large quantities of hIL-10 by Northern blot analysis and ELISA (range, 3,101 to 25,915 pg/mL), and that both teleocidin and PMA induce hIL-10 in these cell lines. In contrast, six of seven EBV-negative cell lines did not express hIL-10 even by RT-PCR, and hIL-10 was not triggered by PMA or teleocidin. To assure that the 350 bp amplified by PCR was hIL-10 and not BCRF1, we used PCR primers, which do not amplify a fragment from plasmid templates containing BCRF1. Cloning and sequencing of the 350 bp product also demonstrated that B-cell IL-10 is identical to hIL-10 from the T-cell clone B21. Correlation of hIL-10 with other B-cell lymphokines secreted by these B-cell lines demonstrated that hIL-10 secretor cell lines also

  6. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas.

    PubMed

    Grange, Florent; Petrella, Tony; Beylot-Barry, Marie; Joly, Pascal; D'Incan, Michel; Delaunay, Michele; Machet, Laurent; Avril, Marie-Francoise; Dalac, Sophie; Bernard, Philippe; Carlotti, Agnes; Esteve, Eric; Vergier, Beatrice; Dechelotte, Pierre; Cassagnau, Elisabeth; Courville, Philippe; Saiag, Philippe; Laroche, Liliane; Bagot, Martine; Wechsler, Janine

    2004-05-15

    Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multiple skin lesions were identified as adverse prognostic factors. The prognostic value of bcl-2 protein expression has not been studied in large series of patients. We evaluated 80 primary cutaneous large B-cell lymphomas collected by the French Study Group on Cutaneous Lymphomas. The prognostic value of age, sex, number of lesions, cutaneous extent, location, serum lactate dehydrogenase (LDH) level, B symptoms, morphology, and bcl-2 protein expression was studied. The overall 5-year specific survival rate was 65%. In univariate analysis, advanced age, multiple skin lesions (n = 48), location on the leg (n = 25), round-cell morphology (n = 32), and bcl-2 expression (n = 39) were significantly related to death from lymphoma. In multivariate analysis, bcl-2 expression (P =.0003), multiple skin lesions (P =.004), and age remained independent prognostic factors. The 5-year specific survival rates in bcl-2-positive and bcl-2-negative patients were 41% and 89%, respectively (P <.0001). A new prognostic classification of primary cutaneous B-cell lymphoma should be based primarily on bcl-2 protein expression rather than the location of skin lesions. PMID:14726400

  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

    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; Dave, Sandeep S

    2016-06-01

    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. 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

  10. Immunotherapy for B-cell lymphoma: current status and prospective advances.

    PubMed

    Hollander, Nurit

    2012-01-01

    Therapy for non-Hodgkin's lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radio labeled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect. PMID:22566889

  11. Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas.

    PubMed

    Broutier, Laura; Creveaux, Marion; Vial, Jonathan; Tortereau, Antonin; Delcros, Jean-Guy; Chazot, Guillaume; McCarron, Mark J; Léon, Sophie; Pangault, Céline; Gadot, Nicolas; Colombe, Amélie; Boulland, Marie-Laure; Blachier, Jonathan; Marie, Julien C; Traverse-Glehen, Alexandra; Donzé, Olivier; Chassagne-Clément, Catherine; Salles, Gilles; Tarte, Karin; Mehlen, Patrick; Castets, Marie

    2016-02-01

    DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin-1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC-induced apoptosis is associated with lymphomagenesis. In human diffuse large B-cell lymphoma (DLBCL), an imbalance of the netrin-1/DCC ratio suggests a loss of DCC-induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up-regulation of netrin-1 in activated B-cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin-1 interfering antibody, we demonstrate both in vitro and in vivo that netrin-1 acts as a survival factor for ABC-DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin-1/DCC interaction could represent a promising therapeutic strategy in netrin-1-positive DLBCL and MCL. PMID:26882243

  12. Is rituximab sub-optimally dosed in indolent B cell lymphoma?

    PubMed

    Sawalha, Yazeed; Rouphail, Basel; Jia, Xuefei; Dean, Robert M; Hill, Brian T; Jagadeesh, Deepa; Pohlman, Brad L; Smith, Mitchell R

    2016-09-01

    Rituximab pharmacokinetics are affected by gender, age and weight and can affect outcomes in aggressive B cell lymphoma. Less is known about the pharmacokinetics of rituximab in indolent B cell lymphoma (iNHL). We analysed the effects of gender, age, weight and body surface area on the outcomes of 303 patients treated with first line rituximab-based regimens for iNHL. The patients were divided into 3 treatment cohorts: rituximab only, rituximab + chemotherapy (R-CTX) and R-CTX followed by rituximab maintenance; furthermore, each cohort was subdivided as follicular (FL) or non-FL, based on histology. Older males and patients with higher weight had worse outcomes when treated with R-CTX, probably due to faster rituximab clearance. Our results concur with studies of R-CTX for DLBCL. As this effect was not observed in patients treated with rituximab alone or R-CTX followed by rituximab maintenance, we hypothesize that higher rituximab levels reached with weekly rituximab and/or prolonged exposure achieved with maintenance therapy exceed the therapeutic threshold, even with faster clearance, which nullifies the negative effect of higher weight and male gender. In conclusion, under current practices, a subset of patients with iNHL, i.e., FL treated with R-CTX, may be sub-optimally dosed with rituximab. PMID:27136331

  13. 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

  14. 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

  15. A new model of LMP1–MYC interaction in B cell lymphoma

    PubMed Central

    Ontiveros, Evelena P.; Halwani, Ahmad; Stunz, Laura L.; Kamberos, Natalie; Olivier, Alicia K.; Janz, Siegfried; Bishop, Gail A.

    2014-01-01

    Epstein–Barr virus (EBV) is associated with aggressive B cell lymphomas (BCLs). Latent membrane protein 1 (LMP1) of EBV is an oncogenic protein required for EBV B cell transformation. However, LMP1 is a weak oncogene in mice. Mice expressing Myc inserted 5′ of the Eμ enhancer (iMycEμ), mimicking the t(8;14) translocation of endemic Burkitt lymphoma, develop delayed onset BCLs. To investigate potential cooperation between LMP1 and oncogenic MYC, we produced mice expressing the LMP1 signaling domain via a hybrid CD40–LMP1 transgene (mCD40–LMP1), and the dysregulated MYC protein of aggressive EBV+ BCLs. mCD40-LMP1/iMycEμ mice trended toward earlier BCL onset. BCLs from mCD40–LMP1/iMycEμ mice expressed LMP1 and were transplantable into immunocompetent recipients. iMycEμ and mCD40–LMP1/iMycEμ mice developed BCLs with similar immunophenotypes. LMP1 signaling was intact in BCLs as shown by inducible interleukin-6. Additionally, LMP1 signaling to tumor cells induced the two isoforms of Pim1, a constitutively active prosurvival kinase implicated in lymphomagenesis. PMID:24605938

  16. Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma

    PubMed Central

    Nagel, Stefan; Ehrentraut, Stefan; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A. F.

    2015-01-01

    In Hodgkin lymphoma (HL) we recently reported that deregulated homeobox gene MSX1 mediates repression of the B-cell specific transcription factor ZHX2. In this study we investigated regulation of MSX1 in this B-cell malignancy. Accordingly, we analyzed expression and function of OTX homeobox genes which activate MSX1 transcription during embryonal development in the neural plate border region. Our data demonstrate that OTX1 and OTX2 are aberrantly expressed in both HL patients and cell lines. Moreover, both OTX loci are targeted by genomic gains in overexpressing cell lines. Comparative expression profiling and subsequent pathway modulations in HL cell lines indicated that aberrantly enhanced FGF2-signalling activates the expression of OTX2. Downstream analyses of OTX2 demonstrated transcriptional activation of genes encoding transcription factors MSX1, FOXC1 and ZHX1. Interestingly, examination of the physiological expression profile of ZHX1 in normal hematopoietic cells revealed elevated levels in T-cells and reduced expression in B-cells, indicating a discriminatory role in lymphopoiesis. Furthermore, two OTX-negative HL cell lines overexpressed ZHX1 in correlation with genomic amplification of its locus at chromosomal band 8q24, supporting the oncogenic potential of this gene in HL. Taken together, our data demonstrate that deregulated homeobox genes MSX1 and OTX2 respectively impact transcriptional inhibition of (B-cell specific) ZHX2 and activation of (T-cell specific) ZHX1. Thus, we show how reactivation of a specific embryonal gene regulatory network promotes disturbed B-cell differentiation in HL. PMID:26406991

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

    ClinicalTrials.gov

    2016-05-10

    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

  18. Whole-Body Diffusion-weighted Imaging in Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma.

    PubMed

    Toledano-Massiah, Sarah; Luciani, Alain; Itti, Emmanuel; Zerbib, Pierre; Vignaud, Alexandre; Belhadj, Karim; Baranes, Laurence; Haioun, Corinne; Lin, Chieh; Rahmouni, Alain

    2015-01-01

    Whole-body imaging, in particular molecular imaging with fluorine 18 ((18)F)-fluorodeoxyglucose (FDG) positron emission tomography (PET), is essential to management of lymphoma. The assessment of disease extent provided by use of whole-body imaging is mandatory for planning appropriate treatment and determining patient prognosis. Assessment of treatment response allows clinicians to tailor the treatment strategy during therapy if necessary and to document complete remission at the end of treatment. Because of rapid technical developments, such as echo-planar sequences, parallel imaging, multichannel phased-array surface coils, respiratory gating, and moving examination tables, whole-body diffusion-weighted (DW) magnetic resonance (MR) imaging that reflects cell density is now feasible in routine clinical practice. Whole-body DW MR imaging allows anatomic assessment as well as functional and quantitative evaluation of tumor sites by calculation of the apparent diffusion coefficient (ADC). Because of their high cellularity and high nucleus-to-cytoplasm ratio, lymphomatous lesions have low ADC values and appear hypointense on ADC maps. As a result, whole-body DW MR imaging with ADC mapping has become a promising tool for lymphoma staging and treatment response assessment. The authors review their 4 years of experience with 1.5-T and 3-T whole-body DW MR imaging used with (18)F-FDG PET/computed tomography at baseline, interim, and end of treatment in patients with Hodgkin lymphoma and diffuse large B-cell lymphoma and discuss the spectrum of imaging findings and potential pitfalls, limitations, and challenges associated with whole-body DW MR imaging in these patients. PMID:25815803

  19. Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis?

    PubMed

    Iqbal, Javeed; Naushad, Hina; Bi, Chengfeng; Yu, Jiayu; Bouska, Alyssa; Rohr, Joseph; Chao, Wang; Fu, Kai; Chan, Wing C; Vose, Julie M

    2016-03-01

    Current genomic technologies have immensely improved disease classification and prognostication of major subtypes of B-cell lymphomas. This novel genetic information has not only aided in diagnosis, but has also revealed a landscape of critical molecular events that determine the biological and clinical behavior of a lymphoma. In this review, we summarized the genetic characteristics of major subtypes of B-cell lymphomas, including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). We illustrated how genomic profiling had identified molecular subgroups in DLBCL with varied clinical outcomes, and how a subset of genes defined prognosis in MCL and aided in BL diagnoses. We also highlighted some Phase II/III clinical trials using new therapeutic agents to determine clinical efficacy in novel molecular subgroups with distinct gene expression patterns. We believe that refinement of genomic signatures will require more intensive efforts from the biomedical research community to improve targeted therapy designs and bring a substantial change in the treatment decisions. In the next era of genomic medicine, we anticipate that a clinically and biologically relevant molecular profile of each tumor will be obtained at diagnosis to guide therapy. PMID:26432520

  20. Aggressive primary cutaneous B-cell lymphomas show increased Angiopoietin-2-induced angiogenesis.

    PubMed

    Teichert, Martin; Stumpf, Christine; Booken, Nina; Wobser, Marion; Nashan, Dorothee; Hallermann, Christian; Mogler, Carolin; Müller, Cornelia S L; Becker, Jürgen C; Moritz, Rose K C; Andrulis, Mindaugas; Nicolay, Jan P; Goerdt, Sergij; Thomas, Markus; Klemke, Claus-Detlev; Augustin, Hellmut G; Felcht, Moritz

    2015-06-01

    Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease. PMID:25776770

  1. Hypernatremia associated with intracranial B-cell lymphoma in a cat.

    PubMed

    Morrison, Jo Ann; Fales-Williams, Amanda

    2006-09-01

    An 8-year-old, spayed female, domestic shorthair cat with a history of hyperthyroidism, anorexia, dehydration, cervical ventroflexion, and behavioral changes was referred to the Iowa State University College of Veterinary Medicine. The cat was obtunded, with severe dehydration (15%) and hypothermia (86 degrees F), and severe muscle atrophy and fasciculations. Serum biochemical abnormalities included severe hypernatremia (195 mmol/L, reference interval 155-165 mmol/L), hyperchloridemia (161 mmol/L, reference interval 123-131 mmol/L), and hypokalemia (3.6 mmol/L, reference interval 4.0-5.7 mmol/L). Calculated osmolality was 418 mOsm/kg (reference interval 280-305 mOsm/kg), attributable to the hypernatremia. The cat was kept warm and given fluid and glucocorticoid therapy and supportive measures but remained unresponsive. Hypernatremia and hyperosmolality improved through day 3, when the cat died suddenly. At necropsy, a 1.25-cm mass was found in the area of the thalamus and interthalamic adhesion that extended to the ventral aspect of the cerebrum. The histologic and immunohistochemical diagnosis was B-cell lymphoma. Hypernatremia and hyperosmolality in this cat were attributed to primary adipsia and hypothalamic dysfunction secondary to effacement of central nervous system tissue by neoplastic lymphocytes. To the authors' knowledge, this is the first reported case of central nervous system lymphoma, confirmed by use of immunohistochemical analysis as a B-cell phenotype, associated with hypernatremia. It also is the first reported case of lymphoma in animals limited to the thalamus, hypothalamus, and cerebrum, with no involvement of the spinal cord. PMID:16967428

  2. N-acetylcysteine renoprotection in methotrexate induced nephrotoxicity and its effects on B-cell lymphoma

    PubMed Central

    Singh, Ruchi; Shah, Rikin; Turner, Curtis; Regueira, Osvaldo; Vasylyeva, Tetyana L.

    2015-01-01

    Background: Nephrotoxicity is one of the known side effects of methotrexate (MTX) therapy despite the use of conventional protective measures. Our objectives were to evaluate the effects of N-acetylcysteine (NAC) on MTX-induced toxicity in renal tubular cells and to evaluate whether adjunctive use of NAC interferes with MTX antitumor activity in the B-cell lymphoma. Methods: Kidney Epithelial (Madin-Darby canine kidney [MDCK]) cells were exposed to MTX (10 μM or 100 μM) alone and with NAC (0.2 mM or 0.4 mM). Reactive oxygen species (ROS) generation at 1, 2, 4, and 24 h was measured by flow cytometer. Quantification of total glutathione (GSH) was performed by using GSH assay kit. To measure the impact of NAC on the antitumor activity of MTX, B lymphoma cells were exposed to MTX alone and with NAC. A percentage of apoptosis was measured using fluorescein isothiocyanate in both cell lines. Quantitative data was presented as a means ± standard deviation, and P values were analyzed using the Student's t-test. Results: Apoptosis in MDCK cells were observed after 24 h of incubation with both 10 μM and 100 μM MTX. Maximum ROS generation was observed at 4 h and corresponded to GSH production. Treatment with 0.2 and 0.4 mM of NAC led to decrease percentages of apoptotic MDCK cells. NAC did not change either proliferation or apoptosis of B-cell lymphoma. Conclusion: Using NAC for kidney protection may not interfere with the antitumor activity of MTX. Further in vivo studies are warranted to confirm noninterference between MTX and NAC and assess synergistic antitumor effects. PMID:26811594

  3. 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

  4. Clinical characteristics and prognostic analysis of Chinese patients with diffuse large B-cell lymphoma.

    PubMed

    Ke, Xiaoyan; Wang, Jing; Gao, Zifen; Zhao, Lingzhi; Li, Min; Jing, Hongmei; Wang, Jijun; Zhao, Wei; Gilbert, Heather; Yang, Xiao-Feng

    2010-01-15

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults. As it is a highly heterogenous disease, many studies have focused on finding useful prognostic factors to help guide therapy. In this report, we examine several biological markers in 83 patients with DLBCL enrolled in our hospital, including cell origin, serum lactate dehydrogenase (LDH) levels, and international prognostic index (IPI), in order to find the best combination of prognostic factors. We also examined whether DLBCL has a significant geographic difference, since several studies have suggested that the prevalence and potential etiological factors of lymphomas in China may be different from those in other countries. Our results demonstrate that: (1) patients in China have higher extranodal tissue involvement and different extranodal organ distribution than patients reported from other countries; (2) Chinese patients have higher rates of germinal center (GC) cell origin; and (3) among nine prognostic variables, lower IPI scores, GC cell origin determined by immunohistochemical staining, and no more than 1.5 times of normal levels of LDH are statistically significant good prognostic factors in Chinese patients with DLBCL, whereas age at the time of diagnosis, clinical stage, beta(2)-microglobulin levels, extranodal tissue involvement, and expression levels of Bcl-6 protein were not useful in determining prognosis. PMID:19819170

  5. Sequential transcription factor targeting for diffuse large B-cell lymphomas

    PubMed Central

    Cerchietti, Leandro C; Polo, Jose M; Da Silva, Gustavo F; Farinha, Pedro; Shaknovich, Rita; Gascoyne, Randy D; Dowdy, Steven F; Melnick, Ari

    2009-01-01

    Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCLs) and controls downstream checkpoints including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small molecule activators provided a more powerful anti-lymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy. PMID:18451163

  6. 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

  7. [A rare etiology of anasarca in Africa: gastric lymphoma].

    PubMed

    Klotz, F; Dupouy, P; Nguemby Mbina, C; Aubry, P

    1988-10-01

    The authors report the case of a young 16 year-old woman from Gabon hospitalized because of edemas. The laboratory tests show a hypoproteinemia of 32 g/l with hypoalbuminemia of 9.4 g/l. After ruling out a renal, cardiac or hepatic etiology as well as malnutrition, the endoscopic exploration of the G.I tract, performed because of abdominal pain, enables to make the diagnosis: malignant, non-Hodgkin gastric lymphoma, confirmed by biopsies during the procedure. Edemas and hypoproteinemia were related to an exudative enteropathy secondary to ulcerations of the gastric mucosa. PMID:3207351

  8. 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. PMID:14979479

  9. A Case of a Laryngeal MALT Lymphoma in a Patient with a History of Gastric MALT

    PubMed Central

    Ashamalla, Mark; Teng, Marita S.; Brody, Joshua; Parikh, Rahul; Dharmarajan, Kavita

    2015-01-01

    We are reporting a case of a 62-year-old African American woman with a history of gastric MALT lymphoma successfully treated with radiation who presented with a laryngeal MALT lymphoma 4 years after her original diagnosis. She received definitive radiation with a complete response. The case presented is unique for the rare presentation of a MALT lymphoma in the larynx, especially in light of the patient's previously treated gastric MALT lymphoma years ago. PMID:25664189

  10. 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

  11. 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

  12. Expression of D-type cyclins in mantle cell and diffuse large B-cell lymphomas.

    PubMed

    Zlamalikova, Lenka; Moulis, Mojmir; Salek, David; Jarkovsky, Jiri; Smarda, Jan; Smardova, Jana

    2016-05-01

    D-type cyclins are involved in cell cycle regulation and play an important role in the pathogenesis of lymphomas. Aberrant expression of cyclin D1 is associated with mantle cell lymphoma (MCL) and serves as a diagnostic marker of MCL. Analysis of cyclin D expression in tumor tissues of patients with diffuse large B-cell lymphoma (DLBCL) which comprises a heterogeneous group of tumors may contribute to their stratification. We analyzed expression of cyclin D1, D2, and D3 mRNAs in 30 MCL and 104 DLBCL patients using qRT-PCR and addressed their significance for disease outcome. We confirmed a high level of cyclin D1 mRNA in 29 MCL cases (97%). One case (3%) was identified as positive for cyclin D2. Expression of cyclin D1 was limited to MCL and did not occur in DLBCL. Overexpression of cyclin D2, which is rare in MCL, occurred more frequently in DLBCL (11 cases, 10.6%). We showed that high expression of cyclin D2 in DLBCL cases de novo decreased the overall survival rate (P=0.016) and progression-free survival (P=0.009). The expression pattern of cyclin D3 was similar in both types of studied lymphomas and it did not affect the disease outcome. PMID:26985765

  13. 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

  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.

  15. Autoantibody-Mediated Sensory Polyneuropathy Associated with Indolent B-Cell Non-Hodgkin's Lymphoma: A Report of Two Cases

    PubMed Central

    2015-01-01

    Background and Purpose Abnormalities of the peripheral nervous system occur in 5% of patients with lymphoma. Polyneuropathy has not been described in patients with mantle-cell and marginal-zone B-cell lymphomas. Case Report Two elderly patients with indolent non-Hodgkin's lymphoma developed a progressive sensory polyneuropathy that was associated with serum autoantibodies directed against asialosyl/sialosyl gangliosides and myelin-associated glycoprotein/sulfated glucuronyl paragloboside, respectively, which are peripheral-nerve antigens. The oligoclonal pattern of these antibodies hinted at a lymphoma-induced immune dysregulation. The neuropathy stabilized clinically during treatment with intravenous immunoglobulin G. B-cell lymphoma was managed with a "watchful waiting" approach. Conclusions The concept of antigen-specific, immune-mediated neuropathy associated with slow-growing lymphoma of mature B-cells may be underrecognized. The principle of treating the illness underlying neuropathy may not be always indicated or necessary if risk-benefit and cost-benefit analyses are taken into account. PMID:25749823

  16. 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

  17. Discordant expression of immunoglobulin and its associated molecule mb-1/CD79a is frequently found in mediastinal large B cell lymphomas.

    PubMed Central

    Kanavaros, P.; Gaulard, P.; Charlotte, F.; Martin, N.; Ducos, C.; Lebezu, M.; Mason, D. Y.

    1995-01-01

    Mediastinal large B cell lymphomas are uncommon neoplasms that are thought to originate from thymic B cells. An unusual feature of these neoplasms is that they often lack surface immunoglobulin (Ig), a molecule ubiquitously expressed by most mature B cells. In the present study we have analyzed 12 cases of mediastinal large B cell lymphoma for the expression of the mb-1/CD79a polypeptide. This is a component, together with B29/CD79b, of a heterodimer that is associated with surface Ig on normal B cells. Our aim was to see whether loss of Ig in this type of lymphoma is associated with loss of the accompanying CD79a molecule. We have also evaluated 128 B cell lymphomas of other categories to see whether any of them show discordance between mb-1 and Ig expression and analyzed 30 T cell lymphomas as Ig-negative controls. We found that 5 of the 7 mediastinal large B cell lymphomas with interpretable staining results for both mb-1 and Ig, lack Ig but expressed CD79a (mb-1). This phenotype was very rare in other categories of B cell lymphoma, being found among 110 cases in only 5 cases that were all follicular lymphoma. The remaining 105 B cell lymphomas displayed mb-1+/Ig+ phenotype. All 30 T cell lymphomas were mb-1 negative. We conclude that discordant mb-1/Ig expression occurs commonly in mediastinal large B cell lymphomas. In addition, the finding that 11 of 12 of these neoplasms express a phenotype (CD10-, CD19+, CD20+, CD21-, CD22+, CD23-/+) that is very similar to that described for thymic medullary B cells reinforces the idea that most mediastinal large B cell lymphomas are of thymic B cell origin. The correlation between mb-1 and Ig staining patterns in B cell lymphomas of other categories reveals that in the majority (90%), expression of the antigen receptor complex parallels that of mature B cells. These data therefore confirm that the expression of the mb-1 protein provides independent strong evidence for the B lineage of lymphomas and may be used for their

  18. 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

  19. Diffuse large B-cell lymphoma in the sphenoid sinus mimicking fibrous dysplasia in CT and MRI

    PubMed Central

    Yoshihara, Shintaro; Kondo, Kenji; Ochi, Atsushi

    2014-01-01

    We present a 70-year-old man with lymphoma who presented with a right eye movement disorder. CT examinations showed ‘ground-glass’ appearance extending around the right sphenoid sinus which suggested fibrous dysplasia. However, biopsy from the mass histologically proved it to be diffusing large B-cell lymphoma and positron emission tomography examinations revealed increased fluorodeoxyglucose (FDG) uptake around the right sphenoid bone and multiple spinal bones. After chemotherapy for lymphoma, abnormal FDG uptake disappeared from the body. PMID:25100815

  20. 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

  1. 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

  2. Retroperitoneal fibrosis due to B-cell non-Hodgkin lymphoma: Responding to rituximab!

    PubMed

    Alvarez Argote, Juliana; Bauer, Frank A; Posteraro, Anthony F; Dasanu, Constantin A

    2016-02-01

    Retroperitoneal fibrosis is a rare disease manifesting as chronic soft tissue fibrosis in the retroperitoneum, with potential anatomic and/or functional compromise of adjacent organs. It can be primary (idiopathic) or secondary to other conditions such as cancers, autoimmune disorders, or drugs. We report herein a 66-year-old patient with symptomatic retroperitoneal fibrosis leading to bilateral hydronephrosis and renal failure, in whom, after a complex diagnostic work-up and protracted clinical course, a B-cell non-Hodgkin lymphoma in the retroperitoneal space and several vertebral bodies was identified. The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain. We include a thorough literature review on etiopathogenesis, diagnosis, therapy, and prognosis of retroperitoneal fibrosis. A meticulous search for malignancy is necessary in this rare condition that, if positive, may have significant therapeutic and prognostic implications. PMID:25013186

  3. Targeting the B-Cell Lymphoma/Leukemia 2 Family in Cancer

    PubMed Central

    Davids, Matthew S.; Letai, Anthony

    2012-01-01

    The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer. PMID:22649144

  4. 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

  5. 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

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

    PubMed

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

    2015-05-01

    The expression of carbonic anhydrase IX (CA IX) and its relationship 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 relationship with hypoxia. An imaging method, acidoCEST magnetic resonance imaging (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

  7. 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

  8. Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma

    PubMed Central

    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

    2016-01-01

    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. PMID:26497687

  9. 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. PMID:26497687

  10. MOZ regulates B-cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development.

    PubMed

    Sheikh, Bilal N; Lee, Stanley C W; El-Saafin, Farrah; Vanyai, Hannah K; Hu, Yifang; Pang, Swee Heng Milon; Grabow, Stephanie; Strasser, Andreas; Nutt, Stephen L; Alexander, Warren S; Smyth, Gordon K; Voss, Anne K; Thomas, Tim

    2015-03-19

    The histone acetyltransferase MOZ (MYST3, KAT6A) is the target of recurrent chromosomal translocations fusing the MOZ gene to CBP, p300, NCOA3, or TIF2 in particularly aggressive cases of acute myeloid leukemia. In this study, we report the role of wild-type MOZ in regulating B-cell progenitor proliferation and hematopoietic malignancy. In the Eμ-Myc model of aggressive pre-B/B-cell lymphoma, the loss of just one allele of Moz increased the median survival of mice by 3.9-fold. MOZ was required to maintain the proliferative capacity of B-cell progenitors, even in the presence of c-MYC overexpression, by directly maintaining the transcriptional activity of genes required for normal B-cell development. Hence, B-cell progenitor numbers were significantly reduced in Moz haploinsufficient animals. Interestingly, we find a significant overlap in genes regulated by MOZ, mixed lineage leukemia 1, and mixed lineage leukemia 1 cofactor menin. This includes Meis1, a TALE class homeobox transcription factor required for B-cell development, characteristically upregulated as a result of MLL1 translocations in leukemia. We demonstrate that MOZ localizes to the Meis1 locus in pre-B-cells and maintains Meis1 expression. Our results suggest that even partial inhibition of MOZ may reduce the proliferative capacity of MEIS1, and HOX-driven lymphoma and leukemia cells. PMID:25605372

  11. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers.

    PubMed

    Bentebibel, Salah-Eddine; Schmitt, Nathalie; Banchereau, Jacques; Ueno, Hideki

    2011-08-16

    T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 (Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6-expressing CD4(+) T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5(lo)ICOS(lo)), and it was found exclusively outside GCs. CXCR5(lo)ICOS(lo) CD4(+) T cells secreted larger amounts of IL-21 and IL-10 than CXCR5(hi)ICOS(hi) GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS-ligand interaction. CXCR5(lo)ICOS(lo) CD4(+) T cells expressed equivalent amounts of BCL6 transcript with CXCR5(hi)ICOS(hi) GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5(lo)ICOS(lo) CD4(+) T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs. PMID:21808017

  12. 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

  13. Current strategies in the diagnosis of diffuse large B-cell lymphoma of the central nervous system.

    PubMed

    Baraniskin, Alexander; Deckert, Martina; Schulte-Altedorneburg, Gernot; Schlegel, Uwe; Schroers, Roland

    2012-02-01

    Lymphomas can arise within the central nervous system (CNS) as primary CNS lymphoma (PCNSL) typically involving the brain and less often the leptomeninges, eyes, and spinal cord. In contrast to PCNSL, secondary CNS lymphoma (SCNSL) is considered to originate as quasi metastasis from systemic lymphoma spreading to the CNS. Both types of CNS lymphomas are predominantly tumours of the diffuse large B-cell type and represent aggressive diseases necessitating a rapid diagnosis. Following neuroimaging based on magnetic resonance imaging, stereotaxy and histopathological diagnosis of CNS lymphoma currently remain obligatory to plan treatment. However, progress in cytopathological, immunophenotypic, and molecular genetic analyses of the cerebrospinal fluid (CSF) has been achieved recently and potentially will facilitate lymphoma diagnosis in the future. This review describes the diagnostic procedures in patients with suspected CNS lymphomas, primarily PCNSL. In addition to a summary of the standard diagnostic work-up, an overview and discussion of current data on different techniques for evaluation of the CSF in CNS lymphoma are given. PMID:22077417

  14. Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma.

    PubMed

    Matthews, Julie Marie; Bhatt, Shruti; Patricelli, Matthew P; Nomanbhoy, Tyzoon K; Jiang, Xiaoyu; Natkunam, Yasodha; Gentles, Andrew J; Martinez, Ezequiel; Zhu, Daxing; Chapman, Jennifer Rose; Cortizas, Elena; Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana; Tan, Li; Zhang, Jianming; Choi, Hwan Geun; Tibshirani, Robert; Buhrlage, Sara J; Gratzinger, Dita; Verdun, Ramiro; Gray, Nathanael S; Lossos, Izidore S

    2016-07-14

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients. PMID:27151888

  15. 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. PMID:21030533

  16. 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.

  17. 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

  18. 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

  19. Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice.

    PubMed

    Zhong, Y; Jiang, L; Hiai, H; Toyokuni, S; Yamada, Y

    2007-10-18

    LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor 1alpha promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavy-chain gene rearrangement analyses. Mammalian two-hybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis. PMID:17486074

  20. 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

  1. 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

  2. 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

  3. Primary Pulmonary Diffuse Large B-Cell Lymphoma on FDG PET/CT-MRI and DWI

    PubMed Central

    Xu, Huiting; Xu, Kai; Wang, Ru; Liu, Xiaohua

    2015-01-01

    Abstract Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) directly arising from lung tissue is extremely rare. It may usually be misdiagnosed as inflammation including pulmonary tuberculosis, even lung cancer, because its clinical symptoms and signs are often nonspecific. The final diagnosis usually depends on lung biopsy. Herein, we report a case of PPDLBCL and review of diagnosis of this disease, particularly in radiology. A 44-year-old man presented with cough, sputum, and intermittent chest pain for 4 weeks. Multiple radiological examinations showed an irregular mass in the right upper lobe with ground-glass opacities around it and air-filled bronchi in the consolidation. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (MRI) detected positive FDG uptake, and diffusion-weighted imaging indicated abnormal hyperintension in the lesion. Inflammation was suspected, but malignance cannot be excluded. Finally, ultrasound-guided fine-needle aspiration cytology was performed for histological examination and definitive diagnosis yielded lymphomatous cells infiltration in the right upper lobe. This report emphasizes the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, staging, and management of lymphomas. PMID:26200643

  4. 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

  5. [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

  6. Role of Rituximab and Rituximab Biosimilars in Diffuse Large B-Cell Lymphoma.

    PubMed

    Coleman, Morton; Lammers, Philip E; Ciceri, Fabio; Jacobs, Ira A

    2016-04-01

    Diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma (NHL), is the most-common subtype of NHL. DLBCL can be classified into at least 3 major immunologically distinct types, which contributes to considerable variation in disease prognosis and response to treatment. DLBCL potentially is curable, even when diagnosed at advanced stages. The current standard of care for most patients with untreated or relapsed/refractory DLBCL is chemoimmunotherapy containing rituximab, an anti-CD20 monoclonal antibody. With advanced understanding of the molecular mechanisms involved in the pathogenesis of DLBCL and specific signaling pathways that are activated in different subtypes, potential new therapeutic targets have been identified, some of which are at the late stages of clinical development. This review summarizes the critical role of rituximab in the current standard of care treatment for DLBCL and discusses why rituximab is likely to remain an important component of treatment options for DLBCL in the foreseeable future. In addition, current and emerging therapeutic agents, including potential benefits of rituximab biosimilars, for patients with DLBCL are discussed. The advent of rituximab biosimilars may facilitate accessibility of rituximab-based chemotherapies to patients with DLBCL and has potential cost-saving benefits for healthcare systems globally. PMID:26906106

  7. 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

  8. 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

  9. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice

    PubMed Central

    Costinean, Stefan; Zanesi, Nicola; Pekarsky, Yuri; Tili, Esmerina; Volinia, Stefano; Heerema, Nyla; Croce, Carlo M.

    2006-01-01

    MicroRNAs (miRNAs) represent a newly discovered class of posttranscriptional regulatory noncoding small RNAs that bind to targeted mRNAs and either block their translation or initiate their degradation. miRNA profiling of hematopoietic lineages in humans and mice showed that some miRNAs are differentially expressed during hematopoietic development, suggesting a role in hematopoietic cell differentiation. In addition, recent studies suggest the involvement of miRNAs in the initiation and progression of cancer. miR155 and BIC, its host gene, have been reported to accumulate in human B cell lymphomas, especially in diffuse large B cell lymphomas, Hodgkin lymphomas, and certain types of Burkitt lymphomas. Here, we show that Eμ-mmu-miR155 transgenic mice exhibit initially a preleukemic pre-B cell proliferation evident in spleen and bone marrow, followed by frank B cell malignancy. These findings indicate that the role of miR155 is to induce polyclonal expansion, favoring the capture of secondary genetic changes for full transformation. PMID:16641092

  10. 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.

  11. Peritoneal fluid immunocytochemistry used for the diagnosis of a possible case of equine gastrointestinal B-cell lymphoma.

    PubMed

    Duran, Maria Carolina; Starrak, Gregory; Dickinson, Ryan; Montgomery, Julia

    2016-06-01

    After physical examination, ultrasonographic evaluation of thorax and abdomen, and peritoneal fluid analysis, gastrointestinal neoplasia with suspected diffuse peritoneal metastasis was diagnosed in a 17-year-old Arabian gelding. The owner elected euthanasia and declined postmortem examination. Immunocytochemistry analysis of the peritoneal fluid resulted in a diagnosis of B-cell lymphoma. PMID:27247458

  12. Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR.

    PubMed

    Xue, Xuemin; Zeng, Naiyan; Gao, Zifen; Du, Ming-Qing

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Gene expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III subtypes, with ABC-DLBCL characterized by a poor prognosis and constitutive NF-κB activation. A major challenge for the application of this cell of origin (COO) classification in routine clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies. In this study, we investigated the possibility of COO-classification using FFPE tissue RNA samples by massive parallel quantitative reverse transcription PCR (qRT-PCR). We established a protocol for parallel qRT-PCR using FFPE RNA samples with the Fluidigm BioMark HD system, and quantified the expression of the COO classifier genes and the NF-κB targeted-genes that characterize ABC-DLBCL in 143 cases of DLBCL. We also trained and validated a series of basic machine-learning classifiers and their derived meta classifiers, and identified SimpleLogistic as the top classifier that gave excellent performance across various GEP data sets derived from fresh-frozen or FFPE tissues by different microarray platforms. Finally, we applied SimpleLogistic to our data set generated by qRT-PCR, and the ABC and GCB-DLBCL assigned showed the respective characteristics in their clinical outcome and NF-κB target gene expression. The methodology established in this study provides a robust approach for DLBCL sub-classification using routine FFPE diagnostic biopsies in a routine clinical setting. PMID:25418578

  13. USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma.

    PubMed

    Engel, Katharina; Rudelius, Martina; Slawska, Jolanta; Jacobs, Laura; Ahangarian Abhari, Behnaz; Altmann, Bettina; Kurutz, Julia; Rathakrishnan, Abirami; Fernández-Sáiz, Vanesa; Brunner, Andrä; Targosz, Bianca-Sabrina; Loewecke, Felicia; Gloeckner, Christian Johannes; Ueffing, Marius; Fulda, Simone; Pfreundschuh, Michael; Trümper, Lorenz; Klapper, Wolfram; Keller, Ulrich; Jost, Philipp J; Rosenwald, Andreas; Peschel, Christian; Bassermann, Florian

    2016-01-01

    The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event-free survival in patients treated with spindle poison-containing chemotherapy. Accordingly, aggressive B-cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ-Myc lymphoma model. Together, we specify the USP9X-XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B-cell lymphoma. PMID:27317434

  14. 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

  15. 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

  16. Primary diffuse large B-cell lymphoma in the anterior hard palate: A rare case report with review of literature

    PubMed Central

    Sahoo, Sujit Ranjan; Misra, Satya Ranjan; Mishra, Lora; Mishra, Sobhan

    2014-01-01

    Diffuse large B-cell lymphomas (DLBCLs) are defined as neoplasms of large transformed B cells, i.e. with nuclear diameter more than twice that of a normal lymphocyte. These account for 30-40% of all adult non-Hodgkin's lymphomas (NHL). Intraoral lymphomas are relatively rare and often difficult to diagnose in clinical settings. In this case report, we describe a case of primary DLBCL affecting the anterior part of the hard palate of an elderly male patient. DLBCL of anterior part of hard palate is yet to be reported in the English literature, even though DLBCL cases involving the posterior palate have been recorded, thus making the present case to be first of its kind. Emphasis has also been given on the subclassification, differential diagnosis and prognostic antibody factors determining the outcome of DLBCL. PMID:24959047

  17. Indication for liver transplantation in a patient with a history of a gastric lymphoma.

    PubMed

    Ruiz Pardo, José; Cascales Campos, Pedro Antonio; Parrilla Paricio, Pascual

    2016-06-01

    The indication for liver transplantation in patients with history of lymphoma is little-known, and the references documented in the medical literature are still limited. We present the case of a 63-year-old man who was diagnosed with chronic hepatopathy due to HBV 15 years ago. He was operated on for hepatocellular carcinoma in the segment VI of the liver 4 years ago, finding a macronodular liver cirrhosis during the surgery. Fifteen months later, the patient was diagnosed with diffuse large B-cell gastric lymphoma (fig.1). After a good response to chemotherapy treatment with R-CHOP scheme, the patient has been in complete remission for 36 months. Currently, the patient has a Child-Pugh score of 5 points, MELD score of 6 points, an undetectable viral load and it does not exist any evidence of hepatocellular carcinoma recurrence. With respect to this case, could it be considered liver transplantation in any assumption or would it be rejected in any case due to the recent history of lymphoma? In this case report, it has decided to do a periodic follow-up of the patient, but because of the good prognosis of the lymphoma, liver transplantation may be performed in the case of hepatocellular recurrence, worsening of liver function (Child-Pugh B or C) or fulminant hepatic failure due to HBV reactivation. There is not yet consensus about the interval between lymphoma remission and liver transplantation, therefore it recommends an individual oncologic evaluation in order to establish the recurrence risk before deciding on the indication for liver transplantation. PMID:26937630

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

    PubMed

    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

    1994-02-01

    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

  19. 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

  20. A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma

    PubMed Central

    Suhasini, Avvaru N.; Lin, An-Ping; Bhatnagar, Harshita; Kim, Sang-Woo; Moritz, August W.; Aguiar, Ricardo C. T.

    2015-01-01

    Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to down-modulate VEGF secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher microvessel density. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL. PMID:26503641

  1. 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

  2. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells.

    PubMed

    Mathews Griner, Lesley A; Guha, Rajarshi; Shinn, Paul; Young, Ryan M; Keller, Jonathan M; Liu, Dongbo; Goldlust, Ian S; Yasgar, Adam; McKnight, Crystal; Boxer, Matthew B; Duveau, Damien Y; Jiang, Jian-Kang; Michael, Sam; Mierzwa, Tim; Huang, Wenwei; Walsh, Martin J; Mott, Bryan T; Patel, Paresma; Leister, William; Maloney, David J; Leclair, Christopher A; Rai, Ganesha; Jadhav, Ajit; Peyser, Brian D; Austin, Christopher P; Martin, Scott E; Simeonov, Anton; Ferrer, Marc; Staudt, Louis M; Thomas, Craig J

    2014-02-11

    The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT-mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL. PMID:24469833

  3. Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients

    PubMed Central

    Hennequin, Audrey; Derangère, Valentin; Boidot, Romain; Apetoh, Lionel; Vincent, Julie; Orry, David; Fraisse, Jean; Causeret, Sylvain; Martin, François; Arnould, Laurent; Beltjens, Françoise; Ghiringhelli, François; Ladoire, Sylvain

    2016-01-01

    Tumor-infiltrating T and B lymphocytes could have the potential to affect cancer prognosis. The objective of this study was to investigate the prognostic significance of tumor infiltration by CD8 and CD4 T cells, and B lymphocytes in patients with localized gastric cancer. In a retrospective cohort of 82 patients with localized gastric cancer and treated by surgery we quantitatively assessed by immunohistochemistry on surgical specimen, immune infiltrates of IL-17+, CD8+, Foxp3+, Tbet+ T cells and CD20+ B cells both in the tumor core and at the invasive margin via immunohistochemical analyses of surgical specimens. We observed that CD8+ and IL17+ T-cell densities were not significantly associated with gastric cancer prognosis. In contrast, high infiltration of Tbet+ T cells, high numbers of CD20+ B-cell follicles, and low infiltration of Foxp3+ T cells, were associated with better relapse-free survival. Interestingly, treatment with neoadjuvant chemotherapy or histological tumor type (diffuse versus intestinal) did not influence type and density of immune infiltrates or their prognostic value. Immunohistochemical analysis of the gastric cancer stromal microenvironment revealed organized T and B cell aggregates, with strong structural analogies to normal secondary lymphoid organs and which could be considered as tertiary lymphoid structures. Using transcriptomic data from an independent cohort of 365 localized gastric cancer, we confirmed that a coordinated Th1, and B cell stromal gene signature is associated with better outcome. Altogether, these data suggest that tumor infiltration by B and Th1 T cells could affect gastric cancer prognosis and may be used to better define the outcome of patients with localized gastric cancer. PMID:27057426

  4. Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas.

    PubMed

    Menter, Thomas; Bodmer-Haecki, Andrea; Dirnhofer, Stephan; Tzankov, Alexandar

    2016-08-01

    Activation of the programmed death 1 (PD1)/PD1 ligand (PDL1) pathway is important for tumor cells to escape from immune control. The clinical efficacy of therapeutic modulation of the PD1-PDL1 pathway has been recently shown in classical Hodgkin lymphoma (cHL), but little is known about the frequency and diagnostic and prognostic importance of PDL1 expression in lymphomas. The available anti-PDL1 antibody clones E1L3N and SP142 were compared, and a large cohort of Hodgkin lymphomas (n=280) and B-cell lymphomas (n=619) was examined for PDL1 using E1L3N. The results were correlated with the expression of other phenotypic markers, interphase fluorescence in situ hybridization data of the 9p24.1 region (PDL1 locus), and the clinical outcome. PDL1 was expressed on more than 5% of tumor cells in 70% of cHL, 54% of nodular lymphocyte-predominant Hodgkin lymphoma, and 35% of primary mediastinal B-cell lymphomas; in the latter, PDL1 expression correlated with PDL1 gains (ρ=0.573). PDL1 was expressed in 31% of primary diffuse large B-cell lymphomas (DLBCLs), whereas most other entities did not express PDL1. In cHL, expression of PDL1 correlated with increased numbers of granzyme+ T cells (ρ=0.251) and CD68+ macrophages (ρ=0.221) but with decreased numbers of FoxP3+ T cells (ρ=0.145). In activated B-cell-like DLBCL, PDL1 positively correlated with PD1+ T cells, whereas an inverse correlation with FoxP3+ T cells was seen in the germinal center B-cell-like DLBCL. PDL1 expression can be diagnostically valuable in some gray zones around DLBCL and cHL; it identifies an "immune escape" cluster of cHL and activated B-cell-like DLBCL with increased granzyme+ and PD1+ T cells and macrophages and decreased regulatory T cells. PMID:27045512

  5. 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

  6. The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.

    PubMed

    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

    2016-06-30

    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-κB signalling in

  7. 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

  8. 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

  9. 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

    O'Hayre, M; Inoue, A; Kufareva, I; Wang, Z; Mikelis, C M; Drummond, R A; Avino, S; Finkel, K; Kalim, K W; DiPasquale, G; Guo, F; Aoki, J; Zheng, Y; Lionakis, M S; Molinolo, A A; Gutkind, J S

    2016-07-21

    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

  10. 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

  11. 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

  12. 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.

  13. A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma

    PubMed Central

    Gossmann, Jennifer; Stolte, Manfred; Lohoff, Michael; Yu, Philipp; Moll, Roland; Finkernagel, Florian; Garn, Holger; Brendel, Cornelia; Bittner, Alwina; Neubauer, Andreas; Huynh, Minh Q.

    2016-01-01

    Gastric mucosa-associated lymphoid tissue (MALT) lymphomas develop from a chronic Helicobacter infection. Phospholipase C gamma 2 (PLCG2) is important for B-cell survival and proliferation. We used BALB/c mice with a gain-of-function mutation in the Plcg2 gene (Ali5) to analyze its role in the development of gastric MALT lymphoma. Heterozygous BALB/c Plcg2Ali5/+ and wildtype (WT) mice were infected with Helicobacter felis (H. felis) and observed up to 16 months for development of gastric MALT lymphomas. In contrast to our initial hypothesis, Plcg2Ali5/+ mice developed MALT lymphomas less frequently than their WT littermates after long-term infection of 16 months. Infected Plcg2Ali5/+ mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific IgG1 and IgG2a antibody responses. These results suggested a blunted immune response of Plcg2Ali5/+ mice towards H. felis infection. Intriguingly, Plcg2Ali5/+ mice harboured higher numbers of CD73 expressing regulatory T cells (Tregs), possibly responsible for impaired immune response towards Helicobacter infection. We suggest that Plcg2Ali5/+ mice may be protected from developing gastric MALT lymphomas as a result of elevated Treg numbers, reduced response to H. felis and decrease of proinflammatory cytokines. PMID:26966907

  14. 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

  15. Lectin-like transcript 1 is a marker of germinal center-derived B-cell non-Hodgkin's lymphomas dampening natural killer cell functions

    PubMed Central

    Germain, Claire; Guillaudeux, Thierry; Galsgaard, Elisabeth D; Hervouet, Catherine; Tekaya, Nedra; Gallouet, Anne-Sophie; Fassy, Julien; Bihl, Franck; Poupon, Gwenola; Lazzari, Anne; Spee, Pieter; Anjuère, Fabienne; Pangault, Céline; Tarte, Karin; Tas, Patrick; Xerri, Luc; Braud, Veronique M

    2015-01-01

    Non-Hodgkin's lymphomas (NHLs) are malignant neoplasms which are clinically and biologically diverse. Their incidence is constantly increasing and despite treatment advances, there is a need for novel targeted therapies. Here, we identified Lectin-like transcript 1 (LLT1) as a biomarker of germinal center (GC)-derived B-cell NHLs. LLT1 identifies GC B cells in reactive tonsils and lymph nodes and its expression is maintained in B-cell NHLs which derive from GC, including Burkitt lymphoma (BL), follicular lymphoma (FL), and GC-derived diffuse large B-cell lymphoma (DLBCL). We further show that LLT1 expression by tumors dampens natural killer (NK) cell functions following interaction with its receptor CD161, uncovering a potential immune escape mechanism. Our results pinpoint LLT1 as a novel biomarker of GC-derived B-cell NHLs and as a candidate target for innovative immunotherapies. PMID:26405582

  16. Hepatitis C virus-associated B-cell non-Hodgkin’s lymphomas: what do we know?

    PubMed Central

    Vannata, Barbara; Arcaini, Luca; Zucca, Emanuele

    2015-01-01

    Epidemiological studies have shown an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. There is, however, a great geographic variability and it remains unclear whether additional environmental and genetic factors are involved or whether the international discrepancies represent simply a consequence of the variable prevalence of HCV infection in different countries. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used and the year of publication. The most convincing evidence for a causal relationship comes from the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after successful HCV eradication with antiviral treatment. Yet, the molecular mechanism of HCV-induced lymphomagenesis are mainly hypothetical. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by the chronic viral infection. This review will summarize the current knowledge on HCV-associated lymphomas and their management. PMID:27054025

  17. The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism☆☆☆

    PubMed Central

    Huang, Jianfeng; Das, Suman Kumar; Jha, Pooja; Al Zoughbi, Wael; Schauer, Silvia; Claudel, Thierry; Sexl, Veronika; Vesely, Paul; Birner-Gruenberger, Ruth; Kratky, Dagmar; Trauner, Michael; Hoefler, Gerald

    2013-01-01

    Obesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer. PMID:23628473

  18. 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

  19. 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

  20. Malaria Hidden in a Patient with Diffuse Large-B-Cell Lymphoma and Sickle-Cell Trait▿

    PubMed Central

    Linares, María; Albizua, Enriqueta; Méndez, Darío; Rubio, José M.; Martínez-Serna, Alejandra; Martínez, Miguel A.; Salto, Efren; Puyet, Antonio; Diez, Amalia; Martinez-López, Joaquin; Bautista, José M.

    2011-01-01

    We report a case of an African patient with sickle cell trait who was diagnosed in Spain with B-cell lymphoma. Blood smears were negative for malaria, and no plasmodium antigens were detected in the blood. To treat his lymphoma, the patient underwent chemotherapy and autologous stem cell transplantation. Following a splenectomy due to a worsening condition, he developed clinical malaria with detectable parasitemia. This case suggests that the humoral response and parasite removal by the spleen may afford protection from overt disease and may even help maintain subclinical human reservoirs of the disease. PMID:21976762

  1. (18)FDG PET/CT appearance in primary cutaneous diffuse large B-cell lymphoma, leg type.

    PubMed

    Samarghandi, Amin; Gru, Alejandro Ariel; Natwa, Mona; Barker, David W

    2015-06-01

    We report the case of a 70-year-old woman who presented with a small and painless red skin nodule in the right lower leg, which rapidly and significantly increased in size over few weeks and developed a central eschar. Skin biopsy was consistent with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDBCL-LT), an aggressive and rare cutaneous lymphoma. F-FDG PET/CT showed a hypermetabolic soft tissue mass in the right leg with no evidence of systemic involvement of disease. PMID:25742229

  2. Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression.

    PubMed

    Valera, Alexandra; Epistolio, Samantha; Colomo, Lluis; Riva, Alice; Balagué, Olga; Dlouhy, Ivan; Tzankov, Alexandar; Bühler, Marco; Haralambieva, Eugenia; Campo, Elias; Soldini, Davide; Mazzucchelli, Luca; Martin, Vittoria

    2016-08-01

    MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression. PMID:27125356

  3. PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma

    PubMed Central

    Brault, L; Menter, T; Obermann, E C; Knapp, S; Thommen, S; Schwaller, J; Tzankov, A

    2012-01-01

    Background: PIM serine/threonine kinases are often highly expressed in haematological malignancies. We have shown that PIM inhibitors reduced the survival and migration of leukaemic cells. Here, we investigated PIM kinases in diffuse large B-cell lymphoma (DLBCL) biopsy samples and DLBCL cell lines. Methods: Immunohistochemical staining for PIM kinases and CXCR4 was performed on tissue microarrays from a cohort of 101 DLBCL cases, and the effects of PIM inhibitors on the survival and migration of DLBCL cell lines were determined. Results: PIM1 expression significantly correlated with the activation of signal transducer and activator of transcription (STAT) 3 and 5, P-glycoprotein expression, CXCR4-S339 phosphorylation, and cell proliferation. Whereas most cases exhibited cytoplasmic or cytoplasmic and nuclear PIM1 and PIM2 expression, 12 cases (10 of the non-germinal centre DLBCL type) expressed PIM1 predominately in the nucleus. Interestingly, nuclear expression of PIM1 significantly correlated with disease stage. Exposure of DLBCL cell lines to PIM inhibitors modestly impaired cellular proliferation and CXCR4-mediated migration. Conclusion: This work demonstrates that PIM expression in DLBCL is associated with activation of the JAK/STAT signalling pathway and with the proliferative activity. The correlation of nuclear PIM1 expression with disease stage and the modest response to small-molecule inhibitors suggests that PIM kinases are progression markers rather than primary therapeutic targets in DLBCL. PMID:22722314

  4. Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma.

    PubMed

    Rosewick, Nicolas; Momont, Mélanie; Durkin, Keith; Takeda, Haruko; Caiment, Florian; Cleuter, Yvette; Vernin, Céline; Mortreux, Franck; Wattel, Eric; Burny, Arsène; Georges, Michel; Van den Broeke, Anne

    2013-02-01

    Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III)-transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5'-LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent ∼40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation. PMID:23345446

  5. 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

  6. [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

  7. Complex Chromosomal Rearrangements in B-Cell Lymphoma: Evidence of Chromoanagenesis? A Case Report

    PubMed Central

    Ortega, Veronica; Chaubey, Alka; Mendiola, Christina; Ehman, William; Vadlamudi, Kumari; Dupont, Barbara; Velagaleti, Gopalrao

    2016-01-01

    Genomic instability is a well-known hallmark of cancer. Recent genome sequencing studies have led to the identification of novel phenomena called chromothripsis and chromoanasynthesis in which complex genomic rearrangements are thought to be derived from a single catastrophic event rather than by several incremental steps. A new term chromoanagenesis or chromosomal rebirth was coined recently to group these two one-step catastrophic events together. These phenomena suggest an evolutionary modality for cancer cells to circumvent individual mutational events with one simultaneous shattering of chromosomes resulting in the random reassembling of segmented genetic material to form complex derivative chromosomes. We report a case of possible chromoanagenesis in a patient with diffuse large B-cell lymphoma. Chromosome analysis from the biopsy showed a complex karyotype with multiple numerical and structural rearrangements including a translocation of chromosomes 3 and 7 involving the BCL6 gene region, with the derivative chromosome further rearranging with chromosomes 14, 7, and 22 with involvement of the IGH gene region. Fluorescence in situ hybridization studies confirmed these findings. Chromosomal microarray studies showed multiple complex copy number variations including a chromosome 12 abnormality, the complexity of which appears to suggest the phenomenon of chromoanagenesis. Our case further illustrates that lymphomagenesis can be complex and may arise from a catastrophic event resulting in multiple complex chromosome rearrangements. PMID:27108385

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

    PubMed

    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; Alizadeh, Ash A

    2015-06-11

    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 (18)fluoro-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. 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

  10. Complex Chromosomal Rearrangements in B-Cell Lymphoma: Evidence of Chromoanagenesis? A Case Report.

    PubMed

    Ortega, Veronica; Chaubey, Alka; Mendiola, Christina; Ehman, William; Vadlamudi, Kumari; Dupont, Barbara; Velagaleti, Gopalrao

    2016-04-01

    Genomic instability is a well-known hallmark of cancer. Recent genome sequencing studies have led to the identification of novel phenomena called chromothripsis and chromoanasynthesis in which complex genomic rearrangements are thought to be derived from a single catastrophic event rather than by several incremental steps. A new term chromoanagenesis or chromosomal rebirth was coined recently to group these two one-step catastrophic events together. These phenomena suggest an evolutionary modality for cancer cells to circumvent individual mutational events with one simultaneous shattering of chromosomes resulting in the random reassembling of segmented genetic material to form complex derivative chromosomes. We report a case of possible chromoanagenesis in a patient with diffuse large B-cell lymphoma. Chromosome analysis from the biopsy showed a complex karyotype with multiple numerical and structural rearrangements including a translocation of chromosomes 3 and 7 involving the BCL6 gene region, with the derivative chromosome further rearranging with chromosomes 14, 7, and 22 with involvement of the IGH gene region. Fluorescence in situ hybridization studies confirmed these findings. Chromosomal microarray studies showed multiple complex copy number variations including a chromosome 12 abnormality, the complexity of which appears to suggest the phenomenon of chromoanagenesis. Our case further illustrates that lymphomagenesis can be complex and may arise from a catastrophic event resulting in multiple complex chromosome rearrangements. PMID:27108385

  11. Central nervous system prophylaxis in diffuse large B-cell lymphoma.

    PubMed

    Zahid, Mohammad Faizan; Khan, Nadia; Hashmi, Shahrukh K; Kizilbash, Sani Haider; Barta, Stefan K

    2016-08-01

    Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks. PMID:27096423

  12. MicroRNA and gene networks in human diffuse large B-cell lymphoma.

    PubMed

    Wang, Kunhao; Xu, Zhiwen; Wang, Ning; Xu, Ting; Zhu, Minghui

    2014-11-01

    Molecular biologists have collected considerable data regarding the involvement of genes and microRNAs (miRNAs) in cancer. However the underlying mechanisms of cancer with regard to genes and miRNAs remain unclear. The aim of the present study was to evaluate diffuse large B-cell lymphoma (DLBCL) and construct regulatory networks of genes and miRNAs to gradually reveal the underlying mechanisms of DLBCL development. The first differential expression network that is presented is an experimentally validated network of miRNAs and genes. This network presents known biological regulatory associations among miRNAs and genes in the human body. The second network is a DLBCL differential expression network. Differentially expressed gene and miRNA data regarding DLBCL were collected and, based on the first network and the differentially expressed data, the second network was inferred, which demonstrates the irregular regulatory associations that may lead to the occurrence of DLBCL. The third network is a DLBCL-associated network. This network is comprised of non-differentially expressed genes and miRNAs that contribute to numerous DLBCL processes. The similarities and differences among the three networks were extracted and compared to distinguish key regulatory associations; furthermore, important signaling pathways in DLBCL were identified. The present study partially clarified the pathogenesis of DLBCL and provided an improved understanding of the underlying molecular mechanisms, as well as a potential treatment for DLBCL. PMID:25289101

  13. 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

  14. B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells.

    PubMed

    Muschol-Steinmetz, Cornelia; Jasmer, Britta; Kreis, Nina-Naomi; Steinhäuser, Kerstin; Ritter, Andreas; Rolle, Udo; Yuan, Juping; Louwen, Frank

    2016-03-18

    Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity and its pathogenesis is not fully understood. B-cell lymphoma 6 (BCL6), a key regulator of B-lymphocyte development, is altered in preeclamptic placentas. We show here that BCL6 is present in all 3 studied trophoblast cell lines and it is predominantly expressed in trophoblastic HTR-8/SVneo cells derived from a 1(st) trimester placenta, suggestive of its involvement in trophoblast expansion in the early stage of placental development. BCL6 is strongly stabilized upon stress stimulation. Inhibition of BCL6, by administrating either small interfering RNA or a specific small molecule inhibitor 79-6, reduces proliferation and induces apoptosis in trophoblastic cells. Intriguingly, depletion of BCL6 in HTR-8/SVneo cells results in a mitotic arrest associated with mitotic defects in centrosome integrity, indicative of its involvement in mitotic progression. Thus, like in haematopoietic cells and breast cancer cells, BCL6 promotes proliferation and facilitates survival of trophoblasts under stress situation. Further studies are required to decipher its molecular roles in differentiation, migration and the fusion process of trophoblasts. Whether increased BCL6 observed in preeclamptic placentas is one of the causes or the consequences of preeclampsia warrants further investigations in vivo and in vitro. PMID:27029530

  15. The anti-lymphoma activity of antiviral therapy in HCV-associated B-cell non-Hodgkin lymphomas: a meta-analysis.

    PubMed

    Peveling-Oberhag, J; Arcaini, L; Bankov, K; Zeuzem, S; Herrmann, E

    2016-07-01

    Many epidemiological studies provide solid evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin's lymphoma (B-NHL). However, the most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). We conducted a literature search to identify studies that included patients with HCV-associated B-NHL (HCV-NHL) who received AVT, with the intention to treat lymphoma and viral disease at the same time. The primary end point was the correlation of sustained virological response (SVR) under AVT with lymphoma response. Secondary end points were overall lymphoma response rates and HCV-NHL response in correlation with lymphoma subtypes. We included 20 studies that evaluated the efficacy of AVT in HCV-NHL (n = 254 patients). Overall lymphoma response rate through AVT was 73% [95%>confidence interval, (CI) 67-78%]. Throughout studies there was a strong association between SVR and lymphoma response (83% response rate, 95%>CI, 76-88%) compared to a failure in achieving SVR (53% response rate, 95%>CI, 39-67%, P = 0.0002). There was a trend towards favourable response for AVT in HCV-associated marginal zone lymphomas (response rate 81%, 95%>CI, 74-87%) compared to nonmarginal zone origin (response rate 71%, 95%>CI, 61-79%, P = 0.07). In conclusion, in the current meta-analysis, the overall response rate of HCV-NHL under AVT justifies the recommendation for AVT as first-line treatment in patients who do not need immediate conventional treatment. The strong correlation of SVR and lymphoma regression supports the hypothesis of a causal relationship of HCV and lymphomagenesis. PMID:26924533

  16. Follicular lymphoma transforming into anaplastic diffuse large B-cell lymphoma of oral cavity: A case report with review of literature

    PubMed Central

    Mittal, Megha; Puri, Abhiney; Nangia, Rajat; Sachdeva, Alisha

    2015-01-01

    Follicular lymphoma (FL) is a common form of non-Hodgkin's lymphoma (NHL) with the ability to transform into a more aggressive disease, frequently to B cell-lymphoblastic lymphoma. Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL, which is characterized by diffuse proliferation of large neoplastic B-lymphocytes. It accounts for 30% of all NHL and its occurrence in the mandible is very rare. It is often seen in young adults, but in the present case, a 50-year-old male patient presented with painless swelling in left lower jaw since 25 days following extraction of left lower molar teeth. There was a history of fever and submandibular lymph nodes were enlarged. On incisional biopsy, features of NHL-like lesion were observed and confirmed by immunohistochemistry using CD20, bcl-2, CD10, CD3, CD5, Ki67 markers to be FL (3A) lymphoma transforming into DLBCL. This is a very uncommon presentation. PMID:26980969

  17. Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-07-25

    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

  18. 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

  19. The Role of Surgery in Primary Gastric Lymphoma

    PubMed Central

    Avilés, Agustin; Nambo, M Jesús; Neri, Natividad; Huerta-Guzmán, Judith; Cuadra, Ivonne; Alvarado, Isabel; Castañeda, Claudia; Fernández, Raúl; González, Martha

    2004-01-01

    Objective: We began a controlled clinical trial to assess efficacy and toxicity of surgery (S), surgery + radiotherapy (SRT), surgery + chemotherapy (SCT), and chemotherapy (CT) in the treatment of primary gastric diffuse large cell lymphoma in early stages: IE and II1. Summary Background Data: Management of primary gastric lymphoma remains controversial. No controlled clinical trials have evaluated the different therapeutic schedules, and prognostic factors have not been identified in a uniform population. Patients and Methods: Five hundred eighty-nine patients were randomized to be treated with S (148 patients), SR (138 patients), SCT (153 patients), and CT (150 patients). Radiotherapy was delivered at doses of 40 Gy; chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) at standard doses. International Prognostic Index (IPI) and modified IPI (MIPI) were assessed to determine outcome. Results: Complete response rates were similar in the 4 arms. Actuarial curves at 10 years of event-free survival (EFS) were as follows: S: 28% (95% confidence interval [CI], 22% to 41%); SRT: 23% (95% CI, 16% to 29%); that were statistically significant when compared with SCT: 82% (95% CI, 73% to 89%); and CT: 92% (95% CI, 84% to 99%) (P < 0.001). Actuarial curves at 10 years showed that overall survivals (OS) were as follows: S: 54% (95% CI, 46% to 64%); SRT: 53% (95% CI, 45% to 68%); that were statistically significant to SCT: 91% (95% CI, 85% to 99%); CT: 96% (95% CI, 90% to 103%)(P < 0.001). Late toxicity was more frequent and severe in patients who undergoing surgery. IPI and MIPI were not useful in determining outcome and multivariate analysis failed to identify other prognostic factors. Conclusion: In patients with primary gastric diffuse large cell lymphoma and aggressive histology, diffuse large cell lymphoma in early stage SCT achieved good results, but surgery was associated with some cases of lethal complications. Thus it appears that CT

  20. 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

  1. 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.

  2. Bowel perforation from occult ileal involvement after diagnosis in a case of primary mediastinal large B-cell lymphoma.

    PubMed

    De Philippis, Chiara; Di Chio, Maria Chiara; Sabattini, Elena; Bolli, Niccolo

    2016-01-01

    Primary mediastinal large B-cell lymphoma (PMBCL) is confined to the mediastinum or contiguous nodal areas in most cases. Extramediastinal and abdominal involvement, especially at diagnosis, is extremely rare. Our case describes the first case of histologically proven ileal involvement of PMBCL at diagnosis that led to ileal perforation. Positron emission tomography CT could increase the sensitivity of staging by detecting unusual sites of disease localisation, and could impact clinical management. PMID:27417993

  3. 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.  

  4. Exosomes Derived from Burkitt’s Lymphoma Cell Lines Induce Proliferation, Differentiation, and Class-Switch Recombination in B Cells

    PubMed Central

    Gutzeit, Cindy; Nagy, Noemi; Gentile, Maurizio; Lyberg, Katarina; Gumz, Janine; Vallhov, Helen; Puga, Irene; Klein, Eva; Gabrielsson, Susanne; Cerutti, Andrea; Scheynius, Annika

    2014-01-01

    Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell–independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt’s lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells. PMID:24829410

  5. Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.

    PubMed

    Salaverria, Itziar; Philipp, Claudia; Oschlies, Ilske; Kohler, Christian W; Kreuz, Markus; Szczepanowski, Monika; Burkhardt, Birgit; Trautmann, Heiko; Gesk, Stefan; Andrusiewicz, Miroslaw; Berger, Hilmar; Fey, Miriam; Harder, Lana; Hasenclever, Dirk; Hummel, Michael; Loeffler, Markus; Mahn, Friederike; Martin-Guerrero, Idoia; Pellissery, Shoji; Pott, Christiane; Pfreundschuh, Michael; Reiter, Alfred; Richter, Julia; Rosolowski, Maciej; Schwaenen, Carsten; Stein, Harald; Trümper, Lorenz; Wessendorf, Swen; Spang, Rainer; Küppers, Ralf; Klapper, Wolfram; Siebert, Reiner

    2011-07-01

    The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma. PMID:21487109

  6. Dual expression of MYC and BCL2 proteins predicts worse outcomes in diffuse large B-cell lymphoma.

    PubMed

    Clark Schneider, Kelli M; Banks, Peter M; Collie, Angela M B; Lanigan, Christopher P; Manilich, Elena; Durkin, Lisa M; Hill, Brian T; Hsi, Eric D

    2016-07-01

    Recent studies suggested that MYC and BCL2 protein co-expression is an independent indicator of poor prognosis in diffuse large B-cell lymphoma. However, the immunohistochemistry protocols for dual-expression staining and the scoring cut-offs vary by study. Sixty-nine cases of diffuse large B-cell lymphoma were evaluated for MYC and BCL2 protein expression using various cut-offs that have been recommended in prior studies. Independent of the International Prognostic Index risk group, cases with dual protein expression of BCL2 and MYC using ≥50%/40% cut-offs and ≥70%/40% had significantly shorter overall survival than cases without. It was verified in this patient population that the use of BCL2 and MYC immunohistochemistry, performed with available in vitro diagnostic-cleared antibodies, provides rapid prognostic information in patients with de novo diffuse large B-cell lymphoma. This study has practical implications for diagnostic laboratories and serves as a guide for implementation in the setting of future clinical trials. PMID:26421520

  7. 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

  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. Clinicopathological features of 49 primary gastrointestinal diffuse large B-cell lymphoma cases; comparison with location, cell-of-origin, and frequency of MYD88 L265P.

    PubMed

    Nagakita, Keina; Takata, Katsuyoshi; Taniguchi, Kohei; Miyata-Takata, Tomoko; Sato, Yasuharu; Tari, Akira; Ohnishi, Nobuhiko; Noujima-Harada, Mai; Omote, Shizuma; Nakamura, Naoya; Iwamuro, Masaya; Maeda, Yoshinobu; Okada, Hiroyuki; Tanimoto, Mitsune; Yoshino, Tadashi

    2016-08-01

    The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P. PMID:27439595

  10. Primary Diffuse Large B-cell Lymphoma Arising in the Tongue Accompanied by Ataxia-telangiectasia: A Case Report

    PubMed Central

    Kaneoya, Ayano; Mochizuki, Yumi; Harada, Hiroyuki

    2015-01-01

    Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder that is characterized by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and a predisposition to leukemia/lymphoma. Here we report a rare case of lymphoma of the tongue accompanied by AT. Tumour extirpation was performed and diffuse large B-cell lymphoma was diagnosed following pathologic examination. A whole-body survey showed no other enlarged lymph nodes or tumour. The female patient then received a modified dosage of COPAD (cyclophosphamide, vinblastine, pirarubicin, and prednisolone) plus rituximab to avoid severe complications. As of follow-up after 3 years and 5 months, she remains in complete remission. Patients showing AT need careful surveillance and long-term continuous follow-up. PMID:26266230

  11. 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

  12. miR-4284 and miR-4484 as Putative Biomarkers for Diffuse Large B-Cell Lymphoma

    PubMed Central

    Tamaddon, Gholamhossein; Geramizadeh, Bita; Karimi, Mohammad Hossein; Mowla, Seyed Javad; Abroun, Said

    2016-01-01

    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

  13. Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma

    PubMed Central

    Patel, Jayeshkumar; Hatzi, Katerina; Malik, Alka; Tam, Wayne; Martin, Peter; Leonard, John; Melnick, Ari; Cerchietti, Leandro

    2016-01-01

    The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of “oncogene-addiction switching” by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL. PMID:26657288

  14. MicroRNA-187 induces diffuse large B-cell lymphoma cell apoptosis via targeting BCL6

    PubMed Central

    HUANG, FANG; JIN, YAOFENG; WEI, YAFENG

    2016-01-01

    MicroRNAs (miRs) are endogenous non-coding RNAs that serve key functions in a wide range of biological processes, including cell growth, development, apoptosis and carcinogenesis. However, the association between miR-187 and B-cell lymphoma 6 (BCL6) has yet to be fully investigated in lymphoma cell apoptosis. The present study hypothesized that a post-translational mechanism may exist for BCL6 expression, which is regulated by miR-187 in lymphoma cells. The present study demonstrated that the expression of miR-187 in diffuse large B-cell lymphoma (DLBCL) cells was significantly decreased, and its expression was negatively correlated with BCL6 expression. It was also observed that miR-187 directly binds to the 3′-untranslated region of BCL6 mRNA and subsequently suppresses the expression of BCL6. Additionally, the induced expression of miR-187 significantly promoted DLBCL cell apoptosis in vitro. The drug sensitivity of human DLBCL SUDHL2 cells was increased following induction of miR-187 overexpression via an miR-187 mimic. In conclusion, the results of the present study suggest that the modulation of miR-187 expression in DLBCL cells may improve the sensitivity of chemotherapy through BCL6 targeting. PMID:27073562

  15. 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. PMID:22743653

  16. Endogenous bcl-2 is not required for the development of Emu-myc-induced B-cell lymphoma.

    PubMed

    Kelly, Priscilla N; Puthalakath, Hamsa; Adams, Jerry M; Strasser, Andreas

    2007-06-01

    Although myc and bcl-2 synergize in tumor development, particularly lymphomagenesis, it is not known whether endogenous bcl-2 is required for myc-induced tumorigenesis. To investigate the role of endogenous Bcl-2 in myc-induced lymphomagenesis, we bypassed the early death of Bcl-2-deficient mice by reconstituting lethally irradiated wild-type (wt) mice with a hematopoietic system from fetal liver-derived stem cells of Emu-myc/bcl-2(-/-) or control Emu-myc transgenic embryos. In premalignant (healthy) recipients, loss of Bcl-2 caused a moderate decrease in pre-B and immature B cells, and a dramatic reduction of mature B lymphocytes expressing the Emu-myc transgene. Furthermore, cultured preneoplastic Emu-myc/bcl-2(-/-) mature B cells displayed accelerated apoptosis compared with Emu-myc B cells. However, despite the striking reduction in B-cell numbers in vivo, ablation of endogenous Bcl-2 did not prevent or even delay development of Emu-myc lymphoma. Moribund mice presented with similar degrees of splenomegaly, blood leukocyte numbers, and tumor dissemination at death. These findings demonstrate that the initiation, development, continued growth, and severity of Emu-myc lymphoma do not depend upon endogenous Bcl-2, nor upon the total number of B lymphoid cells driven by the Emu-myc transgene. These results have implications for the treatment of hematopoietic tumors, particularly those that are not caused by Bcl-2 overexpression. PMID:17317859

  17. 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

  18. 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.

  19. 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

  20. Primary bladder lymphoma, diffuse large B-cell type: Case report and literature review of 26 cases

    PubMed Central

    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

  1. The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing.

    PubMed

    Swerdlow, Steven H; Kuzu, Isinsu; Dogan, Ahmet; Dirnhofer, Stephan; Chan, John K C; Sander, Birgitta; Ott, German; Xerri, Luc; Quintanilla-Martinez, Leticia; Campo, Elias

    2016-03-01

    Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities. PMID:26454445

  2. The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing

    PubMed Central

    Kuzu, Isinsu; Dogan, Ahmet; Dirnhofer, Stephan; Chan, John K. C.; Sander, Birgitta; Ott, German; Xerri, Luc; Quintanilla-Martinez, Leticia; Campo, Elias

    2016-01-01

    Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities. PMID:26454445

  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. microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma.

    PubMed

    Imig, Jochen; Motsch, Natalie; Zhu, Jia Yun; Barth, Stephanie; Okoniewski, Michal; Reineke, Tanja; Tinguely, Marianne; Faggioni, Alberto; Trivedi, Pankaj; Meister, Gunter; Renner, Christoph; Grässer, Friedrich A

    2011-03-01

    The Epstein-Barr virus (EBV) is an oncogenic human Herpes virus found in ∼15% of diffuse large B-cell lymphoma (DLBCL). EBV encodes miRNAs and induces changes in the cellular miRNA profile of infected cells. MiRNAs are small, non-coding RNAs of ∼19-26 nt which suppress protein synthesis by inducing translational arrest or mRNA degradation. Here, we report a comprehensive miRNA-profiling study and show that hsa-miR-424, -223, -199a-3p, -199a-5p, -27b, -378, -26b, -23a, -23b were upregulated and hsa-miR-155, -20b, -221, -151-3p, -222, -29b/c, -106a were downregulated more than 2-fold due to EBV-infection of DLBCL. All known EBV miRNAs with the exception of the BHRF1 cluster as well as EBV-miR-BART15 and -20 were present. A computational analysis indicated potential targets such as c-MYB, LATS2, c-SKI and SIAH1. We show that c-MYB is targeted by miR-155 and miR-424, that the tumor suppressor SIAH1 is targeted by miR-424, and that c-SKI is potentially regulated by miR-155. Downregulation of SIAH1 protein in DLBCL was demonstrated by immunohistochemistry. The inhibition of SIAH1 is in line with the notion that EBV impedes various pro-apoptotic pathways during tumorigenesis. The down-modulation of the oncogenic c-MYB protein, although counter-intuitive, might be explained by its tight regulation in developmental processes. PMID:21062812

  5. 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

  6. 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

  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. Prognostic and Clinicopathological Value of Survivin in Diffuse Large B-cell Lymphoma

    PubMed Central

    Zhang, Ya; Wang, Jianhong; Sui, Xiaohui; Li, Ying; Lu, Kang; Fang, Xiaosheng; Jiang, Yujie; Wang, Xin

    2015-01-01

    Abstract Up to date, survivin, a well-known inhibitor of apoptosis, has attracted considerable attention as a potential biomarker and therapeutic target in diffuse large B-cell lymphoma (DLBCL). Nevertheless, there still remains no consensus on heterogeneous results. Herein, a meta-analysis was performed to clarify a convincing significance of survivin status on prognosis and clinicopathology of DLBCL patients. Eligible studies were identified by searching Medline, Embase, Scopus, CNKI, and Wanfang databases (last updated on November 30, 2014). Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Heterogeneity and sensitivity were also analyzed. Moreover, Begg, Egger test, and funnel plots were applied to evaluate the publication bias. We finally included 17 eligible studies with the total number of 1352 patients in the meta-analysis. The pooled results showed that positive survivin expression in DLBCL was associated with inferior overall survival (OS) (HR: 1.880, 95% CI: 1.550–2.270) in patients. Moreover, a significant association was revealed between survivin expression and advanced clinical stage (III + IV) (OR: 0.611, 95% CI: 0.452–0.827), higher International Prognosis Index (IPI) score (Score 3–5) (OR: 0.559; 95% CI: 0.410–0.761), elevated serum lactic dehydrogenase (LDH) (OR: 0.607, 95% CI: 0.444–0.831), presence of bone marrow involvement (OR: 2.127, 95% CI: 1.154–3.921) together with reduced complete remission (CR) rate (OR: 0.478, 95% CI: 0.345–0.662). The results suggest that survivin could be a useful prognostic biomarker, and a promising target for DLBCL therapeutic intervention. Considering limited HR data adjusted for standard prognostic variables could be retrieved, future high-quality studies will be needed in evaluating the independent prognostic value of survivin expression in DLBCL. PMID:26356696

  9. Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma

    PubMed Central

    2013-01-01

    Background We previously showed that B-cell receptor (BCR) signaling pathways are important for in vitro survival of mantle cell lymphoma (MCL) cells. To further identify early BCR-activated signaling pathways involved in MCL cell survival, we focused our study on BCR-proximal kinases such as LYN whose dysregulations could contribute to the aggressive course of MCL. Methods Primary MCL cells were isolated from 14 leukemic patients. Early BCR-induced genes were identified by qRT-PCR array. The basal and BCR-induced phosphorylation of LYN and JNK were evaluated by immunoblottting. Cell survival signals were evaluated by apoptosis using flow cytometry. Results We showed that LYN was constitutively phosphorylated in MCL cell lines and in 9/10 leukemic MCL cases. Treatment with dasatinib or with a specific inhibitor of Src kinases such as PP2 suppressed constitutive LYN activation and increased in vitro spontaneous apoptosis of primary MCL cells. BCR engagement resulted in an increase of LYN phosphorylation leading to activation of c-JUN NH2-terminal kinase (JNK) and over-expression of the early growth response gene-1 (EGR-1). Inhibition of JNK with SP600125 induced apoptosis and reduced level of basal and BCR-induced expression of EGR-1. Furthermore, decreasing EGR1 expression by siRNA reduced BCR-induced cell survival. Treatment with PP2 or with dasatinib suppressed BCR-induced LYN and JNK phosphorylation as well as EGR-1 upregulation and is associated with a decrease of cell survival in all cases analysed. Conclusions This study highlights the importance of BCR signaling in MCL cell survival and points out to the efficiency of kinase inhibitors in suppressing proximal BCR signaling events and in inducing apoptosis. PMID:23422267

  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. PMID:26667793

  11. Inactivation of p16INK4a/CDKN2A gene may be a diagnostic feature of large B cell lymphoma leg type among cutaneous B cell lymphomas.

    PubMed

    Belaud-Rotureau, Marc-Antoine; Marietta, Virginie; Vergier, Beatrice; Mainhaguiet, Guillaume; Turmo, Michelle; Idrissi, Yamina; Ferrer, Jacky; Beylot-Barry, Marie; Dubus, Pierre; Merlio, Jean-Philippe

    2008-06-01

    The World Health Organization-European Organization for Research and Treatment of Cancer has individualized three main categories among the primary cutaneous B cell lymphoma (PCBCL): leg-type primary cutaneous large B cell lymphoma (PCLBCL leg type), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous marginal zone lymphoma (PCMZL). The genetic features of 21 PCBCL cases (six PCLBCL leg type four PCFCL large cells, seven PCFCL small cells, and four PCMZL) were investigated by comparative genomic hybridization (CGH array). Fluorescent in situ hybridization (FISH) analysis was performed to confirm CGH array data and to detect lymphoma-associated gene rearrangements. p14(ARF)/p16(INK4a) CDKN2A gene quantification, methylation analysis, and immunohistochemical detection were also performed. CGH array showed a higher number of recurrent genetic imbalances in PCLBCL leg type (mean 62) than in PCFCL large cells (mean 34). PCFCL small cells and PCMZL exhibited fewer chromosomal alterations (mean 24 and 9). FISH analysis provided concordant results with CGH array data in 97% (98 of 101) assays and demonstrated a t(8;14)(q24;q32) in two of six PCLBCL leg type. Recurrent deletions in 9p21 (p14(ARF)/p16(INK4a)CDKN2A) were a constant finding in PCLBCL leg type (six of six). Conversely, PCFCL large cells exhibited recurrent 1p36 deletions (four of four) without deletion in 9p21 (zero of four). The diagnostic and prognostic impact of the p16(INK4a)CDKN2A gene status in PCBCL should therefore be confirmed on a larger series. PMID:18311490

  12. Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1.

    PubMed

    Zukerberg, L R; Benedict, W F; Arnold, A; Dyson, N; Harlow, E; Harris, N L

    1996-07-01

    The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B-cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B-chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1-2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases

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

    PubMed

    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

    2016-03-01

    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

  14. A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

    PubMed Central

    Habineza Ndikuyeze, Georges; Gaurnier-Hausser, Anita; Patel, Reema; Baldwin, Albert S.; May, Michael J.; Flood, Patrick; Krick, Erika; Propert, Kathleen J.; Mason, Nicola J.

    2014-01-01

    Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL. PMID:24798348

  15. 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

  16. High resolution copy number analysis of IRF4 translocation-positive diffuse large B-cell and follicular lymphomas.

    PubMed

    Salaverria, Itziar; Martin-Guerrero, Idoia; Burkhardt, Birgit; Kreuz, Markus; Zenz, Thorsten; Oschlies, Ilske; Arnold, Norbert; Baudis, Michael; Bens, Susanne; García-Orad, Africa; Lisfeld, Jasmin; Schwaenen, Carsten; Szczepanowski, Monika; Wessendorf, Swen; Pfreundschuh, Michael; Trümper, Lorenz; Klapper, Wolfram; Siebert, Reiner

    2013-02-01

    Translocations affecting chromosome subband 6p25.3 containing the IRF4 gene have been recently described as characteristic alterations in a molecularly distinct subset of germinal center B-cell-derived lymphomas. Secondary changes have yet only been described in few of these lymphomas. Here, we performed array-comparative genomic hybridization and molecular inversion probe microarray analyses on DNA from 12 formalin-fixed paraffin-embedded and two fresh-frozen IRF4 translocation-positive lymphomas, which together with the previously published data on nine cases allowed the extension of copy number analyses to a total of 23 of these lymphomas. All except one case carried chromosomal imbalances, most frequently gains in Xq28, 11q22.3-qter, and 7q32.1-qter and losses in 6q13-16.1, 15q14-22.31, and 17p. No recurrent copy-neutral losses of heterozygosity were observed. TP53 point mutations were detected in three of six cases with loss of 17p. Overall this study unravels a recurrent pattern of secondary genetic alterations in IRF4 translocation-positive lymphomas. PMID:23073988

  17. Immunoglobulin VH Gene Mutational Analysis Suggests that Primary Effusion Lymphomas Derive from Different Stages of B Cell Maturation

    PubMed Central

    Matolcsy, András; Nádor, Roland G.; Cesarman, Ethel; Knowles, Daniel M.

    1998-01-01

    Primary effusion lymphoma (PEL) is a recently described distinct subtype of non-Hodgkin’s lymphoma associated with infection by the Kaposi’s sarcoma-associated herpesvirus, also called human herpesvirus-8. Most cases of PEL are also associated with the Epstein-Barr virus (EBV). In order to better characterize the cellular origin of PEL, we investigated the immunoglobulin (Ig) heavy chain variable region (VH) genes expressed by tumor cells of the BC-1 and BC-3 cell lines derived from PELs and five original PEL specimens. In the six EBV-positive PELs examined, including the BC-1 cell line, the expressed VH gene sequences showed numerous point mutations relative to the putative germline VH gene sequences. In addition, the VH segment of one of these cases showed intraclonal sequence heterogeneity, indicating ongoing somatic mutation. In five cases, the distribution and type of mutations indicated that tumor cells had been selected by antigen. Because somatically mutated Ig genes are expressed by B cells that have reached a germinal center/post-germinal center stage of development, these findings suggest that the PEL cell of origin is a germinal center or post-germinal center B cell in most cases. In contrast, the VH gene segment expressed by tumor cells of the BC-3 cell line, which was originated from an EBV-negative PEL obtained from an HIV-negative patient, was unmutated, suggesting a pre-germinal center B cell origin for tumor cells of this particular PEL cell line. Taken together, these findings suggest that development of PELs may not be restricted to one stage of B cell differentiation and may represent transformation of B cells at different stages of ontogeny. PMID:9811353

  18. [Mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by valproic acid combined with temsirolimus].

    PubMed

    Zheng, Zhong; Zhao, Yan; Dong, Li-Hua; Wang, Li; Cheng, Shu; Zhao, Wei-Li

    2013-12-01

    The aim of this study was to illustrate the mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by histone deacetylase inhibitor valproic acid (VPA) combined with mTOR inhibitor temsirolimus (TEM). MTT assay and Wright's stain were used to assess cell growth inhibition and to detect the cell morphological changes respectively. The cell apoptosis, cell cycle and cell autophagy were determined by flow cytometry. Ultrastructure changes were confirmed by electron microscopy. Protein changes were detected by Western blot. The results showed that both VPA and TEM alone inhibited cell proliferation and the effect was more obvious in the combination group. VPA combined with TEM induced cell arrest in G0/G1 phase and upregulated the expression of autophagy-related protein LC3, without cell apoptosis. Moreover, typical autophagosomes were observed, further confirming the presence of autophagy. Western blot showed the changes of proteins involved in autophagy signaling pathway. VPA decreased HDAC1 and HDAC3 expression and increased histone acetylation, suggesting that VPA also affected lymphoma cell proliferation through epigenetic modification. It is concluded that the combined treatment of VPA and TEM induces cell cycle arrest and cell autophagy, which provides a new clue for their clinical application in diffuse large B-cell lymphoma. PMID:24370026

  19. Rare case of a primary non-dural central nervous system low grade B-cell lymphoma and literature review

    PubMed Central

    Papanicolau-Sengos, Antonios; Wang-Rodriguez, Jessica; Wang, Huan-You; Lee, Roland R; Wong, Anna; Hansen, Lawrence A; Mahooti, Sepi; Rashidi, Hooman H

    2012-01-01

    We present a case of a 70-year-old HIV negative man with a five-year history of progressive dysnomia and new onset right extremity numbness, dysarthria, and blurry vision. On magnetic resonance imaging (MRI), an infiltrative enhancing tumor was noted. Follow up brain biopsy results revealed a small lymphocytic infiltrate with scattered plasma cells in a predominantly perivascular growth pattern. Flow-cytometric findings revealed a lambda monotypic B-cell population. The morphology and the flow cytometric findings were consistent with involvement by a low grade B-cell lymphoma. Subsequent positron emission tomography (PET) studies along with bone marrow biopsy and serum protein electrophoresis showed no evidence of systemic disease. The above findings are consistent with involvement by a non-dural extranodal marginal zone B-cell lymphoma (MZBCL) primary to the central nervous system (CNS). This is the first reported case of a primary CNS MZBCL with flow cytometric analysis. A review of literature on this rare entity is also included. PMID:22295152

  20. 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

  1. 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

  2. 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

  3. Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of "germinotropic" lymphoproliferative disorder.

    PubMed

    Lorenzi, Luisa; Lonardi, Silvia; Essatari, Murad H M; Pellegrini, Vilma; Fisogni, Simona; Gazzola, Anna; Agostinelli, Claudio; Vermi, William; Rossi, Giuseppe; Massarelli, Giovannino; Pileri, Stefano A; Facchetti, Fabio

    2016-04-01

    Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals. PMID:26762526

  4. 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.

  5. Genetic aberrations in small B-cell lymphomas and leukemias: molecular pathology, clinical relevance and therapeutic targets.

    PubMed

    Bogusz, Agata M; Bagg, Adam

    2016-09-01

    Small B-cell lymphomas and leukemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of clonal lymphoid neoplasms, including entities such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterized by distinct translocations, for example t(11;14) in the majority of cases of MCL and t(14;18) in most cases of FL, whereas other entities are associated with a variety of recurrent but nonspecific numeric chromosomal abnormalities, as exemplified by del(13q14), del(11q22), and +12 in CLL, and yet others such as LPL and HCL that lack recurrent or specific cytogenetic aberrations. The recent surge in next generation sequencing (NGS) technology has shed more light on the genetic landscape of SBCLs through characterization of numerous driver mutations including SF3B1 and NOTCH1 in CLL, ATM and CCND1 in MCL, KMT2D and EPHA7 in FL, MYD88 (L265P) in LPL, KLF2 and NOTCH2 in splenic MZL (SMZL) and BRAF (V600E) in HCL. The identification of distinct genetic lesions not only provides greater insight into the molecular pathogenesis of these disorders but also identifies potential valuable biomarkers for prognostic stratification, as well as specific targets for directed therapy. This review discusses the well-established and recently identified molecular lesions underlying the pathogenesis of SBCLs, highlights their clinical relevance and summarizes novel targeted therapies. PMID:27121112

  6. 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

  7. 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

  8. Sporadic Burkitt's lymphoma/acute B-cell leukaemia presenting with progressive proptosis and orbital mass in a child.

    PubMed

    Grasso, Daniela; Borreggine, Carmela; Ladogana, Saverio; De Santis, Raffaela; Delle Noci, Nicola; Grilli, Gianpaolo; Macarini, Luca

    2016-06-01

    Burkitt's lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma that is found predominantly in children, with the highest incidence occurring in Africa. The sporadic form occurs in non-endemic areas and typically involves the ileo-caecum and the bowel, whereas orbital and paranasal sinus involvement is rare. Here, we present an unusual case of sporadic BL in a Caucasian male child with rapidly progressive painful proptosis of the right eye. Magnetic resonance imaging showed an oval-shaped, extraconal mass in the supero-lateral part of the right orbit that deformed and dislocated the eyeball antero-inferiorly. The patient underwent anterior orbitotomy, and a biopsy of the excised tissue revealed a starry-sky appearance characteristic of BL. Postoperative aggressive chemotherapy was initiated with a good response after one week. PMID:27006106

  9. Structurally Defined αMHC-II Nanobody-Drug Conjugates: A Therapeutic and Imaging System for B-Cell Lymphoma.

    PubMed

    Fang, Tao; Duarte, Joao N; Ling, Jingjing; Li, Zeyang; Guzman, Jonathan S; Ploegh, Hidde L

    2016-02-12

    Antibody-drug conjugates (ADCs) of defined structure hold great promise for cancer therapies, but further advances are constrained by the complex structures of full-sized antibodies. Camelid-derived single-domain antibody fragments (VHHs or nanobodies) offer a possible solution to this challenge by providing expedited target screening and validation through switching between imaging and therapeutic activities. We used a nanobody (VHH7) specific for murine MHC-II and rendered "sortase-ready" for the introduction of oligoglycine-modified cytotoxic payloads or NIR fluorophores. The VHH7 conjugates outcompeted commercial monoclonal antibodies (mAbs) for internalization and exhibited high specificity and cytotoxicity against A20 murine B-cell lymphoma. Non-invasive NIR imaging with a VHH7-fluorophore conjugate showed rapid tumor targeting on both localized and metastatic lymphoma models. Subsequent treatment with the nanobody-drug conjugate efficiently controlled tumor growth and metastasis without obvious systemic toxicity. PMID:26840214

  10. Primary uterine diffuse large B-cell lymphoma involving the urinary bladder with urinary cytology mimicking carcinomas: A case report.

    PubMed

    Adachi, Sumiyo; Yamazaki, Kazuto; Liang, Shan-Guang; Ishida, Yasuo

    2015-01-01

    We report a rare case of a 69-year-old woman in whom diffuse large B-cell lymphoma (DLBCL) originated from the uterus and involved the urinary bladder. The cervical smears of the case mostly consisted of discohesive atypical round cells, which were highly suggestive of lymphoma; however, in voided urine smears, a majority of the cells formed large aggregates of degenerated cells, mimicking those of urothelial carcinoma (UC). The smears also represented some small loose clusters, in which tumor cells formed short chains with nuclear molding, mimicking those of small cell carcinoma. The cytodiagnosis got definitive when we identified the atypical cells that showed CD20+/CD3-/cytokeratin-/NSE- immunophenotype. These are of particular concern as they may have misleading similarities to other epithelial neoplasms when examining lymphoma involving the urinary bladder. Accordingly, this case highlights the importance of immunocytochemistry to rule out malignant lymphoma when encountering large and/or small loose clusters of atypical round cells on urinary cytology. PMID:26729979

  11. Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas.

    PubMed

    Ruan, J; Shah, B; Martin, P; Schuster, S J

    2016-07-01

    Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the 'R(2)' regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R(2), immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R(2) treatment, and optimal strategies for managing adverse events are discussed here. PMID:27052651

  12. Mediastinal B-Cell Lymphoma Presenting with Jugular-Subclavian Deep Vein Thrombosis as the First Presentation

    PubMed Central

    Eltawansy, Sherif Ali; Ceniza, Sidney; Sharon, David

    2015-01-01

    Jugular venous thrombosis infrequently could be secondary to malignancy and has seldom been reported secondary to mediastinal large B-cell lymphomas. The postulated mechanisms are mechanical compression that leads to stagnation of blood in the venous system of the neck and/or an increase in the circulating thrombogenic elements that could cause venous thromboembolism as a paraneoplastic phenomenon. We report the case of a middle aged male presenting with right sided neck pain and arm swelling secondary to ipsilateral jugular-subclavian deep vein thrombosis. Investigations revealed it to be secondary to a mediastinal mass shown on CT scan of the chest. PMID:25821628

  13. Anti-tumor activity of the combination of bendamustine with vorinostat in diffuse large B-cell lymphoma cells.

    PubMed

    Fernández-Rodríguez, Concepción; Salar, Antonio; Navarro, Alfons; Gimeno, Eva; Pairet, Silvia; Camacho, Laura; Ferraro, Mariana; Serrano, Sergi; Besses, Carles; Bellosillo, Beatriz; Sanchez-Gonzalez, Blanca

    2016-03-01

    Current standard-of-care therapy for diffuse large B-cell lymphoma (DLBCL) results in up to 40% of patients who either relapse or develop refractory disease. In this setting, further therapeutic improvements are needed. This study analyzed the in vitro effects of the combination of bendamustine with the histone deacetylase inhibitor vorinostat in DLBCL cells. This combination enhanced histone acetylation and double strand DNA breaks resulting in an additive to synergistic cytotoxic effect in both ABC- and GCB-type DLBCL cells, independently of their TP53 mutational status. These results support the rationale for considering bendamustine and vorinostat combination as a novel approach in DLBCL treatment. PMID:26084206

  14. Synthetic Peptide Ligands of the Antigen Binding Receptor Induce Programmed Cell Death in a Human B-Cell Lymphoma

    NASA Astrophysics Data System (ADS)

    Renschler, Markus F.; Bhatt, Ramesh R.; Dower, William J.; Levy, Ronald

    1994-04-01

    Peptide ligands for the antigen binding site of the surface immunoglobulin receptor of a human B-cell lymphoma cell line were identified with the use of filamentous phage libraries displaying random 8- and 12-amino acid peptides. Corresponding synthetic peptides bound specifically to the antigen binding site of this immunoglobulin receptor and blocked the binding of an anti-idiotype antibody. The ligands, when conjugated to form dimers or tetramers, induced cell death by apoptosis in vitro with an IC50 between 40 and 200 nM. This effect was associated with specific stimulation of intracellular protein tyrosine phosphorylation.

  15. [Intravascular Large B Cell Lymphoma with Cauda Equina Syndrome: A Case Report and Review of the Literature].

    PubMed

    Wada, Shinichi; Matsuo, Ryu; Matsushita, Tomonaga; Fukushima, Yoshihisa; Ago, Tetsuro; Kitazono, Takanari

    2016-01-01

    A 62-year-old man complained of gait disturbance, bladder and bowel dysfunction and paresthesia of both legs one month before admission. His symptoms were suggestive of cauda equina syndrome. After admission, he developed rapid progressive numbness and weakness of both legs and a disturbance of consciousness. A random skin biopsy was performed and a histological diagnosis of intravascular large B cell lymphoma (IVLBCL) was reached. His symptoms were improved after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. PMID:26764304

  16. Primary extranodal B-cell non-Hodgkin lymphoma mimicking an endodontic lesion: report of 2 cases.

    PubMed

    Wong, Gordon B; Spadafora, Silvana; Barbon, Nick; Caputo, Michael

    2013-01-01

    Intrabony oral non-Hodgkin lymphoma (NHL) is rare. We report 2 cases of NHL of the maxilla that initially presented as apical abscesses in endodontically treated teeth. Radiographic findings were nondescript, but tissue biopsy revealed diffuse large B-cell NHL in both instances. No other sites of disease were found. Both patients were treated by chemotherapy and radiation with good results. As primary NHL of the maxilla can mimic a dental inflammatory lesion, tissue biopsy is mandatory in cases where symptoms do not resolve after specific treatment. PMID:24059491

  17. Comparative RNA-Seq and microarray analysis of gene expression changes in B-cell lymphomas of Canis familiaris.

    PubMed

    Mooney, Marie; Bond, Jeffrey; Monks, Noel; Eugster, Emily; Cherba, David; Berlinski, Pamela; Kamerling, Steve; Marotti, Keith; Simpson, Heather; Rusk, Tony; Tembe, Waibhav; Legendre, Christophe; Benson, Hollie; Liang, Winnie; Webb, Craig Paul

    2013-01-01

    Comparative oncology is a developing research discipline that is being used to assist our understanding of human neoplastic diseases. Companion canines are a preferred animal oncology model due to spontaneous tumor development and similarity to human disease at the pathophysiological level. We use a paired RNA sequencing (RNA-Seq)/microarray analysis of a set of four normal canine lymph nodes and ten canine lymphoma fine needle aspirates to identify technical biases and variation between the technologies and convergence on biological disease pathways. Surrogate Variable Analysis (SVA) provides a formal multivariate analysis of the combined RNA-Seq/microarray data set. Applying SVA to the data allows us to decompose variation into contributions associated with transcript abundance, differences between the technology, and latent variation within each technology. A substantial and highly statistically significant component of the variation reflects transcript abundance, and RNA-Seq appeared more sensitive for detection of transcripts expressed at low levels. Latent random variation among RNA-Seq samples is also distinct in character from that impacting microarray samples. In particular, we observed variation between RNA-Seq samples that reflects transcript GC content. Platform-independent variable decomposition without a priori knowledge of the sources of variation using SVA represents a generalizable method for accomplishing cross-platform data analysis. We identified genes differentially expressed between normal lymph nodes of disease free dogs and a subset of the diseased dogs diagnosed with B-cell lymphoma using each technology. There is statistically significant overlap between the RNA-Seq and microarray sets of differentially expressed genes. Analysis of overlapping genes in the context of biological systems suggests elevated expression and activity of PI3K signaling in B-cell lymphoma biopsies compared with normal biopsies, consistent with literature describing

  18. 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

  19. Downregulation of B-cell lymphoma/leukemia-2 by overexpressed microRNA 34a enhanced titanium dioxide nanoparticle-induced autophagy in BEAS-2B cells

    PubMed Central

    Bai, Wenlin; Chen, Yujiao; Sun, Pengling; Gao, Ai

    2016-01-01

    Titanium dioxide (TiO2) nanoparticles (TNPs) are manufactured worldwide for a wide range of applications and the toxic effect of TNPs on biological systems is gaining attention. Autophagy is recognized as an emerging toxicity mechanism triggered by nanomaterials. MicroRNA 34a (miR34a) acts as a tumor suppressor gene by targeting many oncogenes, but how it affects autophagy induced by TNPs is not completely understood. Here, we observed the activation of TNP-induced autophagy through monodansylcadaverine staining and LC3-I/LC3-II conversion. Meanwhile, the transmission electron microscope ultrastructural analysis showed typical morphological characteristics in autophagy process. We detected the expression of miR34a and B-cell lymphoma/leukemia-2 (Bcl-2). In addition, the underlying mechanism of TNP-induced autophagy was performed using overexpression of miR34a by lentivirus vector transfection. Results showed that TNPs induced autophagy generation evidently. Typical morphological changes in the process of autophagy were observed by the transmission electron microscope ultrastructural analysis and LC3-I/LC3-II conversion increased significantly in TNP-treated cells. Meanwhile, TNPs induced the downregulation of miR34a and increased the expression of Bcl-2. Furthermore, overexpressed miR34a decreased the expression of Bcl-2 both in messenger RNA and protein level, following which the level of autophagy and cell death rate increased after the transfected cells were incubated with TNPs for 24 hours. These findings provide the first evidence that overexpressed miR34a enhanced TNP-induced autophagy and cell death through targeted downregulation of Bcl-2 in BEAS-2B cells. PMID:27226226

  20. 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. PMID:27540756

  1. Synchronous invasive ductal carcinoma and intravascular large B-cell lymphoma of the breast: a case report and review of the literature

    PubMed Central

    2014-01-01

    Primary breast lymphomas (PBLs) represent less than 1% of all breast malignancies. Intravascular large B-cell lymphoma (ILBCL) is a rare, aggressive form of extranodal lymphoma. Breast involvement has only been described in the literature once previously. ILBCL is characterized by the proliferation of tumour cells within the lumen of small vessels of involved organs, resulting in their eventual occlusion. Clinical features are often vague, diagnosis is difficult and delayed, and prognosis is usually poor. We report the first ever case of synchronous ILBCL and invasive ductal carcinoma (IDC) of the breast in a patient presenting with pyrexia of unknown origin and altered mental status who underwent modified radical mastectomy and subsequent chemotherapy, and review the literature regarding intravascular large B-cell lymphoma, PBLs and synchronous carcinomas and lymphomas of the breast. PMID:24708809

  2. Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature

    PubMed Central

    Akoum, Riad; Serhal, Wassim; Farhat, Hussein

    2015-01-01

    Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma. PMID:26064133

  3. Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature.

    PubMed

    Akoum, Riad; Serhal, Wassim; Farhat, Hussein

    2015-01-01

    Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma. PMID:26064133

  4. Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma

    ClinicalTrials.gov

    2014-09-10

    Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Untreated Childhood Acute Lymphoblastic Leukemia

  5. Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin | Office of Cancer Genomics

    Cancer.gov

    Morin et al. describe recurrent somatic mutations in EZH2, a polycomb group oncogene. The mutation, found in the SET domain of this gene encoding a histone methyltransferase, is found only in a subset of lymphoma samples. Specifically, EZH2 mutations are found in about 12% of follicular lymphomas (FL) and almost 23% of diffuse large B-cell lymphomas (DLBCL) of germinal center origin. This paper goes on to demonstrate that altered EZH2 proteins, corresponding to the most frequent mutations found in human lymphomas, have reduced activity using in vitro histone methylation assays.

  6. A case of primary pancreatic non-Hodgkin B-cell lymphoma mimicking autoimmune pancreatitis.

    PubMed

    Anderloni, Andrea; Genco, Chiara; Ballarè, Marco; Carmagnola, Stefania; Battista, Serena; Repici, Alessandro

    2015-06-01

    Non Hodgkin lymphoma frequently involves the gastrointestinal tract, in particular the stomach and the small bowel. Rarely, it can also be a cause of pancreatic masses. Clinical presentation is often non-specific and may overlap with other pancreatic conditions such as carcinoma, neuroendocrine tumours and autoimmune pancreatitis. We report a case of primary pancreatic lymphoma in a young woman with jaundice, fever and abdominal pain mimicking autoimmune pancreatitis. Clinical evaluation included the abdominal Computed Tomography scan, Magnetic Resonance Imaging and an upper gastrointestinal endoscopy that revealed a large duodenal mass. Endoscopic biopsies were performed and eventually histological examination was coherent with a diagnosis of primary pancreatic lymphoma. PMID:26114186

  7. Functional Imaging Using 18-Fluorodeoxyglucose PET in the Management of Primary Mediastinal Large B-Cell Lymphoma: The Contributions of the International Extranodal Lymphoma Study Group.

    PubMed

    Cavalli, Franco; Ceriani, Luca; Zucca, Emanuele

    2016-01-01

    Primary mediastinal large B-cell lymphoma (PMLBCL) is recognized as a distinct disease entity. Treatment outcomes appear better than in other diffuse large B-cell lymphoma (DLBCL) types, partly because of their earlier stage at presentation and the younger age of most patients. If initial treatment fails, however, the results of salvage chemotherapy and myeloablative treatment are poor. The need to avoid relapses after initial therapy has led to controversy over the extent of front-line therapy, particularly whether consolidation radiotherapy to the mediastinum is always required and whether the 18-fluorodeoxyglucose ((18)F-FDG) uptake detected by PET-CT scan can be used to determine its requirements. Functional imaging using PET-CT generally allows distinguishing of residual mediastinal masses containing active lymphoma from those with only sclerotic material remaining. The International Extranodal Lymphoma Study Group (IELSG) conducted the prospective IELSG-26 study, which showed that a five-point visual scale can be used to define metabolic response after immunochemotherapy and that a cut point based on liver uptake discriminates effectively between high or low risk of failure, with 5-year progression-free survival (PFS) of 99% versus 68% and 5-year overall survival (OS) of 100% versus 83%. This study also showed that a baseline quantitative PET parameter, namely the total lesion glycolysis describing the metabolic tumor burden, can be a powerful predictor of PMLBCL outcomes and warrants further validation as a biomarker. The ongoing IELSG-37 randomized study addresses the need for consolidation mediastinal radiotherapy in patients in whom a complete metabolic response (CMR) can be seen on PET scans after standard immunochemotherapy. PMID:27249743

  8. Neutrophils trigger a NF-κB dependent polarization of tumor-supportive stromal cells in germinal center B-cell lymphomas.

    PubMed

    Grégoire, Murielle; Guilloton, Fabien; Pangault, Céline; Mourcin, Frédéric; Sok, Phaktra; Latour, Maelle; Amé-Thomas, Patricia; Flecher, Erwan; Fest, Thierry; Tarte, Karin

    2015-06-30

    Both tumor-associated neutrophils (TAN) and cancer-associated fibroblasts (CAFs) display specific phenotypic and functional features and contribute to tumor cell niche. However, their bidirectional crosstalk has been poorly studied, in particular in the context of hematological malignancies. Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) are two germinal center-derived lymphomas where various cell components of infiltrating microenvironment, including TAN and CAFs, have been demonstrated to favor directly and indirectly malignant B-cell survival, growth, and drug resistance. We show here that, besides a direct and contact-dependent supportive effect of neutrophils on DLBCL B-cell survival, mediated through the BAFF/APRIL pathway, neutrophils and stromal cells cooperate to sustain FL B-cell growth. This cooperation relies on an overexpression of IL-8 by lymphoma-infiltrating stromal cells that could thereafter efficiently promote neutrophil survival and prime them to neutrophil extracellular trap. Conversely, neutrophils are able to activate stromal cells in a NF-κB-dependent manner, inducing their commitment towards an inflammatory lymphoid stroma phenotype associated with an increased capacity to trigger malignant B-cell survival, and to recruit additional monocytes and neutrophils through the release of CCL2 and IL-8, respectively. Altogether, a better understanding of the lymphoma-supporting effects of neutrophils could be helpful to design new anti-tumor therapeutic strategies. PMID:26158216

  9. Enhancer mutations of Akv murine leukemia virus inhibit the induction of mature B-cell lymphomas and shift disease specificity towards the more differentiated plasma cell stage

    SciTech Connect

    Sorensen, Karina Dalsgaard; Kunder, Sandra; Quintanilla-Martinez, Leticia; Sorensen, Jonna; Schmidt, Joerg; Pedersen, Finn Skou . E-mail: fsp@mb.au.dk

    2007-05-25

    This study investigates the role of the proviral transcriptional enhancer for B-lymphoma induction by exogenous Akv murine leukemia virus. Infection of newborn inbred NMRI mice with Akv induced 35% plasma cell proliferations (PCPs) (consistent with plasmacytoma), 33% diffuse large B-cell lymphomas, 25% follicular B-cell lymphomas and few splenic marginal zone and small B-cell lymphomas. Deleting one copy of the 99-bp proviral enhancer sequence still allowed induction of multiple B-cell tumor types, although PCPs dominated (77%). Additional mutation of binding sites for the glucocorticoid receptor, Ets, Runx, or basic helix-loop-helix transcription factors in the proviral U3 region, however, shifted disease induction to almost exclusively PCPs, but had no major influence on tumor latency periods. Southern analysis of immunoglobulin rearrangements and ecotropic provirus integration patterns showed that many of the tumors/cell proliferations induced by each virus were polyclonal. Our results indicate that enhancer mutations weaken the ability of Akv to induce mature B-cell lymphomas prior to the plasma cell stage, whereas development of plasma cell proliferations is less dependent of viral enhancer strength.

  10. Akt Inhibitor MK2206 in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2015-07-31

    Adult Grade III Lymphomatoid Granulomatosis; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Secondary Central Nervous System Non-Hodgkin Lymphoma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  11. [Results of immuno-chemotherapeutic treatment of patients with diffuse large B-cell lymphoma].

    PubMed

    Schneider, Tamás; Molnár, Zsuzsanna; Deák, Beáta; Várady, Erika; Tóth, Erika; Csomor, Judit; Matolcsy, András; Lovey, József; Lengyel, Zsolt; Petri, Klára; Gaudi, István; Rosta, András

    2009-11-01

    Treatment with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been considered as the standard therapy for diffuse large B-cell lymphoma (DLBCL) for more than 20 years. CHOP treatment in combination with targeted immunotherapy, rituximab (R-CHOP), resulted in significant improvements in the treatment of this group of patients. In this study, efficacy of R-CHOP and R-CHOP-like treatments was analysed. Results were compared to the data of historical patients only receiving CHOP treatment or CHOP-like treatment. Between September 2002 and April 2005, 140 newly diagnosed, untreated DLBCL patients started to receive R-CHOP treatment in a single centre. The eligibility criteria included advanced stage (clinical stages III-IV), or large tumour size (>7 cm) and/or symptom B or extranodal manifestation in the case of clinical stages I-II. The results were compared to the data of 130 patients only receiving CHOP treatment in the past. In the patients receiving R-CHOP, the therapeutic outcomes were superior for all parameters. During an average follow-up period of 44 or 52 months, the overall remission rate was 73.6% in the R-CHOP group in comparison with 47.7% in the CHOP group. The 5-year overall survival was 68.6% vs. 41.0% (RR: 0.4293, CI: 0.2963-0.6221; p < 0.0001), the event-free survival was 59.8% vs. 33.5% (RR: 0.5038, CI: 0.3606-0.7038; p < 0.0001) and the progression-free survival was 64.4% vs. 37.6% (RR: 0.4915, CI: 0.3442-0.7019; p < 0.0001). Since prognostic parameters were more favourable in the R-CHOP group, patient groups were also compared using the International Prognostic Index score. Again, significant differences were revealed by the subgroup analyses. The 5-year overall survival was 74.4% vs. 47.9% (RR: 0.4475, CI: 0.2418-0.8285; p = 0.0084) and 52.0% vs. 28.8% (RR: 0.4989, CI: 0.3098-0.8035; p = 0.003) in the group with good prognosis and in the group with poor prognosis, respectively. In the group with very good prognosis, the

  12. Clinical characteristics and prognostic factors of primary gastric lymphoma: A retrospective study with 165 cases.

    PubMed

    Wang, Yi-Gao; Zhao, Lin-Yong; Liu, Chuan-Qi; Pan, Si-Cheng; Chen, Xiao-Long; Liu, Kai; Zhang, Wei-Han; Yang, Kun; Chen, Xin-Zu; Zhang, Bo; Chen, Zhi-Xin; Chen, Jia-Ping; Zhou, Zong-Guang; Hu, Jian-Kun

    2016-08-01

    Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma. This retrospective study aimed to analyze the clinical characteristics, prognostic factors, and roles of different treatment modalities in patients with PGL.From January 2003 to November 2014, 165 patients who were diagnosed with PGL at West China Hospital were enrolled in this study. The clinical features, treatment, and follow-up information were analyzed.In this study, diffuse large B-cell lymphoma (DLBCL) (108, 65.5%) and mucosa-associated lymphoid tissue (MALT) lymphoma (52, 31.5%) were two predominant histological subtypes. One-year and 5-year overall survival (OS) rates of all patients were 95.2% and 79.5%, respectively; in whom 110 (66.7%) underwent surgery, 110 (66.7%) received chemotherapy, 12 (7.3%) received radiotherapy, and 10 (6.1%) received Helicobacter pylori eradication. And 75 patients (45.5%) were treated with at least 2 different types of therapies. Elevated lactic dehydrogenase (LDH) levels, poor performance status (PS), advanced stage, International Prognostic Index (IPI) score ≥3, conservative treatment, and high-grade histological subtype were associated with worse prognosis in univariate analysis. Cox regression analysis showed that LDH levels, PS, staging, and histological subtype were independent predictors of survival outcomes. In the DLBCL type, 5-year OS was significantly better in the surgically treated group (80.1%) than that of patients conservatively treated (49.8%) (P = 0.001). Surgical treatment had almost no impact on OS in the MALT type than conservative treatment (P = 0.597). The proportion of patients received conservative treatment increased from 4.5% in period 1 to 51.7% in period 4.High LDH levels, poor PS, advanced staging, and malignant pathological type at diagnosis are significantly associated with poor OS. Our data suggest that surgery is superior in prognosis over conservative treatment in the DLBCL type, but not in the MALT

  13. Histological analysis on adhesive molecules of renal intravascular large B cell lymphoma treated with CHOP chemotherapy and rituximab.

    PubMed

    Kusaba, T; Hatta, T; Tanda, S; Kameyama, H; Tamagaki, K; Okigaki, M; Inaba, T; Shimazaki, C; Sasaki, S

    2006-03-01

    A 48-year-old man was admitted to our hospital for investigation of mild renal dysfunction. A blood examination revealed mild elevation of creatinine level (1.77 mg/dl). Urinary examination revealed mild protein excretion (0.54 g/day) and microhematuria; renal biopsy revealed the focal proliferation of large mononuclear cells with mitosis in glomerular capillaries. According to immunohistochemical analysis, the intravascular lymphomatous cells stained positively with anti-leukocyte common antigen (LCA: CD45) and CD20, indicating a B lymphocyte lineage. In electron microscopy, the glomerular capillary was filled with lymphoma cells and epithelial foot process fusion was noted. Immunohistochemical analysis on adhesive molecules revealed a lack of CD11a expression on lymphoma cells, but positive CD54 expression on endothelial cells. Systemic 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed no abnormal uptake of isotopes. On the basis of these findings, we diagnosed intravascular diffuse large B cell lymphoma localized in the kidney. Despite treatment with rituximab and CHOP (prednisolone, doxorubicin, vincristine, cyclophosphamide) for 3 cycles at 1-month intervals, the renal dysfunction did not change. In histopathological analysis of the second biopsy, lymphoma cells disappeared, but focal segmental glomerulosclerosis and moderate interstitial fibrosis were noted. Electron microscopic findings revealed severe subendothelial edema with mesangial interposition, indicating severe endothelial damage. Epithelial foot process fusion was improved. These pathological analyses let us conclude that a lack of CD11a could be a candidate factor for prevention of the extravasation of lymphoma cells from blood vessels in our patient. We also presumed that the intraglomerular endothelial damage occurred due to chemotherapy-associated cell injury. PMID:16550755

  14. Reconstruction of canine diffuse large B-cell lymphoma gene regulatory network: detection of functional modules and hub genes.

    PubMed

    Zamani-Ahmadmahmudi, M; Najafi, A; Nassiri, S M

    2015-01-01

    Lymphoma is one of the most common malignancies in dogs. Canine lymphoma is similar to human non-Hodgkin's lymphoma (NHL) with shared clinical presentation and histopathological features. This study reports the construction of a comprehensive gene regulatory network (GRN) for canine diffuse large B-cell lymphoma (DLBCL), the most common type of canine lymphoma, and performs analysis for detection of major functional modules and hub genes (the most important genes in a GRN). The canine DLBCL GRN was reconstructed from gene expression data (NCBI GEO dataset: GSE30881) using the STRING and MiMI interaction databases. Reconstructed GRNs were then assessed, using various bioinformatics programmes, in order to analyze network topology and identify major pathways and hub genes. The resultant network from both interaction databases had a logically scale-free pattern. Gene ontology (GO) analysis revealed cell activation, cell cycle phase, immune effector process, immune system development, immune system process, integrin-mediated signalling pathway, intracellular protein kinase cascade, intracellular signal transduction, leucocyte activation and differentiation, lymphocyte activation and differentiation as major GO terms in the biological processes of the networks. Moreover, bioinformatics analysis showed E2F1, E2F4, PTEN, CDKN1A, PCNA, DKC1, MNAT1, NDUFB4, ATP5J, PRKDC, BRCA1, MYCN, RFC4 and POLA1 as the most important hub genes. The phosphatidyl inositol signalling system, P53 signalling pathway, Rac CycD pathway, G1/S checkpoint, chemokine signalling pathway and telomere maintenance were the main signalling pathways in which the protein products of the hub genes are involved. PMID:25678421

  15. Constitutive NF-κB Activation Underlines Major Mechanism of Drug Resistance in Relapsed Refractory Diffuse Large B Cell Lymphoma

    PubMed Central

    2015-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common subtype of B cell non-Hodgkin's lymphoma (NHL), encompassing 30–40% of the estimated 70,000 cases of NHL in 2014 in the USA. Despite major improvements with immune-chemotherapy, the fraction of patients who still succumb to a refractory or relapsed disease remains high. This review addresses whether the better understanding of the biology of DLBCL defines new therapeutic avenues that may overcome the emerging resistance of this disease to traditional immune-chemotherapy, such as rituximab in combination with traditional chemotherapy agents. Emerging targeted therapy for relapsed refractory DLBCL encompasses more complex molecular abnormalities involving signaling pathways other than NF-κB as mechanism of resistance to immune-chemotherapy. Our review suggests that NF-κB pathway is an important crossroad where other pathways converge as phenotype of resistance that emerges in patients who fail frontline and salvage immune-chemotherapy. Future efforts should aim at targeting the role of NF-κB resistance in clinical trials, where novel agents like lenalidomide and proteasome inhibitors with established activity in this perspective will be an important component in combination therapy, along with new monoclonal antibody, BTK-inhibitors, and other novel therapy agents. PMID:25984532

  16. High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma.

    PubMed

    Sebastián, Elena; Alcoceba, Miguel; Martín-García, David; Blanco, Óscar; Sanchez-Barba, Mercedes; Balanzategui, Ana; Marín, Luis; Montes-Moreno, Santiago; González-Barca, Eva; Pardal, Emilia; Jiménez, Cristina; García-Álvarez, María; Clot, Guillem; Carracedo, Ángel; Gutiérrez, Norma C; Sarasquete, M Eugenia; Chillón, Carmen; Corral, Rocío; Prieto-Conde, M Isabel; Caballero, M Dolores; Salaverria, Itziar; García-Sanz, Ramón; González, Marcos

    2016-01-01

    Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development. PMID:26573278

  17. In vivo biotinylation of the vasculature in B-cell lymphoma identifies BST-2 as a target for antibody-based therapy.

    PubMed

    Schliemann, Christoph; Roesli, Christoph; Kamada, Haruhiko; Borgia, Beatrice; Fugmann, Tim; Klapper, Wolfram; Neri, Dario

    2010-01-21

    The discovery of accessible markers of lymphoma may facilitate the development of antibody-based therapeutic strategies. Here, we describe the results of a chemical proteomic study, based on the in vivo biotinylation of vascular proteins in lymphoma-bearing mice followed by mass spectrometric and bioinformatic analysis, to discover proteins expressed at the tissue-blood border of disseminated B-cell lymphoma. From a list of 58 proteins, which were more than 10-fold up-regulated in nodal and extranodal lymphoma lesions compared with their levels in the corresponding normal host organs, we validated BST-2 as a novel vascular marker of B-cell lymphoma, using immunochemical techniques and in vivo biodistribution studies. Furthermore, targeting BST-2 with 2 independent monoclonal antibodies delayed lymphoma growth in a syngeneic mouse model of the disease. The results of this study delineate a strategy for the treatment of systemic B-cell lymphoma in humans and suggest that anti-BST-2 antibodies may facilitate pharmacodelivery approaches that target the tumor-stroma interface. PMID:19903902

  18. Vorinostat and Combination Chemotherapy With Rituximab in Treating Patients With HIV-Related Diffuse Large B-Cell Non-Hodgkin Lymphoma or Other Aggressive B-Cell Lymphomas

    ClinicalTrials.gov

    2016-09-08

    AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Plasmablastic Lymphoma; AIDS-Related Primary Effusion Lymphoma; Grade 3b Follicular Lymphoma; HIV Infection; Plasmablastic Lymphoma; Primary Effusion Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma

  19. Long Noncoding RNA Expression Profiling in Normal B-Cell Subsets and Hodgkin Lymphoma Reveals Hodgkin and Reed-Sternberg Cell-Specific Long Noncoding RNAs.

    PubMed

    Tayari, Mina Masoumeh; Winkle, Melanie; Kortman, Gertrud; Sietzema, Jantine; de Jong, Debora; Terpstra, Martijn; Mestdagh, Pieter; Kroese, Frans G M; Visser, Lydia; Diepstra, Arjan; Kok, Klaas; van den Berg, Anke; Kluiver, Joost

    2016-09-01

    Hodgkin lymphoma (HL) is a malignancy of germinal center (GC) B-cell origin. To explore the role of long noncoding RNAs (lncRNAs) in HL, we studied lncRNA expression patterns in normal B-cell subsets, HL cell lines, and tissues. Naive and memory B cells showed a highly similar lncRNA expression pattern, distinct from GC-B cells. Significant differential expression between HL and normal GC-B cells was observed for 475 lncRNA loci. For two validated lncRNAs, an enhanced expression was observed in HL, diffuse large B-cell lymphoma, and lymphoblastoid cell lines. For a third lncRNA, increased expression levels were observed in HL and part of Burkitt lymphoma cell lines. RNA fluorescence in situ hybridization on primary HL tissues revealed a tumor cell-specific expression pattern for all three lncRNAs. A potential cis-regulatory role was observed for 107 differentially expressed lncRNA-mRNA pairs localizing within a 60-kb region. Consistent with a cis-acting role, we showed a preferential nuclear localization for two selected candidates. Thus, we showed dynamic lncRNA expression changes during the transit of normal B cells through the GC reaction and widely deregulated lncRNA expression patterns in HL. Three lncRNAs showed a tumor cell-specific expression pattern in HL tissues and might therefore be of value as a biomarker. PMID:27423697

  20. Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway

    PubMed Central

    Ramachandiran, Sampath; Adon, Arsene; Guo, Xiangxue; Wang, Yi; Wang, Huichen; Chen, Zhengjia; Kowalski, Jeanne; Sunay, Ustun R.; Young, Andrew N.; Brown, Theresa; Mar, Jessica C.; Du, Yuhong; Fu, Haian; Mann, Karen P.; Natkunam, Yasodha; Boise, Lawrence H.; Saavedra, Harold I.; Lossos, Izidore S.; Bernal-Mizrachi, Leon

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach. PMID:25359525

  1. Primary mediastinal large B-cell lymphoma and its mimickers: a rare case report with literature review.

    PubMed

    Win, T T; Kamaludin, Z; Husin, A

    2016-08-01

    Primary mediastinal large B-cell lymphoma (PMLBL) is an uncommon non-Hodgkin lymphoma with a distinct clinicopathological entity in the WHO classification of lymphoid malignancies. It is known to originate from B-cells of the thymus. It mimics thymic neoplasms and other lymphomas clinically and histopathologically. We reported a 33-year-old obese man who presented with shortness of breath off and on for 4 years. Radiologically, there was a huge anterior mediastinal mass. Tru-cut biopsy was initially diagnosed as type-A thymoma. Histopathological examination of the excised specimen revealed PMLBL with stromal fibrosis and sclerosis which created a diagnostic difficulty. The neoplastic cells varied from medium-sized to large pleomorphic cells, including mononuclear cells with centroblastic and immunoblastic features as well as bi-lobed Reed Sternberg (RS)-like cells and horse-shoe like hallmark cells. Some interlacing spindle cells and epithelioid cells were also present. Immunohistochemically, tumour cells expressed diffuse positivity for LCA, CD20, CD79a, CD23, Bcl2, MUM-1 and heterogenous positivity for CD30 and EMA, and were negative for CD10, CD15 and ALK. Ki67 scoring was very high. Tumour cells infiltrated into peri-thymic fat and pericardium. No malignant cells were detected in the pleural fluid and there was no bone marrow infiltration. The patient showed partial response to 6 cycles of RICE chemotherapy, and was planned for second line chemotherapy using hyper-CVAD regimen followed by autologous stem cell transplantation. This case illustrates the importance of thorough sampling and immunohistochemistry in differentiating PMLBL from its differential diagnoses. PMID:27568673

  2. Epstein-Barr virus-specific CD8(+) T lymphocytes from diffuse large B cell lymphoma patients are functionally impaired.

    PubMed

    Cárdenas, D; Vélez, G; Orfao, A; Herrera, M V; Solano, J; Olaya, M; Uribe, A M; Saavedra, C; Duarte, M; Rodríguez, M; López, M; Fiorentino, S; Quijano, S

    2015-11-01

    Epstein-Barr virus (EBV) is a persistent virus with oncogenic capacity that has been implicated in the development of aggressive B cell lymphomas, primarily in immunosuppressed individuals, although it can be present in immunocompetent individuals. Changes in the function and clonal diversity of T lymphocytes might be implied by viral persistence and lymphoma development. The aim of the present study was to evaluate the frequency, phenotype, function and clonotypical distribution of EBV-specific T cells after peripheral blood stimulation with a virus lysate in newly diagnosed patients with diffuse large B cell lymphoma (DLBCL) aged more than 50 years without prior histories of clinical immunosuppression compared with healthy controls. Our results showed impaired EBV-specific immune responses among DLBCL patients that were associated primarily with decreased numbers of central and effector memory CD8(+) T lymphocytes. In contrast to healthy controls, only a minority of the patients showed CD4(+)/tumour necrosis factor (TNF)-α(+) T cells expressing T cell receptor (TCR)-Vβ17 and CD8(+)/TNF-α(+) T cells with TCR-Vβ5·2, Vβ9 and Vβ18 in response to EBV. Notably, the production of TNF-α was undetectable among TCR-Vβ5·3(+), Vβ11(+), Vβ12(+), Vβ16(+) and Vβ23(+) CD8(+) T cells. In addition, we observed decreased numbers of CD4(+)/TNF-α(+) and CD8(+)/TNF-α(+), CD8(+)/interleukin (IL)-2(+) and CD8(+)/TNF-α(+)/IL-2(+) T lymphocytes in the absence of T cells capable of producing TNF-α, IL-2 and IFN-γ after EBV stimulation simultaneously. Moreover, DLBCL patients displayed higher IL-10 levels both under baseline conditions and after EBV stimulation. These findings were also observed in patients with positive EBV viral loads. Prospective studies including a large number of patients are needed to confirm these findings. PMID:26174440

  3. Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival.

    PubMed

    Corso, Jasmin; Pan, Kuan-Ting; Walter, Roland; Doebele, Carmen; Mohr, Sebastian; Bohnenberger, Hanibal; Ströbel, Philipp; Lenz, Christof; Slabicki, Mikolaj; Hüllein, Jennifer; Comoglio, Federico; Rieger, Michael A; Zenz, Thorsten; Wienands, Jürgen; Engelke, Michael; Serve, Hubert; Urlaub, Henning; Oellerich, Thomas

    2016-05-17

    Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments. PMID:27155012

  4. Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

    PubMed Central

    Bognar, M K; Vincendeau, M; Erdmann, T; Seeholzer, T; Grau, M; Linnemann, J R; Ruland, J; Scheel, C H; Lenz, P; Ott, G; Lenz, G; Hauck, S M; Krappmann, D

    2016-01-01

    Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. PMID:26776161

  5. Super-SILAC Allows Classification of Diffuse Large B-cell Lymphoma Subtypes by Their Protein Expression Profiles*

    PubMed Central

    Deeb, Sally J.; D'Souza, Rochelle C. J.; Cox, Jürgen; Schmidt-Supprian, Marc; Mann, Matthias

    2012-01-01

    Correct classification of cancer patients into subtypes is a prerequisite for acute diagnosis and effective treatment. Currently this classification relies mainly on histological assessment, but gene expression analysis by microarrays has shown great promise. Here we show that high accuracy, quantitative proteomics can robustly segregate cancer subtypes directly at the level of expressed proteins. We investigated two histologically indistinguishable subtypes of diffuse large B-cell lymphoma (DLBCL): activated B-cell-like (ABC) and germinal-center B-cell-like (GCB) subtypes, by first developing a general lymphoma stable isotope labeling with amino acids in cell culture (SILAC) mix from heavy stable isotope-labeled cell lines. This super-SILAC mix was combined with cell lysates from five ABC-DLBCL and five GCB-DLBCL cell lines. Shotgun proteomic analysis on a linear ion trap Orbitrap mass spectrometer with high mass accuracy at the MS and MS/MS levels yielded a proteome of more than 7,500 identified proteins. High accuracy of quantification allowed robust separation of subtypes by principal component analysis. The main contributors to the classification included proteins known to be differentially expressed between the subtypes such as the transcription factors IRF4 and SPI1/PU.1, cell surface markers CD44 and CD27, as well as novel candidates. We extracted a signature of 55 proteins that segregated subtypes and contained proteins connected to functional differences between the ABC and GCB-DLBCL subtypes, including many NF-κB-regulated genes. Shortening the analysis time to single-shot analysis combined with use of the new linear quadrupole Orbitrap analyzer (Q Exactive) also clearly differentiated between the subtypes. These results show that high resolution shotgun proteomics combined with super-SILAC-based quantification is a promising new technology for tumor characterization and classification. PMID:22442255

  6. NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

    PubMed Central

    West, Alison C.; Steegh, Kim; Duret, Helene; Paget, Christophe; Martin, Ben; Matthews, Geoffrey M.; Shortt, Jake; Chesi, Marta; Bergsagel, P. Leif; Bots, Michael; Zuber, Johannes; Lowe, Scott W.; Johnstone, Ricky W.

    2012-01-01

    Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating α-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eμ-myc transgenic mouse model, single therapeutic vaccination of irradiated, α-GalCer–loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12–dependent production of IFN-γ. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-γ and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-γ. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AML-ETO9a acute myeloid leukemia. Replacing α-GalCer with β-mannosylceramide resulted in prolonged protection against Eμ-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell–based immunotherapy in patients with hematologic malignancies. PMID:22932803

  7. 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

  8. Primary Diffuse Large B-Cell Lymphoma of Central Nervous System: Is Still Surgery an Unorthodox Treatment?

    PubMed

    Siasios, Ioannis; Fotiadou, Aggeliki; Fotakopoulos, George; Ioannou, Maria; Anagnostopoulos, Vassilios; Fountas, Konstantinos

    2015-12-01

    Primary central nervous system lymphoma (PCNSL) is characterized as an extra-nodal non-Hodgkin lymphoma which develops from the neuraxis. The purpose was to report a case of a patient with a supra-tentorial tumor who underwent subtotal resection of his tumor as his biopsy was not indicative of a PCNSL tumor and had uneventful recovery until his last follow-up. A 42-year-old man was admitted to our department for generalized epileptic seizures. CT and MRI examinations revealed a tumor in his right parietal-occipital lobe that was surrounded by edema and was enhancing after gadolinium administration. The patient underwent a navigation-assisted parieto-occipital craniotomy and posterior parietal transcortical approach for tumor biopsy which was not indicative of PCNSL tumor. The surgical team decided to remove the tumor on site. Histological analysis of the resected specimen showed primary diffuse large B-cell lymphoma. Combined chemotherapy and radiation therapy was applied to the patient, and at his last follow-up (16 months), he is tumor free. In our case as in several other studies during the last decade, the outcome after the surgical resection of a PCNSL tumor in combination to radiation and chemotherapy was unexpectedly good. The role of surgery probably should be reconsidered for single lesion PCNSL tumors. PMID:26566417

  9. Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect

    PubMed Central

    Grille, Sofía; Moreno, María; Bascuas, Thais; Marqués, Juan M; Muñoz, Natalia; Lens, Daniela; Chabalgoity, Jose A

    2014-01-01

    Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8+ T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials. PMID:24834964

  10. Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

    PubMed Central

    Pulvino, Mary; Chen, Luojing; Oleksyn, David; Li, Jing; Compitello, George; Rossi, Randy; Spence, Stephen; Balakrishnan, Vijaya; Jordan, Craig; Poligone, Brian; Casulo, Carla; Burack, Richard; Shapiro, Joel L.; Bernstein, Steven; Friedberg, Jonathan W.; Deshaies, Raymond J.; Land, Hartmut; Zhao, Jiyong

    2015-01-01

    In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes. PMID:26142707

  11. Durable Regression of Primary Cutaneous B-Cell Lymphoma Following Fever-inducing Mistletoe Treatment: Two Case Reports

    PubMed Central

    Lace, Aija; Fonseca, Maria P.; von Laue, Broder H.; Geider, Stefan; Kienle, Gunver S.

    2012-01-01

    Background: Mistletoe is a complementary cancer treatment that is widely used, usually in addition to and alongside recommended conventional cancer therapy. However, little is known about its use, effectiveness, and safety in the treatment of cutaneous lymphoma. Case Report: Two patients with primary cutaneous B-cell lymphoma (pT2bcNxM0 follicle center and pT2ac-NxM0 marginal zone) either declined or postponed recommended conventional treatment and received high-dose, fever-inducing mistletoe treatment; a combination of intratumoral, subcutaneous, and intravenous application was given; and one patient also underwent whole-body hyperthermia. The lymphoma regressed over a period of 12 and 8 months, respectively, and after administration of a cumulative dose of 12.98 g and 4.63 g mistletoe extract, respectively. The patients are in remission to date, 3.5 years after commencement of treatment. Neither patient received conventional cancer treatment during the entire observation period. PMID:24278797

  12. Prominent expression of sialyl Lewis X-capped core 2-branched O-glycans on high endothelial venule-like vessels in gastric MALT lymphoma

    PubMed Central

    Kobayashi, Motohiro; Mitoma, Junya; Hoshino, Hitomi; Yu, Shin-Yi; Shimojo, Yasuyo; Suzawa, Kenichi; Khoo, Kay-Hooi; Fukuda, Minoru; Nakayama, Jun

    2011-01-01

    High endothelial venule (HEV)-like vessels have been observed in gastric B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma), as well as in its preceding lesion, chronic Helicobacter pylori gastritis. Previously we reported that glycans on HEV-like vessels in the latter lesion served as L-selectin ligands. However, the biochemical and functional nature of glycans on HEV-like vessels in gastric MALT lymphoma remained to be determined. In this study, we performed immunohistochemical analysis for sialyl Lewis X (sLeX)-related glycoepitopes using three monoclonal antibodies MECA-79, HECA-452, and NCC-ST-439, and found that MECA-79−/HECA-452+/NCC-ST-439+ HEV-like vessels preferentially appears in gastric MALT lymphoma compared to chronic H. pylori gastritis, suggesting that appearance of MECA-79−/HECA-452+/NCC-ST-439+ HEV-like vessels marks gastric MALT lymphoma. We then constructed a set of CHO cell lines expressing possible MECA-79−/HECA-452+/NCC-ST-439+ glycans, as well as other sLeX-type glycans, on CD34, and evaluated L-selectin binding to those cells using L-selectin•IgM chimera binding and lymphocyte adhesion assays. L-selectin•IgM chimeras bound to CHO cells expressing 6-sulfo sLeX attached to core 2-branched O-glycans with or without 6-sulfo sLeX attached to extended core 1 O-glycans but only marginally to other CHO cell lines. On the other hand, CHO cells expressing 6-sulfo sLeX attached to extended core 1 and/or core 2-branched O-glycans, and also non-sulfated sLeX attached to core 2-branched O-glycans showed substantial lymphocyte binding, while binding was negligible on cell lines expressing 6-sulfo and non-sulfated sLeX attached to N-glycans and non-sulfated sLeX attached to extended core 1 O-glycans. These results indicate that MECA-79−/HECA-452+/NCC-ST-439+ glycans, namely 6-sulfo and non-sulfated sLeXs attached to core 2-branched O-glycans, expressed on HEV-like vessels in gastric MALT lymphoma, function as L

  13. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma

    PubMed Central

    Ogura, Michinori; Ando, Kiyoshi; Suzuki, Tatsuya; Ishizawa, Kenichi; Oh, Sung Yong; Itoh, Kuniaki; Yamamoto, Kazuhito; Au, Wing Yan; Tien, Hwei-Fang; Matsuno, Yoshihiro; Terauchi, Takashi; Yamamoto, Keiko; Mori, Masahiko; Tanaka, Yoshinobu; Shimamoto, Takashi; Tobinai, Kensei; Kim, Won Seog

    2014-01-01

    Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted. PMID:24617454

  14. An unusual case of anaplastic lymphoma kinase-positive large B-cell lymphoma in an elderly patient: A case report and discussion

    PubMed Central

    XIONG, HANZHEN; LIU, SHAO-YAN; YANG, YUE-XIN; TAN, XUE-XIAN; LUO, QIU-PING; PENG, JUAN; XIONG, ZHONG-TANG; CHEN, HUI; CHEN, JUAN; LI, ZHI; JIANG, QING-PING

    2016-01-01

    We present an unusual case of anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma, with rapid clinical progression, which occurred in a 90-year-old male patient. The patient presented with numerous enlarged lymph nodes in the neck and mediastinum. Histopathological analysis of a single lymph node detected diffuse large immunoblastic- or plasmablastic-like tumor cells, which were strongly immunoreactive for ALK in a granular cytoplasmic distribution, but negative for the expression of CD20 and CD79a. In addition, polymerase chain reaction assays were unable to detect clonal rearrangements of the T cell receptor-γ and immunoglobulin heavy chain genes in the tumor lesion, and in situ hybridization tested negative for infection with Epstein-Barr virus. The patient underwent a single cycle of chemotherapy using the cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (E-CHOP) regimen; however, the patient developed pleural effusions with respiratory distress, associated with clinical deterioration. The patient succumbed to the disease within 4 months of initial presentation. To the best of our knowledge, this is the eldest patient with this type of lymphoma to be reported in the literature. PMID:27168806

  15. 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.

  16. The role of the Chaperonin containing t-complex polypeptide 1, subunit 8 (CCT8) in B-cell non-Hodgkin's lymphoma.

    PubMed

    Yin, Haibing; Miao, Xiaobing; Wu, Yaxun; Wei, Yingze; Zong, Guijuan; Yang, Shuyun; Chen, Xudong; Zheng, Guihua; Zhu, Xinghua; Guo, Yan; Li, Chunsun; Chen, Yali; Wang, Yuchan; He, Song

    2016-06-01

    The chaperonin containing t-complex polypeptide 1 (CCT) is known to mediate folding of proteins. CCT, subunit 8 (CCT8), is the θ subunit of CCT complex chaperonin. CCT8 has been reported to be dysregulated in several tumor tissues. In this study, we investigated the role of CCT8 in B-cell non-Hodgkin's lymphoma (NHL). Clinically, the expression levels of CCT8 in reactive lymphoid hyperplasia (RLH) and B-cell NHL specimens were investigated using immunohistochemical analysis. We found that CCT8 was highly expressed in proliferating germinal center cells compared with the quiescent cells of the follicular mantle zone. Furthermore, CCT8 was highly expressed in progressive lymphomas than in indolent lymphomas. Kaplan-Meier curve showed that high expression of CCT8 was significantly associated with shorter overall survival in patients with diffuse large B-cell lymphoma. Moreover, we demonstrated that CCT8 could promote the proliferation of B-cell NHL cells. In addition, we found that CCT8 could accelerate the G1/S transition in B-cell NHL. Finally, we demonstrated that overexpression of CCT8 could reverse cell adhesion-mediated drug resistance (CAM-DR) phenotype. Our study may shed new insights into the important role of CCT8 in cancer development. PMID:27101149

  17. Hepatic B-cell non-Hodgkin's lymphoma of MALT type in the liver explant of a patient with chronic hepatitis C infection.

    PubMed

    Orrego, Mauricio; Guo, Linsheng; Reeder, Craig; De Petris, Giovanni; Balan, Vijayan; Douglas, David D; Byrne, Thomas; Harrison, Edwyn; Mulligan, David; Rodriguez-Luna, Hector; Moss, Adyr; Reddy, Kunam; Rakela, Jorge; Vargas, Hugo E

    2005-07-01

    B-cell non-Hodgkin's lymphoma (B-NHL) is a well-documented complication of hepatitis C virus (HCV) infection. Marginal zone (mucosa-associated lymphoid tissue; MALT) lymphomas constitute a less common type of B-NHL. In this article, we report a case of liver MALT in a cirrhotic patient, incidentally discovered after liver transplantation (LT). We discuss pertinent diagnostic and management strategies in this clinical setting. PMID:15973702

  18. Sulfhydryl-based tumor antigen-carrier protein conjugates stimulate superior antitumor immunity against B cell lymphomas.

    PubMed

    Betting, David J; Kafi, Kamran; Abdollahi-Fard, Alireza; Hurvitz, Sara A; Timmerman, John M

    2008-09-15

    Therapeutic vaccination of B cell lymphoma patients with tumor-specific Ig (idiotype, or Id) chemically coupled to the immunogenic foreign carrier protein keyhole limpet hemocyanin (KLH) using glutaraldehyde has shown promising results in early clinical trials, and phase III trials are underway. However, glutaraldehyde Id-KLH vaccines fail to elicit anti-Id immune and clinical responses in many patients, possibly because glutaraldehyde reacts with lysine, cysteine, tyrosine, and histidine residues, damaging critical immunogenic epitopes. A sulfhydryl-based tumor Ag-carrier protein conjugation system using maleimide chemistry was used to enhance the efficacy of Id-KLH vaccines. Maleimide Id-KLH conjugates eradicated A20 lymphoma from most tumor-bearing mice, whereas glutaraldehyde Id-KLH had little efficacy. Maleimide Id-KLH elicited tumor-specific IgG Abs and T cells, with CD8(+) T cells being the major effectors of antilymphoma immunity. Maleimide Id-KLH vaccines also demonstrated superior efficacy in 38C13 and BCL-1 lymphoma models, where Abs were shown to be critical for protection. Importantly, standard glutaraldehyde Id-KLH conjugation procedures could result in "overconjugation" of the tumor Ag, leading to decreased efficacy, whereas the heterobifunctional maleimide-based conjugation yielded potent vaccine product regardless of conjugation duration. Under lysosomal processing conditions, the Id-carrier protein linkage was cleavable only after maleimide conjugation. Maleimide KLH conjugation was easily performed with human Igs analogous to those used in Id-KLH clinical trials. These data support the evaluation of sulfhydryl-based Id-KLH vaccines in lymphoma clinical trials and possibly the use of tumor Ag-carrier protein vaccines for other cancers. PMID:18768870

  19. Rearrangements and deletions of immunoglobulin heavy chain genes in the double-producing B cell lymphoma I.29.

    PubMed Central

    Stavnezer, J; Marcu, K B; Sirlin, S; Alhadeff, B; Hammerling, U

    1982-01-01

    The B cell lymphoma I.29 consists of a mixture of cells expressing membrane-bound immunoglobulin M (IgM) (lambda) and IgA (lambda) of identical idiotypes. Whereas most of the cells express either IgM or IgA alone, 1 to 5% of the cells in this tumor express IgM and IgA simultaneously within the cytoplasm and on the cell membrane (R. Sitia et al., J. Immunol. 127:1388-1394, 1981; R. Sitia, unpublished data). When IgM+ cells are purified from the lymphoma and passaged in mice or cultured, a portion of the cells convert to IgA+. These properties suggest that some cells of the I.29 lymphoma may undergo immunoglobulin heavy chain switching, although it is also possible that the mixed population was derived by a prior switching event in a clone of cells. We performed Southern blotting experiments on genomic DNAs isolated from populations of I.29 cells containing variable proportions of IgM+ and IgA+ cells and on a number of cell lines derived from the lymphoma. The results were consistent with the deletion model for heavy chain switching, as the IgM+ cells contained rearranged mu genes and alpha genes in the germ line configuration on both the expressed and nonexpressed heavy chain chromosomes, whereas the IgA+ cells had deleted both mu genes and contained one rearranged and one germ line alpha gene. In addition, segments of DNA located within the intervening sequence 5' to the mu gene, near the site of switch recombination, were deleted from both the expressed and the nonexpressed chromosomes. Although mu genes were deleted from both chromosomes in the IgA+ cells, the sites of DNA recombination differed on the two chromosomes. On the expressed chromosome, Smu sequences were recombined with S alpha sequences, whereas on the nonexpressed chromosome, Smu sequences were recombined with S gamma 3 sequences. Images PMID:6290869

  20. TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma | Office of Cancer Genomics

    Cancer.gov

    Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell-like (GCB) DLBCL is 5% (6 of 115).

  1. [Lymphomas].

    PubMed

    Lohri, Andreas

    2016-01-01

    Although malignant lymphoma is split in over 60 distinct entities, four of them, diffuse large B cell lymphoma, follicular-, Hodgkin's- and mantle cell lymphoma constitute more than half of all new cases. A recent major revision of the Ann Arbor staging system restricts the suffix “A” and “B” just to Hodgkin's lymphoma. Bone marrow exams are abandonned in Hodgkin's and restricted in DLBCL. PET exams at different time points are crucial. PET guided therapy will lead to a reduction of the use of chemo- and radiation therapy. Many new targeted drugs have been introduced. Their therapeutic index is impressive as is their price tag. The radiation and chemotherapy free treatment of malignant lymphoma is within reach. PMID:26732717

  2. Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy

    PubMed Central

    Ghesquieres, Hervé; Slager, Susan L.; Jardin, Fabrice; Veron, Amelie S.; Asmann, Yan W.; Maurer, Matthew J.; Fest, Thierry; Habermann, Thomas M.; Bene, Marie C.; Novak, Anne J.; Mareschal, Sylvain; Haioun, Corinne; Lamy, Thierry; Ansell, Stephen M.; Tilly, Herve; Witzig, Thomas E.; Weiner, George J.; Feldman, Andrew L.; Dogan, Ahmet; Cunningham, Julie M.; Olswold, Curtis L.; Molina, Thierry Jo; Link, Brian K.; Milpied, Noel; Cox, David G.; Salles, Gilles A.; Cerhan, James R.

    2015-01-01

    Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa–Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10−7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10−7), although they did not reach conventional genome-wide significance (P = 5 × 10−8). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10−8) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10−7) were also associated with OS. In exploratory analyses, a two–single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10−12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

  3. Human Leukocyte Antigen Class I and II Alleles and Overall Survival in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

    PubMed Central

    Lu, Yani; Abdou, Amr M.; Cerhan, James R.; Morton, Lindsay M.; Severson, Richard K.; Davis, Scott; Cozen, Wendy; Rothman, Nathaniel; Bernstein, Leslie; Chanock, Stephen; Hartge, Patricia; Wang, Sophia S.

    2011-01-01

    Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01–3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24–4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02–0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20–0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation. PMID:22125456

  4. Human leukocyte antigen class I and II alleles and overall survival in diffuse large B-cell lymphoma and follicular lymphoma.

    PubMed

    Lu, Yani; Abdou, Amr M; Cerhan, James R; Morton, Lindsay M; Severson, Richard K; Davis, Scott; Cozen, Wendy; Rothman, Nathaniel; Bernstein, Leslie; Chanock, Stephen; Hartge, Patricia; Wang, Sophia S

    2011-01-01

    Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01-3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24-4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02-0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20-0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation. PMID:22125456

  5. Combination Chemo, Rituximab, and Bevacizumab in Older Patients With Stage II-IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2014-05-06

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

  6. Large B-cell lymphoma mimicking iliopsoas abscess following open revision of proximal femur infected non-union: a case report

    PubMed Central

    2014-01-01

    Background Extranodal presentation of lymphoma is a rare occurrence. It has been postulated that chronic antigen stimulation may predispose a patient to the development of lymphoma. Case presentation We present a case report of a large extranodal B-cell lymphoma mimicking a postoperative abscess following surgery for an infected proximal femur nonunion in an 80-year-old Caucasian male of Italian descent. Conclusions This case highlights the need to consider malignancy in revision surgery, careful examination of operative specimens and the need for further understanding of the role of metal implants in chronic antigen stimulation. PMID:25056400

  7. Full clinical recovery after topical acyclovir treatment of Epstein-Barr virus associated cutaneous B-cell lymphoma in patient with mycosis fungoides.

    PubMed

    Copur, M Sitki; Deshpande, Anita; Mleczko, Kris; Norvell, Max; Hrnicek, Gordon J; Woodward, Suzette; Frankforter, Scott; Mandolfo, Natalie; Fu, Kai; Chan, Wing C

    2005-06-01

    Primary cutaneous T- and B-cell lymphomas are a heterogeneous group of diseases with varied clinical presentations and prognosis. The use of new molecular, histological, and clinical criteria has improved their recognition. Cutaneous B-cell and T-cell lymphomas are seldom found together in the same patient. Here we report a rare case of mycosis fungoides variant of a cutaneous T-cell lymphoma (CTCL) which later developed Epstein-Barr virus (EBV) associated cutaneous B-cell lymphoproliferative disorder. The patient initially presented with generalized erythroderma, extensive plaques, and axillary lymphadenopathy. Histopathology and immunophenotyping of her tumor from the right breast nodule revealed a T-cell lymphoma consistent with mycosis fungoides. She was initially treated with pentostatin, followed by topical mechlorethamine and topical steroids. After progression of her mycosis fungoides with worsening diffuse skin lesions on this regimen, her treatments were changed to oral bexarotene with an initial partial response followed by stable disease. Three years from her initial presentation, she developed ulcerated cauliflower-like nodules on her forehead. Biopsy of these lesions revealed EBV-positive large- and medium-sized pleomorphic B-cells consistent with EBV-driven B-cell lymphoproliferative disorder. She was treated with topical acyclovir cream on the involved skin areas while continuing with oral bexarotene for mycosis fungoides. Skin lesions gradually diminished and totally disappeared after four weeks of topical acyclovir treatment. Bexarotene treatment was continued for another year until the mycosis fungoides progressed and became wide spread causing her death four and a half years after the initial diagnosis. The coexistence of two cutaneous non-Hodgkin lymphomas of different lineage in the same patient and the complete clinical response of EBV-related B-cell cutaneous component to topical acyclovir makes this rare case particularly interesting. PMID

  8. A Rare Case of Splenic Marginal Zone B-Cell Lymphoma Mimicking Relapsing Polychondritis of the Ear

    PubMed Central

    Huang, Gary J.; Mendes, Bryan; Sheykholeslami, Kianoush

    2014-01-01

    Relapsing polychondritis (RPC) is a poorly understood phenomenon associated with cartilaginous inflammation of the ear, nose, tracheobronchial tree, and peripheral joints. Many cases of RPC respond to anti-inflammatories and resolve with no further complications. However, RPC has also been linked to more insidious conditions such as malignancies, autoimmune disorders, vasculitis, or underlying infections. Given the spectrum of associated disorders, patients with RPC may need to be monitored for more insidious underlying conditions. In this case, we report a unique case of bilateral auricular inflammation and nasal inflammation mimicking RPC as the only presenting symptom of splenic marginal zone B-cell lymphoma and we survey related cases in the literature. PMID:25544924

  9. Silica Encapsulated Gold Nanoparticles as SERS Labels for the Detection of Lymphoma B-Cells in Tissue Sections

    NASA Astrophysics Data System (ADS)

    Al-Faouri, Tamara

    The surface of silica encapsulated gold nanoparticles with trans-1,2-bis (4-pyridyl) ethylene Raman active dye were utilized as SERS labels to target CD20 surface protein on lymphoma B-cells in human tissue sections with CLL or FL. SERS labels were functionalized with various antibody linkers including carboxylic, aldehyde, and heterobifunctional PEG chains with an NHS end, to permit them to bind to tissue section samples. NP samples and tissue sections were characterized through UV-Vis spectroscopy, TEM, XPS, Zeta potential measurements, Dark Field microscopy, Raman spectroscopy, NMR, and AFM. The number of SERS labels present on a tissue sample was estimated using dark field images and a particle counting software. It was found that the heterobifunctional PEG chains linker provided the most specific binding of SERS labels with an estimated NP count of 1.33x106 NPs on the whole tissue and produced the highest Raman scatter intensity of approximately 48600 counts.

  10. MAGE-A3 expression is an adverse prognostic factor in diffuse large B-cell lymphoma.

    PubMed

    Olarte, Irma; Martinez, Adolfo; Ramos-Peñafiel, Christian; Castellanos-Sinco, Humberto; Zamora, Jorge; Collazo-Jaloma, Juan; Gutiérrez, Mario; Gutiérrez-Kobeh, Laila; Chavez-Olmos, Pedro; Manzanilla, Hugo; Garrido-Guerrero, Efraín; Ordoñez-Razo, Rosa M; Miranda, Enrique I

    2011-11-01

    This study evaluates the prognostic value of MAGE-A3 expression in 28 diffuse large B-cell lymphoma (DLBCL) patients. A significant association was observed between MAGE-A3 expressions, assessed by quantitative real-time RT-polymerase chain reaction (PCR), with advanced stages of disease (P < 0.05). Elevated serum lactate dehydrogenase (LDH) levels and International Prognostic Index (IPI) score were significantly higher in MAGE-A3-positive patients (P = 0.025 and P = 0.004, respectively). Expression of MAGE-A3 was associated with poor response to treatment and a significantly shorter overall survival (P < 0.001). Our data address new information in the association of MAGE-A3 expression and poor prognosis in DLBCL patients. PMID:22183072

  11. Validity of reduced radiation dose for localized diffuse large B-cell lymphoma showing a good response to chemotherapy.

    PubMed

    Koiwai, Keiichiro; Sasaki, Shigeru; Yoshizawa, Eriko; Ina, Hironobu; Fukazawa, Ayumu; Sakai, Katsuya; Ozawa, Takesumi; Matsushita, Hirohide; Kadoya, Masumi

    2014-03-01

    To evaluate the validity of a decrease in the radiation dose for patients who were good responders to chemotherapy for localized diffuse large B-cell lymphoma (DLBCL), 91 patients with localized DLBCL who underwent radiotherapy after multi-agent chemotherapy from 1988-2008 were reviewed. Exclusion criteria were as follows: central nervous system or nasal cavity primary site, or Stage II with bulky tumor (≥10 cm). Of these patients, 62 were identified as good responders to chemotherapy. They were divided into two groups receiving either a higher or a lower radiation dose (32-50.4 Gy or 15-30.6 Gy, respectively). There were no statistically significant differences between the lower and higher dose groups in progression-free survival, locoregional progression-free survival or overall survival. Adaptation of decreased radiation dose may be valid for localized DLBCL patients who show a good response to chemotherapy. PMID:24187329

  12. MUM-1 and bcl-2 Positive Primary Diffuse Large B Cell Non-Hodgkin's Lymphoma of the Colon.

    PubMed

    Jurisić, Vladimir; Plećić, Mirjana; Colović, Natasa; Čemerikić-Martinović, Vesna; Janković, Marko; Čolović, Milica

    2016-04-01

    Primary diffuse large B cell lymphoma (DLBCL) presents as a nodal and extranodal disease. The most common extranodal site is the gastrointestinal tract (GI), with the stomach most frequently involved, followed by the small bowel. Primary DLBCL of the large bowel accounts for 0.2%-1.2% of all colonic tumors. We present two patients who underwent radical resections of right colonic tumors. They were diagnosed with primary colonic DLBCL following histological and immunohistochemical testing of the excised tissues, and were determined as being in stage IIE of the disease. The tumors expressed CD20 markers. Both received multi-agent chemotherapy with combined immunotherapy and remain in complete remission at 4 and 5 years. PMID:27041528

  13. Primary diffuse large B-cell lymphoma of the central nervous system: A case report and literature review

    PubMed Central

    CHEN, DAWEI; GU, WEIHONG; LI, WENZHONG; LIU, XIAOLIANG; YANG, XIAOYU

    2016-01-01

    The present study reports the clinical diagnosis and management of a patient with primary diffuse large B-cell lymphoma (Bcl) of the central nervous system (CNS). Making an early diagnosis of primary diffuse large Bcl is challenging due to the variable and complicated clinical manifestations of the disease. The relevant literature was reviewed, and high-dose methotrexate, whole brain radiotherapy and highly active antiretroviral therapy was recommended for the patient. The present study elucidates the role of positron emission tomography-computed tomography scans for the diagnosis and management of primary diffuse large Bcl of the CNS, and demonstrates the importance of resection surgery in the management of the disease. Specifically, the present study proposes that resection surgery may be applied in the early stages of disease for patients with a single occupied lesion and increased intracranial pressure. PMID:27123068

  14. Prediction of survival of diffuse large B-cell lymphoma patients via the expression of three inflammatory genes.

    PubMed

    Zhao, Shuangtao; Bai, Nan; Cui, Jianlin; Xiang, Rong; Li, Na

    2016-08-01

    Currently, several gene-expression signatures that were used to predict survival of diffuse large B-cell lymphoma (DLBCL) patients, showed a restriction on the practical work for lack of convenient operation. In this study, we screened inflammatory genes whose expression correlated with survival of DLBCL and established a predictive model including IL6, IL1A and CSF3 through multivariate Cox regression based on the expression of these three genes. We validated the model at protein level in our clinical serum cohort composed of 101 patients of DLBCL and 50 healthy controls and 534 DLBCL patients at mRNA level from three independent Gene Expression Omnibus (GEO) data sets. We found our model to be independent of the International Prognostic Index (IPI), moreover, it can augment the predictive power of IPI. In summary, our three-gene model is sufficient to predict survival of DLBCL patients via measuring the concentration of three inflammatory cytokines in peripheral blood. PMID:27394196

  15. Ground-glass opacities and a solitary nodule on chest in intravascular large B-cell lymphoma

    PubMed Central

    Katayama, Kumiko; Tomoda, Koichi; Ohya, Takahiro; Asada, Hideo; Ohbayashi, Chiho; Kimura, Hiroshi

    2015-01-01

    A 74-year-old woman presented with dyspnea on exertion and nocturnal cough. Chest computed tomography (CT) revealed scattered bilateral ground-glass opacities without a zonal dominance. Bronchoalveolar lavage elicited increased lymphocytes, but transbronchial lung biopsies were not performed because of hypoxemia during the examination. She received steroid therapy because of her subsequent worsening respiratory condition, but her condition continued to deteriorate. The ground-glass opacities partially consolidated with the appearance of new ground-glass opacities and a nodular shadow. Hepatosplenomegaly was observed on CT while soluble interleukin-2 receptor was elevated. A biopsy of a Campbell de Morgan spot of the trunk yielded a diagnosis of intravascular large B-cell lymphoma. There was marked clearing of the pulmonary infiltrates and significant symptomatic improvement in response to systemic chemotherapy. PMID:26392859

  16. Rare manifestation of the thrombotic microangiopathy in a patient with sarcoidosis, common variable immunodeficiency and large B-cell non-hodgkin lymphoma: case report.

    PubMed

    Ekart, Robert; Grobelšek, Vesna Kovačič; Dai, Klara; Cernelč, Peter; Hojs, Radovan

    2013-06-01

    58-year old Caucasian woman was diagnosed with sarcoidosis. Low immunoglobulin levels were found and common variable immunodeficiency (CVID) was diagnosed 1year later. Laboratory tests and clinical course at this time revealed thrombotic microangiopathy (TMA). Therapeutic plasma exchange was started and her clinical status and laboratory parameters improved. According to CVID she received human immunoglobulin intravenously. Four months later we noticed swelling of the parotid glands and generalized lymphadenopathy. Histology of cervical lymph node confirmed large B-cell non-Hodgkin lymphoma (B-cell NHL). To the best of our knowledge, TMA complicating the course of sarcoidosis, CVID and B-cell NHL has never been reported. PMID:23619325

  17. Extracorporeal Membrane Oxygenation as a Bridge through Chemotherapy in B-Cell Lymphoma.

    PubMed

    Worku, Berhane; DeBois, William; Sobol, Irina; Gulkarov, Iosif; Horn, Evelyn M; Salemi, Arash

    2015-03-01

    A 41-year-old female presented with a large anterior mediastinal mass adjacent to the heart. Biopsy demonstrated lymphoma. Upon administration of chemotherapy, she developed cardiogenic shock requiring a 5-day course of extracorporeal membrane oxygenation (ECMO) as a bridge through her treatment. After one cycle of chemotherapy, ECMO was discontinued and the patient completed her course of chemotherapy and recovered to hospital discharge. PMID:26390681

  18. Extracorporeal Membrane Oxygenation as a Bridge through Chemotherapy in B-Cell Lymphoma

    PubMed Central

    Worku, Berhane; DeBois, William; Sobol, Irina; Gulkarov, Iosif; Horn, Evelyn M.; Salemi, Arash

    2015-01-01

    Abstract: A 41-year-old female presented with a large anterior mediastinal mass adjacent to the heart. Biopsy demonstrated lymphoma. Upon administration of chemotherapy, she developed cardiogenic shock requiring a 5-day course of extracorporeal membrane oxygenation (ECMO) as a bridge through her treatment. After one cycle of chemotherapy, ECMO was discontinued and the patient completed her course of chemotherapy and recovered to hospital discharge. PMID:26390681

  19. Machine Learning-based Classification of Diffuse Large B-cell Lymphoma Patients by Their Protein Expression Profiles

    PubMed Central

    Deeb, Sally J.; Tyanova, Stefka; Hummel, Michael; Schmidt-Supprian, Marc; Cox, Juergen; Mann, Matthias

    2015-01-01

    Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples. Shotgun proteomic analysis on a quadrupole Orbitrap quantified almost 9,000 tumor proteins in 20 patients. The quantitative accuracy of our approach allowed the segregation of diffuse large B-cell lymphoma patients according to their cell of origin using both their global protein expression patterns and the 55-protein signature obtained previously from patient-derived cell lines (Deeb, S. J., D'Souza, R. C., Cox, J., Schmidt-Supprian, M., and Mann, M. (2012) Mol. Cell. Proteomics 11, 77–89). Expression levels of individual segregation-driving proteins as well as categories such as extracellular matrix proteins behaved consistently with known trends between the subtypes. We used machine learning (support vector machines) to extract candidate proteins with the highest segregating power. A panel of four proteins (PALD1, MME, TNFAIP8, and TBC1D4) is predicted to classify patients with low error rates. Highly ranked proteins from the support vector analysis revealed differential expression of core signaling molecules between the subtypes, elucidating aspects of their pathobiology. PMID:26311899

  20. Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma.

    PubMed

    Lock, Frances E; Rebollo, Rita; Miceli-Royer, Katharine; Gagnier, Liane; Kuah, Sabrina; Babaian, Artem; Sistiaga-Poveda, Maialen; Lai, C Benjamin; Nemirovsky, Oksana; Serrano, Isabel; Steidl, Christian; Karimi, Mohammad M; Mager, Dixie L

    2014-08-26

    Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients. PMID:25114248

  1. Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma

    PubMed Central

    Lock, Frances E.; Rebollo, Rita; Miceli-Royer, Katharine; Gagnier, Liane; Kuah, Sabrina; Babaian, Artem; Sistiaga-Poveda, Maialen; Lai, C. Benjamin; Nemirovsky, Oksana; Serrano, Isabel; Steidl, Christian; Karimi, Mohammad M.; Mager, Dixie L.

    2014-01-01

    Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients. PMID:25114248

  2. Machine Learning-based Classification of Diffuse Large B-cell Lymphoma Patients by Their Protein Expression Profiles.

    PubMed

    Deeb, Sally J; Tyanova, Stefka; Hummel, Michael; Schmidt-Supprian, Marc; Cox, Juergen; Mann, Matthias

    2015-11-01

    Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples. Shotgun proteomic analysis on a quadrupole Orbitrap quantified almost 9,000 tumor proteins in 20 patients. The quantitative accuracy of our approach allowed the segregation of diffuse large B-cell lymphoma patients according to their cell of origin using both their global protein expression patterns and the 55-protein signature obtained previously from patient-derived cell lines (Deeb, S. J., D'Souza, R. C., Cox, J., Schmidt-Supprian, M., and Mann, M. (2012) Mol. Cell. Proteomics 11, 77-89). Expression levels of individual segregation-driving proteins as well as categories such as extracellular matrix proteins behaved consistently with known trends between the subtypes. We used machine learning (support vector machines) to extract candidate proteins with the highest segregating power. A panel of four proteins (PALD1, MME, TNFAIP8, and TBC1D4) is predicted to classify patients with low error rates. Highly ranked proteins from the support vector analysis revealed differential expression of core signaling molecules between the subtypes, elucidating aspects of their pathobiology. PMID:26311899

  3. Elevation of serum interleukins 8, 4, and 1β levels in patients with gastrointestinal low-grade B-cell lymphoma

    PubMed Central

    Miyata-Takata, Tomoko; Takata, Katsuyoshi; Toji, Tomohiro; Goto, Naoe; Kasahara, Senji; Takahashi, Takeshi; Tari, Akira; Noujima-Harada, Mai; Miyata, Takafumi; Sato, Yasuharu; Yoshino, Tadashi

    2015-01-01

    Proinflammatory cytokines that are produced by helper T cells (Th) regulate immune reactions, facilitate class switching of B cells, and prolong the lifespan of B and T cells. Eradication therapy using antibiotics is sometimes effective against gastrointestinal (GI) malignant lymphoma, suggesting that the tumor development or progression is affected by the inflammatory microenvironment. In the present study, serum samples from 148 patients with various subtypes of malignant lymphoma were tested for 11 proinflammatory Th1/Th2 cytokines. In the comparison by subtype or GI lesions, serum interleukin (IL)-8 (P = 6.7E−05), IL-4 (P = 7.5E−05), and IL-1β (P = 0.0043) levels showed significant differences among subtypes, being particularly elevated in follicular lymphomas (FL) and mucosa-associated lymphoid tissue (MALT) lymphomas. Serum IL-8 levels were elevated in GI-FL and MALT lymphomas, and serum IL-4 and IL-1 β levels were elevated in MALT lymphomas. These findings show that GI low-grade B-cell lymphoma could develop against the background of an inflammatory microenvironment. Thus, these cytokines may be useful as diagnostic markers and could provide new insights into tumor development. PMID:26674732

  4. Elevation of serum interleukins 8, 4, and 1β levels in patients with gastrointestinal low-grade B-cell lymphoma.

    PubMed

    Miyata-Takata, Tomoko; Takata, Katsuyoshi; Toji, Tomohiro; Goto, Naoe; Kasahara, Senji; Takahashi, Takeshi; Tari, Akira; Noujima-Harada, Mai; Miyata, Takafumi; Sato, Yasuharu; Yoshino, Tadashi

    2015-01-01

    Proinflammatory cytokines that are produced by helper T cells (Th) regulate immune reactions, facilitate class switching of B cells, and prolong the lifespan of B and T cells. Eradication therapy using antibiotics is sometimes effective against gastrointestinal (GI) malignant lymphoma, suggesting that the tumor development or progression is affected by the inflammatory microenvironment. In the present study, serum samples from 148 patients with various subtypes of malignant lymphoma were tested for 11 proinflammatory Th1/Th2 cytokines. In the comparison by subtype or GI lesions, serum interleukin (IL)-8 (P = 6.7E-05), IL-4 (P = 7.5E-05), and IL-1β (P = 0.0043) levels showed significant differences among subtypes, being particularly elevated in follicular lymphomas (FL) and mucosa-associated lymphoid tissue (MALT) lymphomas. Serum IL-8 levels were elevated in GI-FL and MALT lymphomas, and serum IL-4 and IL-1 β levels were elevated in MALT lymphomas. These findings show that GI low-grade B-cell lymphoma could develop against the background of an inflammatory microenvironment. Thus, these cytokines may be useful as diagnostic markers and could provide new insights into tumor development. PMID:26674732

  5. Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2016-08-01

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Recurrent 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

  6. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

    PubMed Central

    Hoellein, Alexander; Fallahi, Mohammad; Schoeffmann, Stephanie; Steidle, Sabine; Schaub, Franz X.; Rudelius, Martina; Laitinen, Iina; Nilsson, Lisa; Goga, Andrei; Peschel, Christian; Nilsson, Jonas A.; Cleveland, John L.

    2014-01-01

    Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCFSkp2-directed destruction of the Cdk inhibitor p27Kip1). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement. PMID:25143484

  7. 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

  8. 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

  9. Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death

    PubMed Central

    Clark, Mary C.; Pang, Mabel; Hsu, Daniel K.; Liu, Fu-Tong; de Vos, Sven; Gascoyne, Randy D.; Said, Jonathan

    2012-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and an aggressive malignancy. Galectin-3 (gal-3), the only antiapoptotic member of the galectin family, is overexpressed in DLBCL. While gal-3 can localize to intracellular sites, gal-3 is secreted by DLBCL cells and binds back to the cell surface in a carbohydrate-dependent manner. The major counterreceptor for gal-3 on DLBCL cells was identified as the transmembrane tyrosine phosphatase CD45. Removal of cell-surface gal-3 from CD45 with the polyvalent glycan inhibitor GCS-100 rende