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The most common non-Hodgkin lymphoma (NHL) subtype is diffuse large B-cell lymphoma (DLBCL). It accounts for roughly 30% of all cases of NHL affecting both nodal and extra nodal sites. There are molecular subtypes of DLBCL, germinal centre subtype (GCB), and activated B-cell (ABC), based on gene expression profiling (GEP), in accumulation to distinct morphological and clinicopathological subtypes. To prognosticate patients, the International Prognostication Index (IPI) and its variants are used. In ABC type DLBCL, limited stage disease is treated with a combination of abbreviated systemic chemotherapy (three cycles) and field radiation therapy. Although advanced stage disease is treated with a full course of chemotherapy as well as novel agents (Bortezomib, Ibrutinib, Lenalidomide). In this review study, we looked at the role of multiple aspects of genetic and microenvironment changes which have effects in DLBCL tumours.

Signet ring cell lymphoma is an exceedingly rare subtype of non-Hodgkin lymphoma that was originally thought to be a morphologic variant of follicular lymphoma. To date, 56 cases have been reported, with the majority occurring in lymph nodes and bone marrow. Herein, we report a case of a 37-year-old female who presented with a left inguinal mass and high suspicion of lymphoma that was rendered on MRI. A successful ultrasound-guided core biopsy was performed. Pathologic examination revealed a diffuse large B-cell lymphoma (DLBCL) with unique signet ring histology and post-germinal center phenotype. In-situ hybridization showed an isolated BCL-6 gene rearrangement and confirmed the absence of a double-hit phenotype. This case would be situated as the second case of activated B-cell (ABC) signet ring lymphoma and the first case to arise in this anatomic location. The patient recently initiated therapy with a standard six-cycle regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The most common non-Hodgkin lymphoma (NHL) subtype is diffuse large B-cell lymphoma (DLBCL). It accounts for roughly 30% of all cases of NHL affecting both nodal and extra nodal sites. There are molecular subtypes of DLBCL, germinal centre subtype (GCB), and activated B-cell (ABC), based on gene expression profiling (GEP), in accumulation to distinct morphological and clinicopathological subtypes. To prognosticate patients, the International Prognostication Index (IPI) and its variants are used. In ABC type DLBCL, limited stage disease is treated with a combination of abbreviated systemic chemotherapy (three cycles) and field radiation therapy. Although advanced stage disease is treated with a full course of chemotherapy as well as novel agents (Bortezomib, Ibrutinib, Lenalidomide). In this review study, we looked at the role of multiple aspects of genetic and microenvironment changes which have effects in DLBCL tumours. [ABSTRACT FROM AUTHOR]

Abstract Although primary pancreatic lymphoma is a rare cause of pancreatic mass, this diagnosis should be considered during work‐up. Furthermore, when adequate diagnostic material is available from biopsy, complete workup of the lymphoma, including not only type but also subtype when applicable, should be performed.

Background: F-box and WD repeat domain-containing 7 (Fbw7) is well known as a tumor suppressor and ubiquitin ligase which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 promotes apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. This study aimed to identify the mechanism of Fbw7-mediated aerobic glycolysis reprogramming in DLBCL. Methods: Expression levels of Fbw7 and Lactate Dehydrogenase A (LDHA) in human DLBCL samples were evaluated by immunohistochemistry. Crosstalk between Fbw7 and LDHA signaling was analyzed by co-immunoprecipitation, ubiquitination assay, western blotting and mRNA quanlitative analyses. In vitro and in vivo experiments were used to assess the effect of the Fbw7-mediated LDHA/lactate/miR-223 axis on DLBCL cells growth. Results: Fbw7 could interact with LDHA to trigger its ubiquitination and degradation. Inversely, lactate negatively regulated Fbw7 via trigging the expression of miR-223, which targeted Fbw7 3'-UTR to inhibit its expression. In vivo and in vitro experiments revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA's ubiquitination. Conclusions: We demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related aerobic glycolysis reprogramming in DLBCL. Our study uncovers a negative functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition. [ABSTRACT FROM AUTHOR]

BackgroundF-box and WD repeat domain-containing 7 (Fbw7) is well known as a tumor suppressor and ubiquitin ligase which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 promotes apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. This study aimed to identify the mechanism of Fbw7-mediated aerobic glycolysis reprogramming in DLBCL.MethodsExpression levels of Fbw7 and Lactate Dehydrogenase A (LDHA) in human DLBCL samples were evaluated by immunohistochemistry. Crosstalk between Fbw7 and LDHA signaling was analyzed by co-immunoprecipitation, ubiquitination assay, western blotting and mRNA quanlitative analyses. In vitro and in vivo experiments were used to assess the effect of the Fbw7-mediated LDHA/lactate/miR-223 axis on DLBCL cells growth.ResultsFbw7 could interact with LDHA to trigger its ubiquitination and degradation. Inversely, lactate negatively regulated Fbw7 via trigging the expression of miR-223, which targeted Fbw7 3’-UTR to inhibit its expression. In vivo and in vitro experiments revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA’s ubiquitination.ConclusionsWe demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related aerobic glycolysis reprogramming in DLBCL. Our study uncovers a negative functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition.

Although primary pancreatic lymphoma is a rare cause of pancreatic mass, this diagnosis should be considered during work‐up. Furthermore, when adequate diagnostic material is available from biopsy, complete workup of the lymphoma, including not only type but also subtype when applicable, should be performed. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 30 percent of all NHL cases, involving both nodal and extra-nodal sites. Apart from distinct morphological and clinicopathological subtypes, DLBCL can be dived into molecular subtypes, Germimal Centre Subtype (GCB) and Activated B-Cell (ABC) based on gene expression profiling. IPI (International Prognostication Index) and its variants are used to prognosticate the patients. Limited stage DLBCL is primarily treated with combined modality therapy consisting of abbreviated systemic chemotherapy (three cycles), and involved field radiation therapy, whereas advanced stage disease is treated with full course of chemotherapy with recommendation of addition of novel agents ( Bortezomib, Ibrutinib, Lenalidomide) in ABC type DLBCL.

Background: The ubiquitin-ligase Fbw7 acts as a tumor suppressor, targeting lots of proto-oncogenes for proteolysis. However, the exact role of Fbw7 in diffuse large B-cell lymphoma (DLBCL) development remains unclear. Methods: We evaluated Fbw7 expression in patient samples of DLBCL using munohistochemical staining. The effect of Fbw7 overexpression on cell viability and apoptosis was investigated using activated B-cell (ABC) like DLBCL cell lines. The mechanism of Fbw7 activity in DLBCL was investigated using immunoprecipitation, ubiquitination, western blot and qualitative analyses. Results: The non-germinal center B-cell-like subtype of DLBCL showed reduced Fbw7 expression compared with the germinal center B-cell (GBC) subtype, and low Fbw7 expression was associated with a worse prognosis. Fbw7 overexpression caused decreased cell viability and increased apoptosis rates in the ABC-DLBCL cell lines SU-DHL-2 and OCI-LY-3. Importantly, Stat3 and phospho-Stat3Tyr705 stability were reduced following Fbw7 overexpression in ABC-DLBCL cell lines. In HEK293T and SU-DHL-2 cells, we demonstrated that Fbw7 interacts with Stat3 and pStat3Tyr705 to regulate their ubiquitylation and degradation. Downstream anti-apoptotic target genes of activated Stat3, including Myc, Survivin, Mcl-1, Pim-1, Bcl-2 and Bcl-xl showed decreased mRNA expression following exogenous Fbw7 overexpression. The negative relationship between Fbw7 and pStat3Tyr705 levels was also confirmed in DLBCL patient samples. Conclusion: The ubiquitin-ligase Fbw7 mediates apoptosis through targeting Stat3 for ubiquitylation and degradation in ABC-DLBCL. Thus, our study may offer a promising approach for ABC-DLBCL therapy through Stat3 inhibition. [ABSTRACT FROM AUTHOR]

Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is an uncommon extranodal lymphoma that accounts for more than 95% of all the CNS lymphomas. Unlike its systemic/nodal counterpart, which is currently subtyped into cell-of origin (COO) subtypes, its feasibility and utility are largely debatable in PCNS-DLBCL., Objectives: To classify PCNS-DLBCL into COO-subtypes based on immunohistochemical algorithms by Hans and Choi and evaluate concordance between the two. A further aim is to investigate the clinicoradiological and histomorphological parameters of the subtypes thus obtained., Materials and Methods: As many as 143 cases of primary CNS lymphoma were evaluated by immunohistochemistry for CD10, BCL6, MUM1, GCET, and FOXP1 and based on which the said 143 cases were further classified into COO subtypes using Hans and Choi algorithms., Results: Mean age was 53.8 years with marginal male preponderance and predominantly centroblastic morphology (75.5%). CD 10 was positive in 8.9% of the cases, BCL6 in 58.6%, MUM1 in 89.9%, GCET in 32.9%, and FOXP1 in 79.5%. As much as 84.9% cases were of non-germinal center B-cell (GCB) subtype and 15.1% cases were of GCB subtype as determined based on Hans algorithm. Furthermore, 90.7% cases were of activated B-cell (ABC) subtype and 9.3% cases were of GCB subtype according to Choi algorithm. A 91.8% concordance was observed between Hans and Choi algorithms. Among the 6 discordant cases, 5 cases were subtyped as GCB by Hans and ABC by Choi and 1 case as ABC by Hans and GCB by Choi., Conclusion: Most of PCNS-DLBCLs are of non-GCB/ABC COO subtype, but inconsistences abound in the utility of IHC algorithms in PCNS-DLBCL COO subtypes., Competing Interests: None

Diffuse large B-Cell lymphoma (DLBCL) is one of the most common and aggressive subtypes of non-Hodgkin's lymphoma (NHL). Gene expression profiling (GEP) studies have identified at least two distinct molecular subtypes of DLBCL termed as germinal center B-cell (GCB) and activated B-cell (ABC). These molecular subtypes represent lymphomas that are driven by very different intracellular oncogenic signaling pathways which have prognostic value and could potentially be exploited for therapeutic benefit in future. There are other oncogenes, namely BCL-2, BCL-6 and MYC, which have been associated with the pathogenesis of DLBCL. Concurrent presence of two oncogenes is present in about 5% of DLBCL and it is termed "double hit lymphoma" (DHL). DHL are associated with an aggressive clinical course and do not respond well to the standard DLBCL immune-chemotherapy regimen, RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Other aggressive therapeutic approaches including autologous bone marrow transplant have not shown any survival benefit in this subgroup of DLBCL patients. New strategies in development to address this resistance in DHL include the regimen DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab). Recent studies have shown increased sensitivity of DHL to DA-EPOCH-R chemotherapy and will likely be the new standard of care in this subset of DLBCL patients in the future. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) infection substantially elevates diffuse large B-cell lymphoma (DLBCL) risk, but its impact on the distinct DLBCL subtypes defined by cell of origin is unclear. We compared DLBCL molecular characteristics and prognosis in 51 HIV-infected and 116 HIV-uninfected cases diagnosed during 1977-2003. Using immunohistochemistry to classify cell of origin based on the Tally algorithm, activated B-cell (ABC)-DLBCL was substantially more common in HIV-infected (83%) than in HIV-uninfected (54%) cases ( p < 0.001). Epstein-Barr virus (EBV) was detected in 63% of DLBCLs in HIV-infected cases, occurring almost exclusively in ABC-DLBCL (74% vs. 13% of germinal center B-cell [GCB]-DLBCL, p = 0.002), but was rarely detected in DLBCLs among HIV-uninfected cases (3%). Among HIV-uninfected cases, MYC/IgH [t(8;14)(q24;q32)] and IgH/BCL2 [t(14;18)(q32;q21)] translocations were significantly more common and BCL6/IgH [t(3;14)(q27;q32)] significantly less common in GCB-DLBCL than in ABC-DLBCL ( p = 0.010, < 0.001 and = 0.039, respectively). Among HIV-infected cases, translocations other than MYC/IgH [t(8;14)(q24;q32)] (21%) were rare (≤ 6%) and unrelated to cell of origin. ABC-DLBCL was associated with adverse overall survival compared with GCB-DLBCL regardless of HIV status ( pHIV-infected = 0.066; pHIV-uninfected = 0.038). Our data demonstrate key differences in the molecular characteristics, cell of origin and prognosis of DLBCL by HIV status in the pre-highly active antiretroviral therapy (HAART) and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma and responds to standard treatment with chemoimmunotherapy in most patients. Standard prognostic scoring systems such as the International Prognostic Index (IPI) are useful for risk stratification, but are unreliable in predicting outcomes in individual patients because of the biologic heterogeneity of this disease. Gene expression profiling has revealed molecular subtypes of DLBCL: those derived from the lymph node germinal center (GCB) and others derived from an activated B-cell (ABC). A third entity, primary mediastinal B-cell lymphoma (unclassifiable DLBCL), displays pathobiologic features distinct from ABC and GCB subtypes. Patients with ABC-DLBCL have inferior progression-free survival and overall survival relative to those with the GCB subtype. In conclusion, molecular subtyping is a powerful tool for discriminating cases of DLBCL into groups that display very disparate biology and clinical outcomes. Although immunohistochemistry (IHC)-based algorithms predict both the molecular subtype as defined by gene expression profiling and clinical outcomes with reasonable concordance, not all experienced centers have been able to reproduce these findings. As techniques to subclassify DLBCL become universally adopted, large prospective trials will be needed to confirm the benefit of therapy tailored to molecular subtype. [ABSTRACT FROM AUTHOR]

Most primary central nervous system lymphomas (PCNSL) occurring in immunocompetent patients are diffuse large B-cell lymphomas (DLBCL), characterized by poor prognosis. An activated B-cell (ABC) origin of PCNSL has been postulated based on bcl-6 and MUM-1 expression by majority of these tumors. ABC DLBCL has been functionally subdivided using gene expression profiling and immunohistochemical analysis into STAT3-high and STAT-3 low subsets. A potentially crucial difference between STAT3-high and STAT3-low ABC DLBCL is in the expression of bcl-2 family members. STAT3-high cases are generally bcl-2 low and STAT3-low cases show higher expression of bcl-2. Further mechanisms such as activation of nuclear factor-kappa B (NF-κB) activation seem to be responsible for upregulation of bcl-2 in ABC subtype of DLBCL with an adverse outcome. As deregulation of STAT-3 pathway is known to play a critical role in ABC DLBCL and majority of the PCNSL are of the ABC subtype we studied the immunohistochemical expression of STAT-3 proteins in PCNSL along with other traditional markers (CD10, bcl-6, MUM-1 and bcl-2) in 17 cases of PCNSL occurring in immunocompetent patients. Despite lack of STAT3 expression in all our cases, majority (70%) of the patients with bcl-2 positive PCNSL had an adverse outcome similar to that reported in systemic lymphomas of ABC subtype. Based on our observations we propose that PCNSL represents a distinct subset of ABC diffuse large B-cell lymphomas with low STAT3 expression and perhaps mechanisms other than interaction of STAT-3 and NF-κB pathways may play a role in upregulation of bcl-2 in PCNSL. To the best of our knowledge expression of STAT-3 protein in PCNSL which represents a distinct anatomical subset of ABC DLBCL with a dismal prognosis has not been studied before. [ABSTRACT FROM AUTHOR]

We evaluated the value of using a panel of GC B-cell (CD10 and Bcl-6) and activation (MUM1, CD138 and Bcl-2) markers by immunohistochemistry to define prognosis in patients with diffuse large B-cell lymphoma (DLBCL). Two different models (Hans’ and modified Chang’s model) were applied on 136 de novo DLBCL patients. Median follow-up in all patients was 39 months (range 5–80 months). According to Hans’ model, patients with GCB had much better overall survival (5-year OS, 75%) than those with non-GCB (5-year OS, 52%) (Kaplan-Meier survival analysis, P < 0.05, log rank test). According to modified Chang’s model, patients with group 1 had much better overall survival (5-year OS, 78%) than those with group 3 (5-year OS, 44%) while group 2 had no significant value compared with group 1 and group 3 in prognosis (Kaplan-Meier survival analysis, P < 0.05, log-rank test). Using multivariate Cox proportional hazards regression analysis, the international prognostic index scores (IPI), expression of CD138 and the expression pattern of modified Chang’s model were independent prognostic indicators. Our results suggest that the expression patterns of the panel of GCB-cell and activation markers by immunohistochemistry correlate with prognosis of patients with DLBCL and both models can be used well in ordinary work. [ABSTRACT FROM AUTHOR]

• Early relapse, failure to achieve complete remission after first-line chemotherapy, and high IPI score were associated with poor survival of the elderly DLBCL patients. • Median overall survival was nine months and median progression-free survival was 4.3 months for patients over the age of 65 who relapsed within 12 months. • Determination of the cell-of-origin had a prognostic impact in patients with DLBCL, however, the prognostic impact was observed in earlier studies before the rituximab era. Immunohistochemical cell origin did not affect survival depending on Hans algorithm in elderly patients in the current study. • R-CHOP is also the standard treatment compared with Non-R-CHOP in elderly patients with DLBCL. The best responses are obtained regardless of age by R-CHOP treatment in DLBCL patients. Diffuse large B cell lymphoma (DLBCL) has an increasing incidence in elderly patients with poorer prognosis than in younger patients. Clinicians should clearly identify the characteristics and prognostic factors of elderly patients. We analyzed the outcome of elderly DLBCL patients, especially factors affecting survival in real-life clinical practice. The data of 330 DLBCL patients at our center were retrospectively evaluated by dividing three groups; younger than 65 years, between 65–79 years, and 80 years and older. We examined the factors affecting survival in DLBCL patients ≥ 65 years old. The median age of the patients was 61 years (range 16–87). 192 (58.2 %) of our patients were younger than 65 years old, 112 (33.9 %) were between 65−79 years, and 26 (7.9 %) patients were 80 years old or older. The median follow-up was 15 (1–120) months. Median PFS was 38 months in the 65−79 years group, ten months in the ≥ 80 years group; meanwhile, median OS was 43 months in the 65−79 years group, 25 months in the ≥80 years group. The number of patients who relapsed within 12 months of the first-line treatment was 69 (35.9 %) in the <65 years group, it was 60 (53.6 %) in 65−79 years group, and 22 (84.6 %) in ≥80 years group (p < 0.001). The median OS was 9 (7.1–10.9) months in DLBCL patients older than 65 years old who relapsed within 12 months. Early relapse, failure to achieve CR after first-line chemotherapy, and high IPI score were associated with poor survival in patients ≥ 65 years old (p:0.001). Advancing age was a poor prognostic factor for survival of DLBCL. Relapsing within the first year, or failure to achieve complete remission were associated with poorer survival of the elderly DLBCL patients. R−CHOP is the standard treatment in DLBCL, and the best responses are obtained regardless of age. Due to difficulty in receiving standard treatments, novel treatment modalities are needed for better outcomes in elderly patients with DLBCL. [ABSTRACT FROM AUTHOR]

Summary: Diffuse large B-cell lymphoma (DLBCL) can be subdivided into prognostically significant groups with germinal center B-cell–like (GCB), activated B-cell–like (ABC), and type 3 groups. In this study, tissue microarray slides composed of 163 de novo DLBCLs from Chinese patients were immunostained for CD20, CD10, Bcl-6, MUM1, CD138, Bcl-2, Ki-67, cyclin D3, geminin, and P27Kip1. One hundred forty-nine of 163 DLBCLs could then be classified into GCB group (pattern A), activated GCB group (pattern B) and activated non-GCB group (pattern C) according to the expression of CD10, Bcl-6, MUM1, and CD138. Of the 149 cases, 40 (26%) showed pattern A expression and were grouped as GCB group, lower than reported frequency of the studies involving mostly Western population. Compared with cases with pattern A, those with pattern B (activated GCB group) and C (activated non-GCB group) more often presented with more aggressive tumors and a shorter survival time. These results indicate that most of DLBCLs from Chinese patients can be classified into prognostically different groups based on the antigenic expression models using a panel of GCB- and ABC-associated markers. Polymerase chain reaction analysis of t(14;18) showed that 11 of 64 cases were t(14;18)–positive, and most (10 of 11) of it occurred in the group with pattern A. The translocation was significantly associated with expression of Bcl-2 protein. The group with pattern B demonstrated more frequent expression of Ki-67, cyclin D3, geminin, and showed higher proliferative activity than the group with pattern A. These findings suggest that high proliferative activity of tumors with pattern B may be associated with aggressive tumor behavior and poor clinical outcome in patients with DLBCL. [Copyright &y& Elsevier]

Memory T-cells and activated B-cells were identified in cryostat sections of adult periodontitis (AP) lesions and categorized in terms of frequency and distribution. Nineteen periodontitis biopsies were obtained at the time of periodontal surgery to remove residual peridontal pockets following the completion of initial preparation. Gingival tissues exhibited various degree of inflammation (G1 of 0-2) but probing depths of > 4mm and > 5 mm loss of attachment. As a control, 5 gingivitis specimens (G1 of 1, probing depth and loss of attachment of ≤ mm) were obtained from premolar and third molar sites requiring extraction for either orthodontic treatment or pericoronitis. Serial cryostat sections (6 μm in thickness) were prepared from each biopsy, on which a double staining avidin-biotin immunoperoxidase and avidin-biotin alkaline phosphatase technique was used to identify CD4+, CD45RO + memory T-cells and activated CD19+ B-cells expressing CD23 or CD25, IN periodontitis lesions, the mean percentage of CD4+ cells expressing CD45RO was consistently high 965.9% in the crevicular (C) one-third (1/3), 61.2% in the middle (M) 1.3 and 62.5% in the oral (O) 1/3). This contrasts with the low mean percentage of CD4+, CD45RA+ naive T-cells (17.1% in the C 1/3, 14.8% in the M 1/3 and 12.4% in the O1/3). In gingivitis specimens, the incidence of CD4+, CD45 RO+ was 81.9% in the C 1/3, 81.1% in the M 1/3 and 89.0% in the O 1/3. This was higher than that of periodontitis biopsies. With CD4+, CD45RA+ the incidence was 10.0% in the C 1/3, 8.0% in the M 1/3, and 6.6% in the O 1/3 and the relationship to the periodontitis biopsies was reversed. However, the percentage of CD23+ and CD25+, CD19+ B-cells which were identified in 13 out of 19 samples from periodontitis varied significantly (0-100% for CD23, 0-36.2% for CD25) in spite of similar clinical status. The frequency of B-cells and activated B-cells in the gingivitis was much lower than that of periodontitis. These results indicate that both T-cells and B-cells were in active stage in periodontitis lesions. Differences of immunohistological features between gingivitis and periodontitis may be attributable to the heterogeneity of profiles of cytokine production by CD4+, CD45RO+ "memory" cells. [ABSTRACT FROM AUTHOR]

Background : Previous studies in Western populations, using immunohistochemistry (IHC) methods to subtype diffuse large B-cell lymphoma (DLBCL), suggest that germinal center B-cell lymphomas (GCBs) have improved outcomes. However, data in Asians have been limited and conflicting. This study aims to evaluate the prognostic impact of cell-of-origin (COO) subtyping by IHC and Lymph2Cx in South-East Asian (SEA) DLBCL patients, and to summarize the existing literature. Methods : A single-center retrospective analysis of 384 DLBCL patients diagnosed 2013-2018 who received Rituximab-based chemotherapy was performed. Hans and Lymph2Cx were used to assign COO and correlated with outcomes. Results : International Prognostic Index (IPI) score was associated with overall survival (OS) and progression-free survival (PFS). The 5-yr-OS for non-GCB versus GCB for COO by Hans was 70% versus 71% p =0.39, while 5-yr-OS for ABC versus GCB for COO by Lymph2Cx was 74% versus 92% p =0.19. The 5-yr-PFS for non-GCB versus GCB for COO by Hans was 65% versus 70% p =0.26, while 5-yr-PFS for ABC versus GCB for COO by Lymph2Cx was 64% versus 86% p =0.07. Conclusions : IPI is reaffirmed to be relevant in the rituximab era. COO by Hans has no prognostic significance, while subtyping by Lymph2Cx trends toward GCBs having better PFS and OS.

Lenalidomide has modest single-agent activity comparable with other newer drugs in recurrent diffuse large B cell lymphoma with response rates between 19% and 28%. Retrospective series and 1 prospective study suggest that clinically significant responses were predominantly limited to patients with activated B cell (ABC) lymphoma, a finding in agreement with lenalidomide's potent inhibition of nuclear factor κB, the key driver of ABC lymphomas. Recently completed trials will determine whether the additional use of lenalidomide with R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) enhances survival compared with R/CHOP alone and whether this activity is limited to ABC lymphomas. Lenalidomide also appears to have activity in the maintenance setting regardless of cell of origin and might play an important role in patients with recurrent disease who are not transplantation candidates. Similarly, because of the ability of lenalidomide to cross the blood-brain barrier, it needs to be further explored in patients with high risk for central nervous system spread. The results of lenalidomide combination studies with chemotherapy and with checkpoint inhibitors are eagerly awaited., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The ubiquitin-ligase Fbw7 acts as a tumor suppressor, targeting lots of proto-oncogenes for proteolysis. However, the exact role of Fbw7 in diffuse large B-cell lymphoma (DLBCL) development remains unclear., Methods: We evaluated Fbw7 expression in patient samples of DLBCL using immunohistochemical staining. The effect of Fbw7 overexpression on cell viability and apoptosis was investigated using activated B-cell (ABC) like DLBCL cell lines. The mechanism of Fbw7 activity in DLBCL was investigated using immunoprecipitation, ubiquitination, western blot and qualitative analyses., Results: The non-germinal center B-cell-like subtype of DLBCL showed reduced Fbw7 expression compared with the germinal center B-cell (GBC) subtype, and low Fbw7 expression was associated with a worse prognosis. Fbw7 overexpression caused decreased cell viability and increased apoptosis rates in the ABC-DLBCL cell lines SU-DHL-2 and OCI-LY-3. Importantly, Stat3 and phospho-Stat3 Tyr705 stability were reduced following Fbw7 overexpression in ABC-DLBCL cell lines. In HEK293T and SU-DHL-2 cells, we demonstrated that Fbw7 interacts with Stat3 and pStat3 Tyr705 to regulate their ubiquitylation and degradation. Downstream anti-apoptotic target genes of activated Stat3, including Myc, Survivin, Mcl-1, Pim-1, Bcl-2 and Bcl-xl showed decreased mRNA expression following exogenous Fbw7 overexpression. The negative relationship between Fbw7 and pStat3 Tyr705 levels was also confirmed in DLBCL patient samples., Conclusion: The ubiquitin-ligase Fbw7 mediates apoptosis through targeting Stat3 for ubiquitylation and degradation in ABC-DLBCL. Thus, our study may offer a promising approach for ABC-DLBCL therapy through Stat3 inhibition.