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We conducted a multi-institutional retrospective study in 100 transplant-ineligible (TI) patients with diffuse large B-cell lymphoma (DLBCL) that relapsed or progressed after first-line R-CHOP (or -like) therapy to develop a robust predictive model for TI relapsed/refractory (r/r) DLBCL, which has a heterogeneous but poor prognosis by currently available treatment modalities other than chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. The median age at relapse or progression was 76 years. The median progression-free survival (PFS) and overall survival (OS) from the first progression were 11.5 months and 21.9 months, respectively. Multivariate analysis identified low lymphocyte-to-monocyte ratio (LMR), elevated high lactate dehydrogenase, and elevated C-reactive protein at progression as independent predictors of OS. A predictive model based on these three factors, here designated as the Kyoto Prognostic Index for r/r DLBCL (KPI-R), successfully stratified their OS and PFS with statistical significance. In addition, event-free survival less than 24 months for R-CHOP and low LMR were identified as significant predictive factors for non-response in any sequence of salvage therapy. We concluded that LMR is a bonafide predictor of treatment response and prognosis in patients with TI r/r DLBCL, and may be helpful in treatment decision-making. [ABSTRACT FROM AUTHOR]

Aortitis is a rare adverse event of granulocyte colony-stimulating factor (G-CSF) treatment. Several previous studies have described recurrent aortitis caused by re-administration of the same G-CSF. However, no previous studies have examined the safety of switching between short-acting G-CSFs in patients who develop aortitis. We report the case of a 55-year-old man with refractory diffuse large B-cell lymphoma, who developed G-CSF-associated aortitis. The aortitis was triggered by filgrastim and recurred after treatment with lenograstim. The patient possessed human leukocyte antigen B52, which has been implicated in Takayasu arteritis. In addition, a drug-induced lymphocyte stimulation test for lenograstim performed upon detection of recurrent G-CSF-associated aortitis produced a positive result. Our case suggests that switching from one short-acting G-CSF to another does not prevent recurrence of G-CSF-associated aortitis. Although the etiology of G-CSF-associated aortitis has not been fully elucidated, our case also suggests that some patients may be genetically predisposed to aortitis. [ABSTRACT FROM AUTHOR]

The efficacy of high-dose methotrexate (HD-MTX) for central nervous system (CNS) relapse prophylaxis in patients with high-risk diffuse large B-cell lymphoma (DLBCL) is controversial. We compared the prophylactic effects of HD-MTX and intrathecal methotrexate (IT-MTX) on CNS relapse in high-risk DLBCL, in a multicenter retrospective study. A total of 132 patients with DLBCL at high risk of CNS relapse who received frontline chemotherapy and IT-MTX from 2003 to 2013 (n = 34) or HD-MTX from 2014 to 2020 (n = 98) were included. After a median follow-up of 52 months (range: 9–174), 11 patients had isolated CNS relapse: six (6.1%) in the HD-MTX group and five (14.7%) in the IT-MTX group. The median time until CNS relapse was 38 months (range: 11–122), and the cumulative incidence of CNS relapse at 3 years was 3.9% in the HD-MTX group and 6.1% in the IT-MTX group (P = 0.93). Similar results were obtained after adjusting for background factors using propensity score-matched analysis (4.5% HD-MTX vs. 7.6% IT-MTX, P = 0.84). The CNS relapse rate in HD-MTX-treated patients was equivalent to that in IT-MTX patients, demonstrating that HD-MTX was not superior to IT-MTX in preventing CNS relapse. [ABSTRACT FROM AUTHOR]

Patient-derived xenograft (PDX) mouse models are useful for deepening our understanding of the biology of malignant lymphoma; however, factors associated with the success of the PDX lymphoma model are largely unknown. We retrospectively analyzed the characteristics of 66 xenotransplantations from 65 patients. In all, 43 (65%) specimens were obtained from patients aged > 60 years, and 42 (64%) specimens were obtained at diagnosis. Specimens were obtained from patients with the following diseases: diffuse large B-cell lymphoma (n = 30), intravascular large B-cell lymphoma (n = 12), follicular lymphoma (n = 8), peripheral T-cell lymphoma (n = 7), mantle cell lymphoma (n = 2), and other (n = 7). The specimens were sourced mainly from bone marrow (n = 31, 47%) and extranodal tumors (n = 13, 20%). Engraftment was successful in 33/66 (50%) xenotransplantations. The median age of patients who provided successful specimens was significantly higher than that for unsuccessful specimens (p = 0.013). Specimens with a high proportion of tumor cells in the graft and those obtained from patients with relapsed/refractory disease showed higher tendencies toward successful engraftment. Taken together, these data suggest that tumor cells with a highly malignant potential might have a high likelihood of engraftment. [ABSTRACT FROM AUTHOR]

We aimed to assess HKII expression and its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. The HKII protein level was determined by immunohistochemistry in 159 newly diagnosed DLBCL patients, and its relationship with overall response rate, progression-free survival (PFS), and overall survival (OS) was analyzed. HKII was expressed in 95 DLBCL patients (59.7%). HKII-positive patients had poorer outcomes than negative patients for 5-y PFS (68% vs. 84%, p = 0.029) and 5-y OS (78% vs. 94%, p = 0.05). When only patients without no bulky disease, B symptoms, or extranodal involvement who had low IPI scores were considered, those with positive HKII had worse 5y-PFS and 5y-OS (p < 0.05). Multivariate analysis indicated that HKII status was an independent prognostic factor of OS. In subgroup analysis, HKII expression was associated with inferior OS in the CHOP group (p = 0.017). In CHOP group patients without bulky disease or extranodal involvement who had low LDH and low IPI scores (p < 0.05), positive HKII was associated with worse PFS and OS. No differences in PFS and OS, or any independent prognostic factors, were found in the RCHOP group. In DLBCL, HKII is valuable as a prognostic biomarker and may be useful as a tool for assessing disease risk. [ABSTRACT FROM AUTHOR]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R2-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2–82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction. [ABSTRACT FROM AUTHOR]

Initial staging by positron emission tomography/computed tomography (PET/CT) scanning is recommended for patients with diffuse large B-cell lymphoma (DLBCL). Whether both PET/CT and bone marrow biopsy (BMB) are required remains unclear. This study examined whether staging by PET/CT is sufficient. Participants with untreated DLBCL assessed using both PET/CT and BMB were included. Patients received independent diagnostic assessments from a radiologist and a hematopathologist. Both hematoxylin–eosin staining and CD20 immunostaining were performed to determine the bone marrow involvement in BMB. A total of 84 patients were included. The number of patients with positive bone marrow involvement identified by PET/CT and BMB was 16 (19%) and 22 (26%), respectively. Eight (10%) patients showed positive results in both tests. When considering BMB as a reference, PET/CT showed 36% sensitivity and 87% specificity, with positive and negative predictive values of 50% and 79%, respectively. BMB-positive patients had shorter progression-free (PFS) and overall (OS) survival than their BMB-negative counterparts. Compared to PET/CT-negative patients, patients with positive results did not show any significant differences in PFS and OS. However, among 16 PET/CT-positive patients, poor PFS and OS were observed among patients who were also BMB positive. BMB remains a mandatory step in staging of untreated DLBCL patients. [ABSTRACT FROM AUTHOR]

The incidence and clinical characteristics of histological transformation (HT) from duodenal type follicular lymphoma (DFL) are unclear. A retrospective analysis was conducted to identify the incidence and clinical features of HT from DFL in 23 cases with DFL. The median follow-up duration was 4.6 years (range, 0.8–20 years). HT to diffuse large B-cell lymphoma was observed in 2 of 23 cases during follow-up (8.7%). One of two cases transformed at 21 months later with increased serum lactate dehydrogenase (LDH; 1655 U/L) and abdominal lymphadenopathy. Partial response was achieved after R-THP (pirarubicin)-COP therapy, but the disease progressed. The other case transformed at 8.3 years with an increase of serum LDH (4022 U/L), abdominal lymphadenopathy, and bone marrow involvement. The disease was refractory to DA-EPOCH-R and a high-dose methotrexate/cytarabine regimen. The patient received allogenic peripheral blood stem cell transplantation and finally achieved complete response. Both cases developed HT at nodal or other intestinal lesions with no progression of the primary duodenal lesion. No significant factors for the occurrence of HT were identified. Although the incidence is low, HT could occur in DFL with aggressive clinical manifestations. [ABSTRACT FROM AUTHOR]

Previous studies showed albumin at diagnosis could be used to predict outcome in patients with diffuse large B-cell lymphoma (DLBCL), but whether albumin could improve the international prognostic index (IPI) risk stratification remains unknown. Herein, we retrospectively analyzed 440 de novo DLBCL patients in this study. The cutoff value of albumin was 39.2 g/L. Patients with high serum albumin showed superior OS and PFS (p = 0.002 and p < 0.001, respectively). According to IPI, there were 163 patients (37.0%) in low-risk group, 107 (24.3%) in low-intermediate risk group, 114 (25.9%) in high-intermediate risk group and 56 (12.7%) in high-risk group. Further analysis showed high albumin could identify a subgroup of patients with extremely superior OS and PFS in low IPI risk patients (p = 0.022 and p = 0.034, respectively). Multivariate analysis revealed that high albumin was an independent prognostic factor for OS (relative ratio [RR] 0.122; 95% confidence interval [CI] 0.021-0.715, p = 0.020) and trend for PFS (RR 0.417; 95% CI 0.168-1.035, p = 0.059). In conclusion, our study suggests that albumin at diagnosis is a simple and effective prognostic factor in DLBCL patients, allowing the identification of a superior outcome subgroup in low-risk patients, which may help to guide treatment in clinical trial. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the value of scheduled imaging for patients who achieved first complete remission after CHOP-like chemotherapy plus rituximab. In this retrospective cohort study, we included 759 patients newly diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) at the Cancer Institute, Japanese Foundation for Cancer Research. Relapsed patients were divided into two groups based on method of diagnosis: clinical symptoms (symptom group, n = 57) or scheduled imaging (imaging group, n = 27). Our primary goal was to compare overall survival and relapse-free survival between the two groups. No significant difference in outcomes was found between the symptom and imaging groups. Median overall survival [7.5 years; 95% confidence interval (CI) 4.0-9.7 vs. 9.1 years; 95% CI 2.7 to not reached; P = 0.747), and median relapse-free survival (1.8 years; 95% CI 1.4-2.5 vs. 2.4 years; 95% CI 1.2-4.4; P = 0.108). Surveillance imaging in patients with DLBCL who achieved first complete remission did not demonstrate an advantage in terms of overall survival or relapse-free survival. [ABSTRACT FROM AUTHOR]

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted. [ABSTRACT FROM AUTHOR]

Treating patients with DLBCL remains a challenge, as the response to first-line immunochemotherapy is somewhat unpredictable. The International Prognostic Index (IPI) is one of the most widely used methods for assessing prognosis. Interim PET/CT (iPET/CT) can play an important role in the early identification of 'non-responder' patients before the end of treatment examination. In this study, we retrospectively analyzed 104 newly diagnosed DLBCL patients treated with R-CHOP-like regimens who underwent iPET/CT imaging during therapy. There was a significant difference in 2-year OS between patients with negative iPET/CT and those with positive iPET/CT. Patients who had positive iPET/CT showed inferior 2-year PFS compared to those with negative iPET/CT. According to IPI, there was a statistically significant difference in 2-year OS and PFS between patients in the lower and higher risk groups. However, these patients can be further subdivided according to iPET/CT. The iPET/CT results in the present study clearly separate good- and poor-prognosis patients according to differences in 2-year OS, both in the lower and higher IPI risk groups. These results are in agreement with those of previous studies that demonstrated that iPET/CT has high negative predictive value, clearly identifying good-prognosis patients even within the poor-prognosis IPI group. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy of systemic high-dose methotrexate (HD-MTX) for CNS prophylaxis in a prospectively recruited cohort of DLBCL patients at high risk of CNS relapse. High-risk CNS relapse was defined as the involvement of ≥ 2 extranodal sites with elevated lactate dehydrogenase (LDH); CNS international prognostic index (CNS-IPI) ≥ 4; or involvement of high-risk extranodal sites, including bone marrow, breasts, testes, and paranasal sinuses. Overall, 130 patients who received at least two cycles of standard chemoimmunotherapy were evaluated; of these, 64 patients received additional systemic HD-MTX, either on day 15 of alternating cycles or 2-5 weeks after completion of primary therapy. Patients receiving HD-MTX showed a generally higher risk of CNS relapse than the other 66 patients not receiving prophylaxis. The estimated 2-year cumulative CNS relapse, progression-free survival and overall survival rates were 8.1%, 66.3%, and 77.5%, respectively, in patients who received systemic HD-MTX and 6.9%, 67.4%, and 71.4%, respectively, in patients without prophylaxis, with no significant between-group differences. Although this study does not show that systemic HD-MTX is definitively effective, these results may be of help to other researchers investigating the utility of HD-MTX prophylaxis in mitigating negative risk factors. [ABSTRACT FROM AUTHOR]

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16-39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40-60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40-60, 61-79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults. [ABSTRACT FROM AUTHOR]

Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been recommended as a complementary tool for the staging of various malignancies, including malignant lymphoma. PET findings often shift patients to higher stages and may affect treatment outcomes. In this study, we retrospectively compared staging and treatment outcomes of newly diagnosed diffuse large B-cell lymphoma (DLBCL) assessed by PET (n = 153) or gallium-67 scintigraphy (Ga) (n = 95). In total, Ga upstaged two (2.1%) of 95 patients, whereas PET upstaged 13 (8.5%) of 153 patients. Bone/bone marrow (15 vs. 4%, P = 0.01) and muscle lesion (5 vs. 0%, P = 0.03) were identified more frequently in the PET group than in the Ga group. The estimated 3-year overall and progression-free survival rates did not differ significantly in the two groups at any stage. However, patients with stage III disease tended to have better progression-free survival in the PET group than in the Ga group [92.3 (95% CI 56.6-98.9%) vs. 58.3% (95% CI 27.0-80.1%), P = 0.086]. These results suggest that PET has a greater potential in detecting musculoskeletal lesions of DLBCL as extranodal lesions than Ga, and may contribute to the optimal staging. [ABSTRACT FROM AUTHOR]

IKZF1 encodes a transcription factor involved in B-cell maturation and differentiation. We genotyped 218 diffuse large B-cell lymphoma (DLBCL) patients and 715 unrelated controls using a TaqMan allelic discrimination assay. No statistical difference was observed in the genotype distribution of the IKZF1 rs4132601 polymorphism between DLBCL patients and controls. However, the 2-year PFS rate of patients with the IKZF1 TT genotype was 54.3% compared to 68.6% in those with the IKZF1 G+ genotypes. Moreover, the IKZF1 rs4132601 polymorphism retained its independent prognostic impact on PFS. A more pronounced effect of the IKZF1 TT genotype on PFS was detected in patients with low/intermediate low IPI-risk group. When analysis was restricted to patients with GCB-type pattern, those with the IKZF1 TT genotype achieved a lower 5-year OS rate than the patients with the IKZF1 G+ genotypes (19.6 vs. 56%). This study provides the first evidence for the association of IKZF1 variants with DLBCL outcome. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that negatively regulates TGF-β signaling. CD109 was originally identified in hematopoietic tumors; however, the significance of CD109 in hematopoietic malignancies remains unclear. Here, we study the association of CD109 with diffuse large B-cell lymphoma (DLBCL) prognosis. Eighty-four DLBCL specimens were immunohistochemically analyzed for CD109 expression, and 31 and 53 cases were classified into low- and high-CD109 expression groups, respectively. CD109 expression was not associated with overall survival using the Kaplan-Meier analysis and log-rank tests (P = 0.17); however, a significant association was observed between high-CD109 expression and low-1-year survival (P = 0.01). Moreover, in combination with the revised International Prognostic Index (R-IPI), R-IPI-poor/CD109-high was associated with poorer prognosis compared with R-IPI-poor alone. We assessed TGF-β signaling in CD109-depleted Nalm6 cells (a human B-lymphoblastic leukemia/lymphoma cell line), and found prolonged Smad2 phosphorylation compared with control cells after TGF-β1 stimulation, suggesting that CD109 attenuates TGF-β1 signaling in human B-cell tumors. These results suggest that CD109 is a putative biomarker for identifying a high-risk group among DLBCL patients. [ABSTRACT FROM AUTHOR]

Prognostic nutritional index (PNI), based on serum albumin concentration and the absolute peripheral lymphocyte count, has been used to predict survival in various tumors. Whether PNI can predict prognosis in patients with diffuse large B-cell lymphoma (DLBCL) remains unknown. We retrospectively analyzed 253 patients with newly diagnosed DLBCL in the present study. The PNI was calculated as: albumin (g/L) + 5 × total lymphocyte count × 10(9)/L. All patients were divided in low and high groups according to the analysis of receiver operating characteristic (ROC) curve. Low PNI was associated with more unfavorable clinical features (p < 0.05). Patients with low PNI tended to have worse event-free survival (EFS) and overall survival (OS) (EFS, p = 0.001; OS, p < 0.001). For patients treated with R-CHOP, PNI proved to be predictive for survival (EFS, p = 0.001; OS, p < 0.001), while no significant effect was found in DLBCL patients who received CHOP chemotherapy (EFS, p = 0.496; OS, p = 0.125). Multivariate analysis showed that low PNI is an independent adverse predictor of OS and EFS, especially in DLBCL patients treated with R-CHOP. In conclusion, this study suggests that PNI is an effective prognostic factor in DLBCL patients treated with R-CHOP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15-60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Secondary central nervous system (CNS) involvement is a fatal complication of diffuse large B-cell lymphoma (DLBCL). We evaluated the efficacy and feasibility of high-dose chemotherapy containing busulfan and thiotepa followed by autologous stem cell transplantation (HDC-ASCT) in DLBCL with secondary CNS involvement. Thirty-one patients with secondary CNS involvement including CNS involvement at diagnosis (n = 9), isolated CNS relapse (n = 14), and CNS involvement with systemic disease progression or relapse (n = 8) were selected and analyzed from our prospective cohorts. Of these, 12 patients, including seven with isolated CNS relapse, successfully completed HDC-ASCT without engraftment failure or transplantation-related mortality. After ASCT, six patients were alive; however, three patients experienced post-transplantation relapse. With a median follow-up of 29 months after secondary CNS involvement, the median overall survival of 31 patients was 9 months (95% CI 5–12 months). The survival outcomes of patients who had undergone HDC-ASCT were significantly better than those of patients who did not (p < 0.01). Accordingly, patients with isolated CNS relapse tended to have a longer survival outcome than other cases. Our results suggest that HDC-ASCT may provide survival benefits in DLBCL patients with secondary CNS involvement, especially in case of isolated CNS relapse. [ABSTRACT FROM AUTHOR]

REV7 is a multifunctional protein involved in DNA damage tolerance, cell-cycle regulation, gene expression, and carcinogenesis. Although its expression is reportedly associated with poor prognosis in human solid tissue cancers, the significance of REV7 expression in hematopoietic malignancies is unclear. This study evaluated the prognostic significance of REV7 expression in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-combined chemotherapy. Using immunohistochemistry, we analyzed 83 specimens of de novo DLBCL [38 germinal center B-cell-like (GCB) and 45 non-GCB DLBCLs] treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone for REV7 expression. Aberrant REV7 expression was detected in DLBCL cell nuclei. High REV7 expression was associated with significantly shorter overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis and log-rank tests (P < 0.01 and P < 0.01, respectively). Multivariate analysis revealed that REV7 expression is an independent prognostic factor for both OS and PFS. Additionally, when patients were divided into four groups using a combination of REV7 expression and international prognostic index (IPI) or Bcl-2 expression, REV7(High)/IPI(Poor) and REV7(High)/Bcl-2(High) patients showed the poorest outcome. These results indicate that REV7 may be a useful biomarker to predict the prognosis of patients with DLBCL treated with rituximab. [ABSTRACT FROM AUTHOR]

Secondary non-Hodgkin lymphoma following acute myeloid leukemia (AML) is extremely rare. We here describe a unique case involving a patient who developed Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) during complete remission (CR) of AML. A 75-year-old Japanese man was initially diagnosed with AML with maturation (FAB M2), bearing chromosomal translocation t(3,4)(p25;q21). After intensive chemotherapy, bone marrow aspiration revealed normal karyotype, and he achieved CR. Six years and 4 months later, he was still in CR from AML, but developed DLBCL presenting in the terminal ileum. Cytogenetic analysis of the DLBCL cells showed the same translocation as the previous AML. The rearrangements of the immunoglobulin heavy chain genes of the two malignancies were examined using polymerase chain reaction amplification, and the rearrangement patterns were found to differ from each other. Our data thus suggest that, in the present case, the AML and DLBCL arose from a common progenitor cell, as indicated by the clonal abnormality t(3,4)(p25;q21), and that different immunoglobulin heavy chain gene rearrangements occurred during each course of clonal evolution. [ABSTRACT FROM AUTHOR]

Even after the advent of rituximab, clinical outcomes of conventional immuno-chemotherapy for high-risk diffuse large B-cell lymphoma (DLBCL) remain unsatisfactory. We retrospectively evaluated the efficacy and safety of R-Double-CHOP (R-D-CHOP), consisting of rituximab (375 mg/m, day −2), cyclophosphamide (750 mg/m, day 1, 2), doxorubicin (50 mg/m, day 1, 2), vincristine [1.4 mg/m (maximum 2.0 mg/body), day 1], and prednisolone (50 mg/m, day 1-5), followed by consolidation high-dose chemotherapy. This treatment was given to 51 de novo DLBCL patients with a median age of 54 (range 19-65), who were categorized as high/high-intermediate risk by the age-adjusted International Prognostic Index. Treatment was given every 3 weeks up to three courses. The overall response and the complete response rate for R-D-CHOP were 94 and 78 %, respectively. A total of 30 responders proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT), whereas 16 received high-dose methotrexate (HD-MTX) alternatively. The 3-year overall survival and the event-free survival for all patients were 78 and 61 %, respectively. Major adverse events included hematological toxicities, but there were no treatment-related deaths during the observation period. We conclude that the R-D-CHOP regimen followed by HDC/ASCT or HD-MTX is a promising treatment option for younger patients with highly advanced DLBCL. [ABSTRACT FROM AUTHOR]

A 49-year-old female from China was referred to our hospital after endocervical polypectomy. Twenty years before admission, after the birth of her first child, an intrauterine device (IUD) had been inserted due to the one-child policy in China. She had noticed abnormal vaginal bleeding with a foul smell 3 years before admission. Then the IUD was removed and a polyp was found at the IUD contact site. Two months before admission, endocervical polypectomy was performed. Lymphoma was suspected by histological examination and she was referred to our hospital. Further examination confirmed the diagnosis of primary uterine diffuse large B-cell lymphoma (DLBCL). Subsequently, a combination of three cycles of R-CHOP regimen and involved-field radiation therapy was performed, followed by maintenance therapy with five cycles of rituximab. She has remained in complete remission for over 1 year. This case suggests that chronic inflammation induced by prolonged IUD insertion may contribute to the development of primary uterine lymphoma. To the best of our knowledge, this is the first reported case of DLBCL associated with prolonged IUD insertion. [ABSTRACT FROM AUTHOR]

The preferentially expressed antigen of melanoma (PRAME), a tumor-associated antigen, is considered a prognostic marker for various human malignancies. The prognostic significance of PRAME expression for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-containing chemotherapy has not been evaluated to date, and the ability of immunohistochemistry (IHC) to detect PRAME expression in these patients has not yet been studied, although IHC is simple to perform in clinical practice. We evaluated the prognostic significance of PRAME expression based on IHC analysis in 160 DLBCL patients treated with R-CHOP therapy. There was a significant association between higher PRAME expression and shorter progression-free survival (PFS), and a trend toward shorter overall survival (OS) in patients with higher PRAME expression than that in patients with lower PRAME expression (5-year PFS, 48.1 vs. 61.1 %; 5-year OS, 65.6 vs. 79.1 %). Patients with high PRAME expression tended to have lower chemotherapeutic responses. Thus, IHC is useful for detecting and assessing PRAME expression in DLBCL. Further, we found a positive correlation between IHC and quantitative real-time RT-PCR measurements of PRAME expression. Our findings indicate that IHC results of PRAME expression can be a novel prognostic maker in DLBCL patients treated with R-CHOP therapy. [ABSTRACT FROM AUTHOR]

The introduction of rituximab has improved the overall prognosis of diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab on central nervous system (CNS) involvement in DLBCL remains a matter of debate. Patients with DLBCL and no CNS involvement at initial diagnosis were eligible for this analysis. Patients must have received treatment either with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP). We analyzed the incidence, clinical features and outcomes of CNS involvement that developed during or after completion of therapy. A cohort of 599 patients was eligible for this analysis. With a median follow-up of 26 and 21 months, respectively, 19 of 294 (6.5 %) in the CHOP group and 13 of 305 (4.3 %) in the R-CHOP group developed CNS involvement. Rituximab did not significantly reduce the risk of CNS involvement either in the univariate ( P = 0.354) or in the multivariate analysis (RR 0.632, 95 % CI 0.301–1.327, P = 0.225). No patient developed CNS disease after 19 months in the R-CHOP group whereas four patients (21.1 %) in the CHOP group developed CNS disease 2 years after initial diagnosis (range 34–83 months). Systemic disease prior to or coincident with CNS occurrence was more common in the CHOP group than in the R-CHOP group (73.7 versus 38.5 %, P = 0.046). Isolated CNS events were more common in the R-CHOP group than those in the CHOP group (53.8 versus 10.5 %, P = 0.015). This study indicates that isolated CNS events are more common in DLBCL patients treated with R-CHOP than those treated with CHOP alone. Our data also suggest that the time and pattern of CNS events and systemic disease status differ with the addition of rituximab. Better methods for earlier detection and prophylaxis of CNS involvement are needed in the rituximab era. [ABSTRACT FROM AUTHOR]

Therapeutic strategies for early-stage diffuse large B-cell lymphoma (DLBCL) are often influenced by tumor extent, but the prognostic value of this parameter is rarely defined. Here, a retrospective analysis was performed to define the impact of tumor extent on survival of patients with early-stage DLBCL. Eighty-six patients with stage II DLBCL, diagnosed from 2000-2007, were categorized into localized ( n = 55, 64 %) and disseminated groups ( n = 31, 36 %) based on tumor extent at time of diagnosis. Treatment modalities, chemotherapy regimen and number of chemotherapy cycles were the same between groups. With a median follow-up of 7.6 years (range 2.1-12.1 years), overall 5-year event-free survival (EFS) and overall survival (OS) were 70.6 and 76.5 %, respectively. EFS ( P = 1.00) and OS ( P = 0.20) did not differ between the two groups. Older age (>60 years) was significantly associated with poor EFS ( P = 0.01) and OS ( P = 0.04). High-risk patients as rated by stage-modified international prognostic index (IPI) had inferior EFS ( P = 0.04) and OS ( P = 0.06) compared with the intermediate-risk group. These results indicate that tumor extent has no prognostic value in patients with early-stage DLBCL. Consistent with previous studies, age and stage-modified IPI were useful prognostic indices for these patients. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that microRNA-21 (miR-21), as an oncogene, is involved in the occurrence of many types of tumor and the sensitivity of tumor cells to chemotherapeutic drugs. In the present study, we investigated whether miR-21 is involved in regulating the sensitivity of the diffuse large B-cell lymphoma (DLBCL) cell line CRL2631 to the cyclophosphamide, vincristine, Adriamycin, and prednisone (CHOP) chemotherapeutic regimen. Knockdown of miR-21 with antisense oligonucleotides significantly increased the cytotoxic effects of the CHOP regimen in CRL2631 cells. A luciferase reporter assay showed that PTEN is a target gene of miR-21 in CRL2631 cells, and subsequent experiments demonstrated that miR-21 impacts the PI3K/AKT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen. Furthermore, knockdown of NF-κB decreased miR-21 expression and sensitized CRL2631 cells to CHOP treatment. These results provide evidence that it may be possible to overcome microRNA-based DLBCL drug resistance. [ABSTRACT FROM AUTHOR]

The prognostic value of absolute lymphocytic count (ALC) has been a recent matter of debate in the study of non-Hodgkin-lymphoma. To evaluate the prognostic value of ALC at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL), we performed a meta-analysis of published studies that provided survival information with reference to ALC at diagnosis. Six studies covering a total of 1,206 subjects were included in this analysis. The summary hazard ratios of low ALC for overall survival were 2.72 (95% confidence interval (CI) 2.15-3.45, P < 0.001) in the entire population, 2.96 (95% CI 2.04-4.29, P < 0.001) in the population that received CHOP, and 2.78 (95% CI 1.87-4.13, P < 0.001) in the population that received R-CHOP. The corresponding ratios for progression-free survival were 2.79 (95% CI 1.90-4.11, P < 0.001) in the entire population, and 2.56 (95% CI 1.66-3.96, P < 0.001) in the population that received R-CHOP. In conclusion, our systematic analysis suggests that low ALC has an adverse effect on outcome in DLBCL. Although it should be borne in mind that this meta-analysis was mainly based on data abstracted from observational studies, these results may justify risk-adapted therapeutic strategies for DLBCL to account for ALC at diagnosis. [ABSTRACT FROM AUTHOR]

The positive regulatory domain I (PRDM1) is a transcriptional repressor that plays an important role in the B-cell differentiation. PRDM1β isoform is functionally impaired and overexpressed in a subset of diffuse large B-cell lymphoma with aggressive behavior. To investigate the possible epigenetic alteration on PRDM1β expression, methylation of PRDM1β promoter was assessed in B-lymphoma cell lines by bisulfite-sequencing PCR and screened in tumor samples of DLBCL patients using MassARRAY-quantitative methylation analysis. PRDM1β expression corresponded to promoter methylation status. CpG island of PRDM1β promoter possessed significant transcriptional activity, which could be modified by methylation. Loss of promoter methylation of PRDM1β was more frequently detected in lymphoma samples than in reactive hyperplasia. Thus, demethylation of abnormal tumor suppressor gene isoform might be linked to lymphoma progression. [ABSTRACT FROM AUTHOR]

Substantial additional insight has been obtained in the past decade regarding the pathogenesis of diffuse large B cell lymphoma (DLBCL). Distinct subtypes of DLBCL have been defined by gene expression profiling (GEP) and they differ not only in GE profiles but also in the pattern of genetic abnormalities. The ability to correlate corresponding genetic and GEP data markedly facilitates the identification of target genes in regions with copy number abnormalities. Oncogenic pathways are often differentially activated in these different subtypes of DLBCL, suggesting that therapy should be targeted according to these differences. The tumor microenvironment plays a significant role in determining outcome and may be a novel target for therapy. The role of microRNA in lymphomagenesis is increasingly being recognized and mutation of key genes has been demonstrated to drive the activation of the NF-kappaB pathway and B cell receptor signaling. The pace of discovery will be even more rapid in the near future with the convergence of data from multiple complementary genome-wide studies and technological innovations including the rapid advance in the technology of high-throughput sequencing. [ABSTRACT FROM AUTHOR]

The introduction of rituximab for diffuse large B-cell lymphoma (DLBCL) has improved the disease's overall prognosis. However, relapse in the central nervous system (CNS) is still an issue. We investigated the prognosis and risk factors of CNS recurrence in DLBCL. A total of 403 patients who were diagnosed with DLBCL without CNS involvement between January 1996 and April 2007 at our institution were included in the study. Subsequently, 42 experienced CNS relapse. Clinical information was gathered by chart review. The median disease-free interval to CNS relapse was 625 days. The mean survival periods after relapse in the cases with CNS and extra-CNS involvement were 513 and 1,615 days, respectively (P = 0.0004). Multivariate analysis identified age >60 years (P = 0.031), involvement in two or more extranodal sites (P = 0.040), bone marrow involvement (P = 0.036), an elevated serum lactate dehydrogenase (LDH) level (P = 0.016), and treatment without rituximab before CNS relapse (P = 0.027) as independent predictors of CNS relapse. We have shown that cases of DLBCL occurring in advanced age, involving two or more extranodal sites or the bone marrow, or showing an elevation of LDH have a higher risk of CNS relapse. Rituximab may prevent CNS relapse by reducing the recurrence of DLBCL at all sites. An effective CNS prophylaxis strategy should be determined according to the risk assessment of CNS relapse. [ABSTRACT FROM AUTHOR]

Leukocyte trafficking is critically regulated by chemokines and their receptors. The involvement of the skin in certain subsets of T-cell malignancies has been explained by the discovery of an interaction between the thymus and activation-regulated chemokine (TARC), which is abundant in the skin, and its receptor, CC chemokine receptor 4 (CCR4), which is expressed in the tumor cells. We describe a diffuse large B-cell lymphoma (DLBCL) that showed CCR4 expression with involvement of the skin. A 55-year-old man presented with a giant skin ulcer of the right axilla, and his disease was diagnosed as DLBCL. Further clinical examination revealed an ulcerated gastric lymphoma lesion. Immunohistochemical and real-time reverse transcriptase-polymerase chain reaction analyses showed that the tumor cells were positive for CCR4, and TARC was expressed at extremely high levels in the lymphoma-affected skin. These observations suggest that the interaction between CCR4 and TARC played a significant role in the involvement of the skin in this case, similar to what has been observed in certain subsets of T-cell malignancies. To the best of our knowledge, this report is the first of a CCR4-positive B-cell lymphoma. The present case provides new insights into the pathogenesis of skin involvement in B-cell lymphomas. [ABSTRACT FROM AUTHOR]