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Natural killer/T-cell lymphoma is rare and aggressive, with poor outcome. Optimal treatment remains unclear. A novel regimen dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE) showed promise in phase 1/2 studies with restrictive recruitment criteria. To define the general applicability of SMILE, 43 newly diagnosed and 44 relapsed/refractory patients (nasal, N = 60, nonnasal, N = 21; disseminated, N = 6; male, N = 59; female, N = 28) at a median age of 51 years (23-83 years) were treated. Poor-risk factors included stage III/IV disease (56%), international prognostic index of 3 to 5 (43%), and Korean prognostic scores of 3 to 4 (41%). A median of 3 (0-6; total = 315) courses of SMILE were administered. Significant toxicities included grade 3/4 neutropenia (N = 57; 5 sepsis-related deaths); grade 3/4 thrombocytopenia (N = 36); and nephrotoxicity (N = 15; 1 acute renal failure and death). Interim analysis after 2 to 3 cycles showed complete remission rate of 56%, partial remission rate of 22%, giving an overall response rate of 78%. On treatment completion, the overall-response rate became 81% (complete remission = 66%, partial remission = 15%). Response rates were similar for newly diagnosed or relapsed/refractory patients. At a median follow-up of 31 months (1-84 months), the 5-year overall survival was 50% and 4-year disease-free-survival was 64%. Multivariate analysis showed that international prognostic index was the most significant factor impacting on outcome and survivals.

We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2'-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHSmu were detected in follicular lymphomas and exclusively in germinal center B cell-ike (GCB)-DLBCLs. CD44 is not expressed in reactive GC B cells. The IGHSmu/CD44 translocations substitute Smu for the CD44 promoter and remove exon 1 of CD44, resulting in the overexpression of Imu-CD44 hybrid mRNA transcripts activated from derivative 11 that encode a new CD44 variant lacking the leader peptide and with a unique C-terminus (CD44DeltaEx1). When overexpressed in vitro in the CD44(-) GCB-DLBCL cell line BJAB, CD44DeltaEx1-green fluorescent protein localized to the cytoplasm and nucleus, whereas CD44s-green fluorescent protein (standard form) localized to the plasma membrane. The ectopic expression of CD44DeltaEx1 in BJAB cells enhanced their proliferation rate and clonogenic ability, indicating a possible pathogenic role of the translocation.

The long-term hepatic complications after allogeneic hematopoietic stem cell transplantation (HSCT) in hepatitis B virus (HBV) endemic area are unknown. We examined the serological and liver-related outcome of 803 consecutive patients who received allogeneic HSCTs, with a median follow-up period of 83 months (range, 0.5-155 months). Late HBV-related hepatitis occurred in 2 of the 721 hepatitis B surface antigen-negative (HBsAg-) recipients compared with 16 of the 82 HBsAg+ recipients after HSCT (0.3% vs 19.5%; P < .001 by log-rank). Liver cirrhosis developed in 8 of the 82 HBsAg+ recipients compared with none of the 721 HBsAg- recipients (9.8% vs 0%; P < .001 by log-rank). Twenty of the 31 (64.5%) HBsAg+ recipients of hematopoietic stem cells from donors with natural immunity to HBV had sustained serologic clearance of HBsAg after HSCT. Eight of the 62 recipients without sustained HBsAg clearance compared with none of the 20 recipients with sustained HBsAg clearance developed liver cirrhosis (12.9% vs 0%; P = .02 by log-rank). Our study showed that long-term hepatic complications occur in a significant proportion of HBsAg+ patients after HSCT and the incidence of liver cirrhosis is reduced in those with sustained serologic clearance of HBsAg after HSCT.

In Epstein-Barr-virus (EBV)-positive lymphomas in immunocompetent patients, release of EBV DNA from tumor cells into the plasma might be useful for disease monitoring and prognostication. To test this hypothesis, we quantified serially plasma EBV DNA by quantitative polymerase chain reaction in 39 cases of EBV-positive (natural killer [NK] cell, n = 23; T cell, n = 8; B cell, n = 4; Hodgkin, n = 4) lymphomas. As control, EBV DNA was undetectable in 34 cases of EBV-negative lymphomas at diagnosis and during chemotherapy. In all cases of EBV-positive lymphomas, EBV DNA was detectable (10(5)-10(10) copies/mL) at diagnosis. It paralleled the clinical course, with EBV DNA becoming undetectable at remission and remaining elevated in refractory disease. On multivariate analysis, high-presentation EBV DNA (> 7.3 x 10(7) copies/mL) was significantly associated with an inferior overall survival (OS). Subgroup analysis of NK cell lymphomas, the largest cohort in this study, showed that presentation EBV DNA was correlated with disease stage and lactate dehydrogenase. On multivariate analysis, high-presentation EBV DNA (> 6.1 x 10(7) copies/mL) was significantly associated with an inferior disease-free survival. During treatment, patients with EBV DNA that showed further increases or failed to become undetectable had significantly inferior OS. In EBV-positive lymphomas, plasma EBV DNA is valuable as a tumor biomarker and for prognostication.

SOCS1 and SHP1 negatively regulate the Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway. The role of promoter hypermethylation leading to epigenetic inactivation of SOCS1 and SHP1 in myeloma was investigated. The methylation-specific polymerase chain reaction (MSP) was used to define SOCS1 and SHP1 methylation in 34 diagnostic myeloma samples. For SOCS1, MSP primers 3' to the translation start site were unreliable and gave positive results in normal controls. However, primers in the 5' promoter region were specific, although no myeloma samples showed methylation. For SHP1, 27 of 34 (79.4%) myeloma samples showed SHP1 hypermethylation. The biologic significance of SHP1 methylation was investigated in the U266 human myeloma line. U266 contained completely methylated SHP1. Furthermore, there was constitutive STAT3 phosphorylation. Treatment with 5-azacytidine led to progressive demethylation of SHP1 on days 2 to 5, with consequent increasing reexpression of SHP1 as shown by reverse transcription-polymerase chain reaction (RT-PCR). Concomitant with increasing SHP1, a parallel down-regulation of phosphorylated STAT3 occurred, so that by day 5 phosphorylated STAT3 was barely detectable. The overall survivals of patients with and without SHP1 methylation were similar. SHP1 methylation leading to epigenetic activation of the Jak/STAT pathway might have a tentative role in the pathogenesis of myeloma, which should be further confirmed by functional studies in primary myeloma samples.

Nasal natural killer (NK) cell lymphoma is rare, so that its optimal therapy, long-term outcome, and prognostic factors are unclear. Data on 52 men and 15 women with well-characterized nasal NK cell lymphomas were analyzed retrospectively to define the impact of primary therapy on remission and long-term outcome and the validity of the International Prognostic Index (IPI). Most (84%) had stage I/II disease with an IPI score of 1 or less (52%). Seven patients received radiotherapy only; 47 patients received anthracycline-containing chemotherapy plus consolidation radiotherapy; and 12 patients received nonanthracycline-containing chemotherapy plus radiotherapy. The overall complete remission (CR) rate was 64.2%; the 20-year overall survival (OS) and disease-free survival (DFS) rates were 37.1% and 33.5%, respectively. Front-line radiotherapy was apparently better than chemotherapy for CR (100% versus 59%, P =.04) and OS (83.3% versus 32.0%, P =.03). Relapses occurred in 4 radiotherapy-treated (all local) and 14 chemotherapy-treated patients (9 local, 4 systemic). Among these, 5 late relapses (4 local, 1 systemic) occurred at 170 months (range, 92-348 months) from CR. The IPI score was of prognostic significance for the whole group (IPI or= 2 for 20-year OS: 57.4% versus 27.6%, P = 0.012), as well as for patients treated with chemotherapy/radiotherapy (IPI or= 2 for CR: 76.7% versus 35.7%, P =.017; and 10-year OS: 63.8% versus 26.8%, P =.003).