Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study.

PURPOSE: The differential diagnosis among the commonest peripheral T-cell lymphomas (PTCLs; ie, PTCL not otherwise specified [NOS], angioimmunoblastic T-cell lymphoma [AITL], and anaplastic large-cell lymphoma [ALCL]) is difficult, with the morphologic and phenotypic features largely overlapping. We performed a phase III diagnostic accuracy study to test the ability of gene expression profiles (GEPs; index test) to identify PTCL subtype. METHODS: We studied 244 PTCLs, including 158 PTCLs NOS, 63 AITLs, and 23 ALK-negative ALCLs. The GEP-based classification method was established on a support vector machine algorithm, and the reference standard was an expert pathologic diagnosis according to WHO classification. RESULTS: First, we identified molecular signatures (molecular classifier [MC]) discriminating either AITL and ALK-negative ALCL from PTCL NOS in a training set. Of note, the MC was developed in formalin-fixed paraffin-embedded (FFPE) samples and validated in both FFPE and frozen tissues. Second, we found that the overall accuracy of the MC was remarkable: 98% to 77% for AITL and 98% to 93% for ALK-negative ALCL in test and validation sets of patient cases, respectively. Furthermore, we found that the MC significantly improved the prognostic stratification of patients with PTCL. Particularly, it enhanced the distinction of ALK-negative ALCL from PTCL NOS, especially from some CD30+ PTCL NOS with uncertain morphology. Finally, MC discriminated some T-follicular helper (Tfh) PTCL NOS from AITL, providing further evidence that a group of PTCLs NOS shares a Tfh derivation with but is distinct from AITL. CONCLUSION: Our findings support the usage of an MC as additional tool in the diagnostic workup of nodal PTCL.

Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.

Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications.

Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated.

Analysis of risk scoring for the outpatient management of acute upper gastrointestinal bleeding.

OBJECTIVE: To determine whether the Glasgow-Blatchford bleeding score (GBS) or pre-endoscopy Rockall score was better at accurately identifying patients with acute upper gastrointestinal bleeding (AUGIB) who were at low risk of the need for clinical intervention and death and therefore suitable for outpatient management. DESIGN: Retrospective database and case note review of all patients admitted to the emergency departments with AUGIB from 1 January 2008 to 31 December 2009. SETTING: Two tertiary centre teaching hospitals. PATIENTS: 432 patients met the inclusion criteria. INTERVENTION: None. MAIN OUTCOME MEASURE: Clinical interventions (blood transfusion, endoscopic therapy and surgery) and death. RESULTS: Of 432 patients, 40 (9.3%) had a GBS of 0 and none required intervention or died. In contrast, 13/104 patients (12.5%) who had a pre-endoscopy Rockall score of 0 and 23/125 patients (18.4%) who had a complete Rockall score <3, required clinical intervention. The performance of the scores at these cut-offs were: GBS (sensitivity 100%, specificity 16.1%, positive predictive value (PPV) 37.8%, negative predictive value (NPV) 100%, accuracy 82.3%), pre-endoscopy Rockall (sensitivity 91.2%, specificity 32.0%, PPV 41.2%, NPV 87.5%, accuracy 70.9%) and complete Rockall (sensitivity 84.5%, specificity 50.7%, PPV 55.8%, NPV 81.6%, accuracy 76.2%). For prediction of the need for intervention or death, the accuracy of the GBS (0.82; 95% CI 0.78 to 0.86) was superior to the pre-endoscopy Rockall score (0.71; 95% CI 0.67 to 0.76). CONCLUSION: The GBS but not the pre-endoscopy Rockall score identifies patients with upper gastrointestinal bleeding who may be suitable for outpatient management, therefore potentially allowing for more efficient use of hospital resources.

CNOP for diffuse aggressive non-Hodgkin's lymphoma: the Nebraska lymphoma study group experience.

The purpose of this study was to evaluate the CNOP regimen (cyclophosphamide, mitoxantrone, vincristine, and prednisone) throughout a community based oncology network with a large number of elderly non-Hodgkin's lymphoma (NHL) patients. Three hundred and seventy-three previously untreated patients with diffuse aggressive NHL received the CNOP regimen administered through a community oncology network, the Nebraska Lymphoma Study Group (NLSG). The complete response rate was 60% with an overall response rate of 73%. The estimated 4-year event-free survival for patients <60years was 44%, compared to 38% for those >age 60 (p = 0.18). However, the 4-year estimated overall survival for patients <60 years was 62% compared to 44% for those >60 years (p < 0.001). Prognostic factors predictive for a poor event-free survival were male gender, stage III/IV disease, Karnofsky score <80, and elevated lactic dehydrogenase (LDH). The lymphoma specific cumulative death rate was 29% for patients <60 years compared with 33% for patients >60 years (p = 0.07). After failing CNOP the 4-year overall survival (OS) was 19%. The estimated 4-year OS for patients who failed CNOP and went on to receive high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplant (ASCT) was 64% for patients < age 60 and 48% for those >60 years (p = 0.23). In conclusion, CNOP chemotherapy administered to patients with diffuse aggressive NHL in a community oncology network produces similar result to that reported for other anthracycline based regimens reported in the literature. Patients >age 60 had a higher rate of failure due to causes other than lymphoma which accounted for a worse survival long-term. However, patients of all ages who failed CNOP and who were able to receive HDC and ASCT demonstrated long-term disease survival after the transplant.