CD30 antigen is a trans-membrane glycoprotein belonging to the tumor necrosis factor receptor superfamily. 1Upon stimulation, CD30 exerts pleiotropic effects on cell growth and survival, which largely depend on the NF-κB pathway activation.2 In normal or inflamed tissues, CD30 expression is restricted to medium/large activated Band/or T-lymphocytes, 1,3 while among lymphoproliferative disorders (LPDs) it was initially reported in classical Hodgkin's lymphoma (cHL) and anaplastic large cell lymphoma (ALCL).4 The specific and highly dense CD30 expression on the lymphomatous cells makes it an attractive target for drug-conjugated antibody-directed therapies, as first reported by Falini et al. in refractory cHL, 5 and later confirmed in experimental models on ALCL.6 In recent years, the anti-CD30 compounds again attracted clinical interest for the availability of a monomethyl auristatin E-conjugated anti-CD30 antibody (Brentuximab Vedotin) which produced encouraging results in clinical trials on refractory/resistant cHL or ALCL patients. 7,8Regarding peripheral T-cell lymphomas (PTCL) CD30 expression was observed in a subset of primary cutaneous LPDs, 9 enteropathy associated T-cell lymphoma (EATL, type 1), 10 extranodal NK/T-cell lymphoma nasal type (ENTL), 11 mycosis fungoides (MF), 12 transformed MF (t-MF) 13 and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).14 Given the extremely poor prognosis of PTCL and the current unavailability of effective therapies, we assessed CD30 expression in 192 PTCL at onset, in order to assess the feasibility of immune-therapy administration in such tumors. The formalin-fixed paraffinembedded samples were retrieved from the archives of the Hematopathology Section, University of Bologna, Italy, and included: 42 angioimmunoblastic T-cell lymphomas (AITL), 41 MF (of which 9 t-MF), 12 EATL (Figure 1). The results for AITL in Table 1 are based on PAX5/CD30 double staining and refer to the PAX5 negative/CD30 positive neoplastic cells. In comparison to the single anti-CD30 staining, that also included PAX5 positive/CD30 positive B blasts, only 5 cases were down-graded (n=3 cases from 4+ to 3+, n=2 cases from 2+ to 1+). Interestingly, a relatively high percentage of MF showed a moderate positivity for CD30 (score ≥2+ 12.50%, 4 of 32): in keeping with our data, similar results have been recently reported in the literature.12 In all cases, staining intensity ranged from moderate to strong within the same section; the variability was often related to cell size, with small/medium cells showing moderate intensity and large cells a stronger one. No further correlation was found between CD30 expression and other morphological parameters.From a clinical perspective, these data potentially include some PTCL in the spectrum of the LPDs suitable for anti-CD30 immunotherapy: this is of special interest given the inefficacy of the current therapies. In particular, EATL type I, ENTL, t-MF and a subset of PTCL-NOS appear ideal candidates, whereas double staining on full sections for CD...

The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%)International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. ResultsClinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% (P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity (P , .001) and more infectious complications (P , .001) were observed in the R-HDS arm. ConclusionIn this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.J Clin Oncol 34.

BackgroundGene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited.Patients and methodsHere, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens.Results In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology.ConclusionsOur study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients’ survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually affects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one year when treated by conventional chemotherapies. The diagnosis is challenging, since neoplastic cells can resemble lymphoblasts or small immunoblasts, and require the use of a large panel of antibodies, including those against CD4, CD56, CD123, CD303, TCL1, and TCF4. The morphologic and in part phenotypic ambiguity explains the uncertainties as to the histogenesis of the neoplasm that led to the use of various denominations. Recently, a series of molecular studies based on karyotyping, gene expression profiling, and next generation sequencing, have largely unveiled the pathobiology of the tumour and proposed the potentially beneficial use of new drugs. The latter include SL-401, anti-CD123 immunotherapies, venetoclax, BET-inhibitors, and demethylating agents. The epidemiologic, clinical, diagnostic, molecular, and therapeutic features of BPDCN are thoroughly revised in order to contribute to an up-to-date approach to this tumour that has remained an orphan disease for too long.