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...

CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition. ERK1/2 kinase activity is favored by the interaction with TRAP1, and TRAP1 is, in turn, phosphorylated in an ERK1/2-dependent way. TRAP1 silencing or mutagenesis at the serine residues targeted by ERK1/2 abrogates tumorigenicity, a phenotype that is reverted by addition of a cell-permeable succinate analog. Our findings reveal that Ras/ERK signaling controls the metabolic changes orchestrated by TRAP1 that have a key role in tumor growth and are a promising target for anti-neoplastic strategies.

Barrett's esophagus (BE) is characterized by the native stratified squamous epithelium (N) lining the esophagus being replaced by a columnar epithelium with intestinal differentiation (Barrett's mucosa; BM). BM is considered as the main risk factor for esophageal adenocarcinoma (Barrett's adenocarcinoma; BAc). MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting messenger RNAs and they are reportedly dysregulated in BM. To test the hypothesis that a specific miRNA expression signature characterizes BM development and progression, we performed miRNA microarray analysis comparing native esophageal mucosa with all the phenotypic lesions seen in the Barrett's carcinogenic process. Specimens were collected from 14 BE patients who had undergone esophagectomy, including: 14 with N, 14 with BM, 7 with low-grade intraepithelial neoplasia, 5 with high-grade intra-epithelial neoplasia and 11 with BAc. Microarray findings were further validated by quantitive real-time polymerase chain reaction and in situ hybridization analyses using a different series of consecutive cases (162 biopsy samples and 5 esophagectomies) of histologically proven, long-segment BE. We identified a miRNA signature of Barrett's carcinogenesis consisting of an increased expression of 6 miRNAs and a reduced expression of 7 miRNAs. To further support these results, we investigated target gene expression using the Oncomine database and/or immunohistochemical analysis. We found that target gene expression correlated significantly with miRNA dysregulation. Specific miRNAs are directly involved in BE progression to cancer. miRNA profiling significantly expands current knowledge on the molecular history of Barrett's carcinogenesis, also identifying molecular markers of cancer progression.

Gastritis staging systems (both OLGA and OLGIM) convey prognostically important information on the gastritis-associated cancer risk. Because of its clinical impact, the stage of gastritis should be included as a conclusive message in the gastritis histology report. Since it focuses on IM alone, OLGIM staging is less sensitive than OLGA staging in the identification of patients at high risk of gastric cancer.