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We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression-free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months. Thrombocytopenia grade 3 (5 patients) and 4 (24 patients) represented the main toxic effect, causing dose reduction or treatment suspension in 19 patients. Genomic analysis was unable to identify any relationship between mutations and response; TP53 mutation appeared not to impact the clinical outcome. Overall, panobinostat has a modest activity in R/R DLBCL patients, however it can induce very long lasting responses in some cases. Thrombocytopenia frequently limits the use of this agent.

Genomic DNA extraction is a primary component of genomic research and diagnostic routine analysis. Recently, the importance of this process has been highlighted by the necessity to standardize the diagnostic procedure. In this regard, the Minimal Residual Disease (MRD) Network of the Fondazione Italiana Linfomi (FIL MRD Network) has performed a comparative study of four different commercially available kits for DNA extraction, applying them on a panel of cellular pellets, with the aim of defining possible technical recommendations in order to harmonize and standardize diagnostic procedures in the clinical setting. Overall, all four kits usually allowed the recovery of a significant quantity of high-quality DNA (in most conditions), although specific indications could be addressed for cellular pellets of different sizes.

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.

In a percentage of cases, conventional morphologic evaluation of bone-marrow needle biopsy (BMNB) in insufficient to achieve a firm diagnosis. Under these circumstances, immunohistochemistry plays a basic role, providing an easy and objective key for the interpretation of the pattern observed in most instances. Herein, the authors focus on the technical procedures, which allow extensive application of immunohistochemistry to the study of BMNB, as well as on the panels of antibodies needed for the identification of the most relevant conditions.

One-hundred-sixteen consecutive bone-marrow biopsies were taken from 76 patients with essential mixed cryoglobulinemia type II (type II cryo), whose median follow-up was 97 months. Fifty-four out of fifty-six subjects who underwent ELISA and RIBA tests for HCV, were found to be positive. At conventional light microscopic examination, 64/76 patients showed discrete lymphoid infiltrates consisting of small elements with plasmacytoid differentiation and with frequent paratrabecular location. Thirty-nine biopsies were studied by immunohistochemistry that revealed the B-cell nature of the infiltrates (CD20+, CD45RA+, CD79 alpha+, CD3-, CD45RO-), with demonstrable monotypic Ig light-chain restriction in 22 cases. It is worthy of note that the lymphoid elements usually appeared protected against apoptosis, because of the strong expression of the bcl-2 oncogene product, and provided with a very low proliferative capacity, the Ki-67 index being lower that 3%. The latter findings are in keeping with the indolent behaviour of the clonal lymphoid population observed in type II cryo and allow some speculation as to the need for environmental stimuli for its maintenance as well as further mutagenic events for its eventual transformation into an overt lymphoma.

The problem of anaplastic large cell lymphoma (ALCL) is extensively reviewed by depicting the clinical, pathological and biological characteristics of the four main varieties of ALCL: common, Hodgkin's like/Hodgkin-related, lympho-histiocytic, and giant-cell rich. Special emphasis is given to the differential diagnosis between ALCL Hodgkin like and Hodgkin's disease in the light of possible therapeutical differences.

The theoretical bases of Hodgkin's disease (HD) have recently been revised in the light of new findings obtained by means of immunohistochemistry and molecular analysis. These findings have questioned the concept that HD is a unique entity and have made the borders between HD and non-Hodgkin's lymphomas unclear. The clinical relevance of nodular lymphocyte predominance HD (LP-HD), the distinction between T-cell rich B-cell lymphoma and diffuse LP-HD, and the relationships between HD and anaplastic large cell lymphoma are reviewed and discussed.

Serial bone-marrow biopsies were obtained from 46 hairy cell leukaemia (HCL) patients at different time intervals during the course of their disease. The patients were treated according to the following schemes: 14 received alpha-lymphoblastoid interferon (alpha-IFN), 11 2-Chlorodeoxyadenosine (2CdA), and 21 alpha-IFN first, followed by 2CdA. All the biopsies were studied by immunohistochemical means for the detection of minimal residual disease. The administration of 2CdA produced the highest reduction of both the tumor burden and HC index, with residual hairy cells (HCs) being undetectable at conventional light microscopy in most cases. In addition, 2CdA induced a higher degree of hypocellularity than alpha-IFN: the reduction in the amount of normal bone-marrow, however, was less pronounced in patients who had alpha-IFN before 2CdA. Of 9 patients who received both alpha-IFN and 2CdA and were followed for more than 2 years, 3 relapsed, while the remaining 6 continued to show rare HCs 2 years after 2CdA administration.

Thirty seven hairy cell leukemia (HCL) patients, 35 males and 2 females with a median age of 53 years, were treated with a single course of 2-Chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily for 7 days by continuous infusion. Twenty nine (78%) achieved a complete remission (CR) and 8 (22%) a partial remission (PR); four of the latter progressed after 6, 12, 18 and 24 months. All have been retreated with 2-CdA and 2 achieved a CR, 1 a PR and the last one is not yet evaluable. The overall median duration of response was 18 months, ranging from 4 to 30 months from the end of therapy. Circulating hairy cells and spleen enlargement, when present, disappeared within 2 weeks after completing treatment. A significant neutropenia was observed in almost all patients mainly in those who had less than 1,000/microliters neutrophils when treatment was started, together with a significant lymphocytopenia which lasted for more than 12 months. The hemoglobin and platelet levels were marginally affected. Fever was observed in 14 patients; in 8 of them it was short-lived (< or = 48 hours) and apparently not infection-related, while in the remaining 6 it was attributed to infection. Clinical tolerance was very good and none of the patients complained of nausea, vomiting or hair loss. In conclusion, our study confirms the efficacy of 2-CdA in HCL, including patients who progressed after treatment with 2-CdA.

The soluble Interleukin-2 Receptor (sIL-2R) serum levels were assessed in 42 patients with Hairy-Cell Leukemia (HCL) at diagnosis and after alpha-Interferon therapy and correlated with spleen size, peripheral hematological values, hairy cell index (HCI) and clinical response. Serum sIL-2R levels were significantly increased in all HCL patients, particularly in those with a higher HCI (> 0.50) and in non-splenectomized patients. Among the 26 HCL patients who were studied before and after 12 months of alpha-IFN treatment, 16 normalized the sIL-2R level and 10 did not. Our findings suggest that sIL-2R levels in HCL patients correlate with the splenic and bone marrow tumor burden as assessed by HCI. In addition patients with low levels of sIL-2R at diagnosis appear to have a better chance of achieving a good clinical response.