Search

Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.

Background: Skin involvement is frequent in ALK-positive anaplastic large cell lymphomas. The role of an insect bite as a triggering event has been postulated but not well documented., Design and Methods: We retrospectively investigated five cases of ALK-positive anaplastic large cell lymphoma who presented with skin lesions occurring after an insect bite. Biopsies were immunostained with antibodies against CD30, ALK, T- and B-cell antigens., Results: Persistent skin lesions developed after solitary insect bites in three patients and after multiple bites in two. Regional lymphadenopathy developed within weeks after the bite in three cases. In four cases the correct diagnosis was delayed due to misinterpretation of the findings as a reactive infiltrate in the skin (n=2) or lymph nodes (n=2); all cases subsequently showed small numbers of cells with nuclear and cytoplasmic staining for ALK. The final diagnoses were lymphohistiocytic variant (n=3) and composite common/small cell type (n=2) anaplastic large cell lymphoma. The patients were treated and three were alive at the last follow-up. Two patients died, one of pneumonia and the other of disseminated disease., Conclusions: In these cases the sequence of events between the insect bites and the occurrence of both skin lesions and satellite lymphadenopathy suggest a direct relationship between the bite and the presentation with anaplastic large cell lymphoma. We postulate that insect bite-associated antigens could result in an influx of T lymphocytes, some bearing the t(2;5). The subsequent release of cytokines at the site of the bite could act as a 'second hit', eliciting activation of the latter cells, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation.

Background and Objectives: We explored the expression of LCK and BAFF-R (B-cell activating factor receptor) both of which are known to play a role in signaling and apoptosis, in routine tissue biopsies. It was hypothesized that their expression patterns might yield information on apoptosis as it occurs in normal and reactive lymphoid cells, and also be of value for the detection of lymphoma subtypes., Design and Methods: Both molecules were studied in paraffin-embedded tissue sections and cell lines by immunoperoxidase staining, and were also studied by western blotting. Human tonsillar B-cell subsets were analyzed by flow cytometry for LCK expression., Results: LCK was detected for the first time in germinal centers and, at lower levels, in mantle zone B cells. The presence of LCK in B cells was confirmed by western blotting. Cross-linking surface IgM reduced LCK expression whereas cross-linking surface CD40 appeared to have the opposite effect. BAFF-R was present on mantle zone B cells but absent or weakly expressed in germinal center cells. Most lymphomas of germinal center origin (e.g. follicular lymphoma) and also many mantle cell lymphomas, chronic lymphocytic leukemia (CLL) and most T-cell neoplasms expressed LCK. In contrast, BAFF-R was expressed in a variety of B-cell lymphomas, but often absent in grade 3 follicular lymphomas and diffuse large B-cell lymphomas (DLBCL). Both LCK-positive and BAFF-R-positive DLBCL tended to be of germinal-center phenotype., Interpretation and Conclusions: The reciprocal expression pattern of LCK and BAFF-R in germinal center and mantle zone B cells may reflect their opposing roles in apoptosis. Their detection in lymphoma tissue biopsies may therefore be of clinical relevance in predicting response to treatment.

Background and Objectives: Although remission of hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) appears to be long lasting, few reports currently provide results from follow-up exceeding 5 years., Design and Methods: We reviewed our HCL patients treated with front-line 2-CdA (by 2-hour infusion) either for 5 consecutive days at 0.14 mg/kg/day (daily subset, n=21) or once a week at 0.14 mg/kg for 5 cycles (weekly subset, n=16)., Results: Of the 37 eligible patients, 30 (81%) achieved complete response (CR) and 7 (19%) partial response (PR) (overall response rate, 100%); identical response rates were recorded in the daily and weekly subsets. After a median follow-up of 122 months (range, 54-156), the overall relapse rate was 27% (8/30): 24% (4/17) had relapsed in the subset treated daily whereas 30% (4/13) had done so in the subset treated weekly (p=ns). The projected 13-year overall and the relapse-free survivals are 96% and 52%, respectively. In terms of hematologic toxicity, the weekly 2-CdA schedule was associated with significantly fewer cases of grade 3-4 neutropenia., Interpretation and Conclusions: In HCL patients, a single dose of 2-CdA induces a long-term CR. Over 90% of patients are alive 13 years later and over 50% of patients appear to be clinically cured by this treatment. The weekly schedule seems to be a safer option for neutropenic HCL patients, while apparently providing equivalent results in terms of response rates and long-term outcome.

Background and Objectives: In this work we examine the characteristics and outcome of patients with Hodgkin's disease (HD) treated with high-dose therapy (HDT) and autologous transplantation at our Institute between 1982 to 2000., Design and Methods: A retrospective analysis was performed examining patients' characteristics, prior chemotherapy regimens, pre-transplant disease status, HDT regimen, source of stem cells, time for hematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and relapse-free survival (RFS)., Results: Ninety-seven patients with HD were treated and had estimated 10-year OS and RFS rates of 32% and 60%, respectively. Disease status (sensitive vs. refractory) before HDT was the most powerful predictive parameter for OS and RFS in both univariate and multivariate analyses. The rate of transplant-related mortality in the whole cohort was only 1% whereas the rate of second malignancies was 3%., Interpretation and Conclusions: Our results confirm that HDT with autologous transplantation is associated with a durable RFS in a remarkable proportion of HD patients and that the procedure has a very low global early and late toxicity.

Background and Objectives: The introduction of high-dose therapy with stem cell support has significantly improved the outcome of patients with multiple myeloma (MM) in terms of increased complete remission (CR) rate and extended survival, both disease-free and overall. Few options, however, are presently available for patients who relapse after single or double autologous stem cell transplantation (SCT). Thalidomide, a glutamic acid derivative with anti-angiogenetic properties, has been recently proposed as salvage treatment for such patients. The present study was aimed at evaluating thalidomide as single agent therapy for patients who had previously received autologous peripheral blood stem cell transplantation., Design and Methods: From October 1999 to August 2000, 11 patients (7 males/4 females) who had relapsed after single (n = 4) or double (n = 7) autologous peripheral blood SCT were enrolled in the trial. Thalidomide, always employed as a single agent, was initially administered at a dose of 100 mg/day; if well tolerated, the dose was increased serially by 200 mg every other week to a maximum of 800 mg/day., Results: The median administered dose was 600 mg/day. WHO grade > II toxic effects were constipation, lethargy, and leukopenia. Four patients (36%) showed > 50% reduction in serum M protein concentration and 4 showed > 25% reduction, for a total response rate averaging 72%. After a median follow-up of 5 months, 3 out of 8 responding patients are alive and progression-free and 5 patients have relapsed. INTERPRETATION AND CONCLUSIONS; These data confirm that thalidomide is active in poor-prognosis MM patients such as those relapsing after autologous SCT, and could thus deserve further testing in combination therapy.

Background and Objectives: The REAL/WHO classification constitutes a new tool for the better understanding and treatment of malignant lymphomas. The authors focus on the key features of aggressive B- and T-cell lymphomas, aiming to contribute to the cross-talk between pathologists and clinicians., Data Sources and Methods: Each lymphoma entity is analyzed on the basis of the most representative contributions in the literature and the authors' experience gained in studying more than 20,000 lymphoid tumors over a 20-year period., Results: Guidelines for diagnosis and areas of interest for future clinico-pathologic studies are identified and discussed. Within this context, selected data obtained by the application of novel markers are presented., Interpretation and Conclusions: The present know- ledge and organization of malignant lymphomas now make the development of tailored therapies a feasible goal.

Background and Objectives: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL., Design and Methods: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992., Results: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively., Interpretation and Conclusions: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.

Anaplastic large cell lymphoma (ALCL) shows a wide morphologic spectrum, including the occurrence of reactive components obscuring the neoplastic population. This makes its distinction from hyperimmune reaction difficult. The authors describe an ALCL in a girl wha had a tick bite 20 days prior to clinical presentation. She developed a huge epithelioid reaction (an unprecedented finding for this tumor). The diagnostic controversies were solved by applying the ALKc antibody against anaplastic large cell lymphoma kinase (ALK), in conjunction with reagents anti-nucleophosmin (NPM), which showed the typical staining pattern observed in ALCL carrying t(2;5). Comprised within the epithelioid component there were large anaplastic cells and small-medium sized atypical elements displaying strong nuclear and cytoplasmic positivity for ALK and NPM (N-terminal region). This pattern, never observed in normal lymphocytes, corresponds to the presence of the product of the hybrid gene NPM/ALK produced by t(2;5). Following the diagnosis, the patient - whose general conditions were critical - underwent aggressive chemotherapy, achieving complete remission.

Background and Objective: In this study we describe a newly established CD30+ Epstein Barr virus (EBV)-infected B cell line derived from an EBV-infected B cell culture (utilized, once irradiated, as a feeder) which showed a B clonal rearrangement and strong CD30 antigen expression., Design and Methods: The cells injected into SCID mice were able to grow giving rise to CD30+ solid tumors with the morphologic features of an anaplastic large cell lymphoma (ALCL). Thus we tried to establish a model to investigate the potency of immunoconjugates containing a CD30 monoclonal antibody (Ber-H2) and ribosome-inactivating proteins (saporin, momordin and ricin A-chain) as toxic moieties., Results: We observed a strong cytotoxic activity of the anti-CD30 immunotoxins on the in vitro growth of D430B cells. High levels of anti-tumor activity were also observed in vivo, in the SCID mouse model., Interpretation and Conclusions: The antitumor immunotoxin therapy was sccessful in our chosen animal model, the effecacy seeming to be associated with strength of CD30 expression. Our data suggest that immunotoxins should be tested (before use) on the tumor cells of the subject to be treated and that immunotoxins should be directed to different tumor-associated antigens to avoid selection of cell populations with different antigenic mosaics.

Background and Objective: With the development and refinement of new guidance methods for percutaneous biopsies, many investigators have reported studies supporting a role for radiologically guided core-needle biopsy in the diagnosis of malignant lymphoma under certain clinical circumstances. The aims of this report are to evaluate the efficacy of findings at ultrasound (US)-guided core-needle biopsy of abdominal lymphoma on patient care and define the key determinants of clinical success., Design and Methods: US-guided core needle biopsies were performed in 55 patients with abdominal lymphoma: 44 non-Hodgkin's lymphoma (NHL) and 11 Hodgkin's disease (HD); 41 had had no prior lymphoma and 14 had previously diagnosed lymphoma. All the biopsies were performed under US control using a 21-gauge modified Menghini needle. Overall, 53/55 (96%) patients were treated on the basis of biopsy findings only, including 14/14 (100%) patients with a history of lymphoma and 39/41 (93%) patients with no such history., Results: In 46/53 (87%) patients it was possible to assess the specific histotype. No differences between the diagnostic rates of HD and high grade-NHL were recorded. There were no complications related to the biopsies., Interpretation and Conclusions: Our data indicate that abdominal US-guided core-needle biopsy should be considered as an effective and safe procedure in the diagnosis of patients with lymphoma offering the possibility of determining the tumor subtype and the subsequent specific treatment.

Background: The mdr-1 gene, which codes for a 170-kd transmembrane glycoprotein (P170), is frequently overexpressed in multidrug resistant (MDR) tumor cell lines and in spontaneous tumors, including leukemia and lymphoma. However, it is also constitutively expressed as a normal gene in normal tissues., Methods: We used human mdr-1 cDNA and three anti-P170 monoclonal antibodies (MoAbs: MRK-16, C-219 and JSB-1) to investigate the normal peripheral blood leukocyte content of mdr-1 specific mRNA and of P170 through immunocytochemistry and flow cytometry., Results: We did not find any increase in mdr-1-specific mRNA, while small amounts of P170 were easily detectable in about two thirds of the lymphocytes and monocytes and in about one third of the granulocytes. The level of P170 expression in leukocytes was similar to that found in non-MDR tumor cell lines., Conclusions: mdr-1 is constitutively expressed in human normal leukocytes at levels that cannot significantly affect drug resistance. Accordingly, low-level mdr-1 expression in leukemic cells should not be considered a label of pleiotropic drug resistance.

On the basis of the experience derived from the study of 2,000 biopsies, the authors critically review the problem of the newly generated monoclonal antibodies (mAbs) working in paraffin sections. The reliability and drawbacks of the most commonly used reagents are examined, with special reference to their employment in the diagnosis of malignant lymphomas. The authors underline that only a few mAbs are really specific, since most reagents give rise to a certain number of cross-reactivities. In the light of this, a wide panel of antibodies should always be applied in the diagnosis of lymphoid tumours in order to avoid possible misinterpretations, which can actually lead to wrong therapeutical decisions.

Background: The treatment strategy for stage I non-Hodgkin's lymphomas (NHL) is far from being clearly established., Methods: Thirty-seven patients (pts) with clinical stage I high-grade NHL treated between 1983 and 1989 have been retrospectively reviewed. Nineteen pts were treated by radiotherapy (RT) alone; 14 pts received chemotherapy (CT) followed by adjuvant RT, 3 pts CT alone and 1 pt underwent surgery alone. All pts with bulky disease were submitted to combined therapy., Results: Estimated 7-yr overall survival (OS) was 82%, while freedom from relapse (FFR) was 73%. No differences in OS and FFR were recorded with regard to the type of treatment, site of the tumor, sex or histology., Conclusions: Our conclusion is that stage I NHL, even with unfavourable histology, may be successfully treated with RT only; however, CT before RT may be recommended in pts with a higher risk of relapse, i.e. the presence of bulky mass.

Background and Methods: From February, 1987 to August, 1988, fifty-one patients with high and intermediate grade non-Hodgkin's lymphoma (NHL) entered a chemotherapy program MNCOP-B (M = Methotrexate, N = Novantrone, C = Cytoxan, O = Oncovin, P = 6 methyl-prednisolone, B = Bleomycin). Forty patients received MNCOP-B as first-line therapy and 11 patients as salvage therapy after relapse-resistance to other schemes or radiotherapy., Results: The overall remission rate was 51% with a similar distribution of remissions between the two groups under study. At a mean follow-up of 28 months, 20 patients (40%) remain in CR with a disease-free probability of 83% for patients treated with MNCOP-B as up-front therapy and 67% for patients treated with MNCOP-B as salvage therapy. The overall survival at 3 years is 45%; bulky, disease stages III-IV and symptoms are not correlated with poorer survival or a lower remission rate. Patients who received less than 70% of the scheduled doses paradoxically figure better than the others, showing an 87% remission rate, as compared to those who received 100% of the scheduled doses and obtained a 35% remission rate. Major toxicity consisted of mucositis, recorded in 15% and 9% of previously untreated and treated patients, respectively; severe neutropenia was recorded in 27% and 63%, respectively. Despite the number of recorded side effects, only one toxic death due to sepsis occurred., Conclusions: MNCOP-B is an effective regimen in intermediate and high grade NHL and easily manageable in the out-patient clinic. The incidence of mucositis is sensibly reduced as compared to the parental regimen MACOP-B reported in the literature; this result allows the use of MNCOP-B in older patients.

As described in the literature, spinal cord compression by extramedullary hematopoietic tissue rarely occurs in thalassemic patients. Laminectomy and/or radiotherapy are the main approaches. We report on a patient with thalassemia intermedia who developed paralysis of both lower extremities due to the compression of the spinal cord by extramedullary hematopoietic tissue.