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Objectives Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein−Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. Methods A total of 130 ART-naive patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL). Results Four lymphomas occurred, a median of 61 weeks [range 40−94 weeks] after randomization at a median CD4 cell count of 396 cells/μL (IQR 234–536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8). Conclusions IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naive patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in adults. It is generally treated by a combination of chemotherapy and CD20-specific mAbs, such as rituximab, which act, at least partially, by activating antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves NK cells, particularly the CD56(dim) NK-cell subset expressing CD16, the low affinity Fcγ receptor. Here, we show that CD16 expression levels are decreased in a cohort of 36 newly diagnosed DLBCL patients compared with those in 20 healthy controls (HCs). CD137, a co-stimulatory molecule expressed on activated NK cells, was also expressed at lower levels in patients compared with controls. Cells sampled from our cohort also showed severely reduced degranulation activity when challenged with rituximab-coated tumor cells, which could not be corrected by stimulation with high doses of IL-2. These results suggest that rituximab-induced NK-cell ADCC could be defective in some DLBCL patients at diagnosis. These patients should be closely monitored and attempts made to improve their NK-cell function.

Summary The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy.

Summary Around 20% of Hodgkin lymphoma (HL) patients are refractory to first-line therapy with ABVD (adriamycin–bleomycin–vinblastine–dacarbazine) or relapse after complete remission. Salvage regimens frequently have delayed courses or require dose-reduction because of haemotoxicity. We evaluated the IVOx (ifosfamide–etoposide–oxaliplatin) salvage regimen in terms of response rate, toxicity and stem-cell mobilization. Thirty-four patients with relapsed/refractory HL after anthracycline-containing chemotherapy prospectively received IVOx, consisting of ifosfamide (1500 mg/m2 days 1–3), etoposide (150 mg/m2 days 1–3) and oxaliplatin (130 mg/m2 day 1). Patients

BACKGROUND: The combination of 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and a tailored, extended irradiation schedule has been used to treat patients with early Hodgkin lymphoma (HL) in the authors’ group since 1981. The randomized H97-E trial (1997-2004) was designed to assess the impact of a slightly reduced irradiation dose on the freedom from treatment failure (FFTF) rate. METHODS: Patients with supradiaphragmatic HL at clinical stages I and II who had � 2 affected lymph node areas and a mediastinal mass ratio

BACKGROUND: Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with the addition of bortezomib in patients with B-cell lymphoma. METHODS: Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R-CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m2 in Arm A and 1.3 mg/m2 in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m2 and 1.6 mg/m2 in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles. RESULTS: Forty-nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively. CONCLUSIONS: R-CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose-limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies. Cancer 2009. © 2009 American Cancer Society.

Aims: To report 16 cases of sclerosing angiomatoid nodular transformation (SANT) of the splenic red pulp. Methods and results: Patients were selected in two phases. An initial group of seven patients was diagnosed with SANT based on the presence of angiomatoid nodules. Sheets of inflammatory fibrosis were found in three patients, resembling inflammatory pseudotumour (IPT); nine further cases of IPT were reviewed. Angiomatoid nodules were detected, leading to the diagnosis of SANT in all cases. The splenic mass (10–150 mm in diameter) was polycyclic, composed of multiple small nodules of loose connective tissue comprising myofibroblasts and a dense network of capillaries as well as some remnants of sinuses. Collagenous fibrosis surrounded them. Bands or large sheets of fibrosis, infiltrated by various inflammatory cells, particularly polytypic plasmacytes, resembling IPT, were present in 10 cases. Conclusions: SANT of the red pulp is a distinct benign pseudotumorous lesion of the spleen characterized by the presence of angiomatoid nodules. We observed such angiomatoid nodules in all our cases of splenic IPT, which were not follicular dendritic cell or myofibroblastic tumours. We therefore recommend careful examination for angiomatoid nodules in all suspected cases of splenic IPT.

BACKGROUND Intermediate or unfavourable stage Hodgkin's lymphoma (HL) definition relies upon at least three different scoring systems defined by cooperative groups (EORTC, GHSG and Canadian-ECOG). We aimed to investigate their efficacy and their correlation with International Prognostic Score (IPS) for advanced HL. PATIENTS AND METHODS We studied a population of 1156 patients with localized stage HL treated prospectively within GELA centres in H8 (518 patients) and H9 (638 patients) protocols. Median age: 30 yr, 18%, Female 50%; stage I: 25%; stage II: 75%. According to scoring systems 70% had 0-1 EORTC factors; 60% 0-1 GHSG factors and 82% 0-1 Canadian factors. The IPS for advanced stages was available only in H9 study with 64% 0-1 factor. RESULTS Survival curves according to each of the different scoring systems could significantly discriminate the subgroup populations. When a multivariate Cox analysis was performed for overall survival (OS) including all the scoring system variables: age > 45 yr, sex male, Haemoglobin < 10.5 g/dL, lymphocytes < 600/microL, B symptoms with elevated ESR, extra nodal sites did retain an independent significant value. Probability of OS was 99%, 98%, 92%, 82% and 73% for patients with 1-5 factors, respectively P < 0.0001. CONCLUSION These factors are similar for most of them with those described in the IPS when stages III and IV are replaced by extra nodal localization. This new score should be validated in other prospective trials, as it will simplify the Hodgkin prognostic scoring systems for localized and advanced stages.

We describe the case of a 51-yr-old man with systemic sarcoidosis, complicated by the occurrence of a lymphoproliferative disease following a 36-month (duration) immunosuppressive treatment with methotrexate (MTX) and methylprednisolone. Four years after the onset of sarcoidosis, the patient presented a large necrotizing anal fistula. Pathological examination of this lesion showed a diffuse polymorphic infiltrate containing large Epstein-Barr virus (EBV)-positive lymphoid cells associated with areas of necrosis, all features similar to classical B-cell lymphoproliferative disorders occurring in immunosuppressed solid-organ recipients. MTX has been recently implicated in the development of lymphoproliferative disease in connective tissue diseases. This case supports the hypothesis that immunosuppression therapy may contribute to an increased risk for the development of EBV-associated lymphoproliferative disorders in patients suffering from sarcoidosis.

Hepatosplenic gamma delta T-cell lymphoma (HS gamma delta TCL) is a rare and aggressive subtype of peripheral T-cell lymphoma that has been associated cytogenetically with the isochromosome 7q [i(7)(q10)]. The incidence of this aberration and its relevance to pathogenesis of HS gamma delta TCL is still unknown. We investigated the status of chromosome 7 in 12 HSTCL cases, including nine with a typical gamma delta phenotype, one with a so-called T-cell receptor (TCR)-silent phenotype, and two with the variant alpha beta phenotype. We analyzed available fresh and archival material using a dual-color interphase fluorescence in situ hybridization (FISH) approach with 7p and 7q probes. A significant population of cells with predominance of 7q signals was detected in 10 cases (eight gamma delta, one alpha beta, and one TCR silent), and two lymphomas did not show clonal 7p/7q signal imbalances. In four of 10 cases with chromosome 7 aberrations, a hybridization pattern indicative of the presence of one chromosome 7 and one i(7)(q10) was found. In four other cases, the configuration of signals (2 x 7p/3 x 7q) suggested the presence of the i(7)(q10) and additional structural aberrations involving the second chromosome 7. In two cases, including one alpha beta phenotypic variant, a variety of FISH patterns equivalent to two to five copies of i(7)(q10) or numerical and structural aberrations of second chromosome 7 has been detected. These findings support cytogenetic data pointing to a characteristic association of i(7)(q10) with HSTCL, irrespective of the immunophenotype of malignant cells. An increased number of 7q signals was found in three cases with cytologic features of progression, indicating a tendency of HSTCL to multiply the i(7)(q10) chromosome during evolution.

Aims We recently showed that refractory sprue is distinct from coeliac disease, the former being characterized by abnormal intraepithelial T-lymphocytes expressing a cytoplasmic CD3 chain (CD3c), lacking CD3 and CD8 surface expression, and showing TCRγ gene rearrangements. To take advantage of the abnormal phenotype of CD3c + CD8 − intraepithelial lymphocytes (IEL) in refractory sprue we developed a simple method to distinguish coeliac disease from refractory sprue. Methods and results Comparative immunohistochemical studies using anti-CD3 and anti-CD8 antibodies were applied on paraffin-embedded and frozen biopsy specimens in refractory sprue (n = 6), coeliac disease (n = 10), healthy controls (n = 5) and suspected refractory sprue (n = 6). Comparable results were obtained on fixed and frozen biopsy specimens. In four of the six patients with suspected refractory sprue, abnormal CD3c + CD8 − IEL and TCRγ gene rearrangements were found, as in refractory sprue; the remaining two patients had normal (CD3 + CD8 +) IEL and no TCRγ gene rearrangements. Both patients had coeliac disease, as one failed to comply with a gluten-free diet, while the other was a slow responder. Conclusion This simplified immunostaining method using anti-CD3 and anti-CD8 antibodies on paraffin sections can distinguish active coeliac disease from refractory sprue and should prove useful in clinical practice.

Two human immunodeficiency virus-infected patients who needed etoposide therapy to control exacerbations of Castleman disease received four infusions of rituximab. Clinical and virologic relapses with increased blood human herpesvirus-8 DNA levels occurred in both patients 4 and 24 weeks later and were associated with a worsening of Kaposi sarcoma.

From January 1979 to December 1987, 35 cases of primary central nervous system lymphoma (CNS-L) were treated. We recently reviewed these cases focusing on treatment results, treatment modalities, and radiotherapy (RT) or chemotherapy-radiotherapy (CT-RT). Variables such as age, risk factors, presenting symptoms, and histologic condition (all were high-grade or intermediate-grade non-Hodgkin's lymphomas [NHL]) and radiologic data were similar to those of series reported previously. The median survival time was 36 months (+/- 0.2 months) and the disease-free survival (DFS) time was 16 months (+/- 0.12 months). Twelve of 32 patients evaluable for treatment results experienced a recurrence (all but one occurred in the CNS). The DFS rate was 70% for the CT-RT group and 50% for the RT group (median follow-up time, 24 months). Therapeutic results in CNS-L are discussed with special emphasis on a putative role of CT in the management of this rare type of tumor.

The survival and the prognostic significance of the diagnostic characteristics of 39 children with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph1-positive CML), seen between 1963-1976 at the Hôpital Saint-Louis of Paris, have been analyzed. The disease predominated in children older than age 4 years (95%), with girls being more affected than boys (24 versus 15). The clinical and hematological picture at presentation was similar to that observed in adults with Ph1-positive CML. Most children of this series were treated with busulfan which, as in adults, led to reduction of leucocytosis and organomegaly but did not prevent the occurrence of blastic crisis. Well-documented blastic crisis was observed in 78% of cases. Of 39 children, 12 were still alive, all in the chronic phase. Twenty-seven have died, 21 of them after blastic crisis, 4-156 months after diagnosis (median survival, 53 months). The effect of each diagnostic characteristic on survival was evaluated using the log-rank test. Of the 14 characteristics studied, only the degree of blood and marrow blastosis was associated with a shorter survival. Age, sex, bleeding, lymphadenopathy, hepatomegaly, degree of splenomegaly, hemoglobin level, total leucocyte, immature granulocyte (promyelocytes + myelocytes + metamyelocytes), eosinophil, basophil, and platelet counts in the peripheral blood were of no prognostic significance. The failure to attain a level of statistical significance for some characteristics found to be of prognostic value for adults, could be due to the small sample size and/or to the disease homogeneity. The results of this study, however, stress the importance of the initial blastic infiltration in determining the duration of survival, which is ultimately determined by the occurrence of terminal acute leukemia. In conclusion, this study shows that the Ph1-positive CML of childhood exhibits the same course, incidence of blastic crisis, and survival as the disease of adults. It also indicates that treatment with moderate chemotherapy, such as busulfan, has no effect on the duration of survival. Therefore, new therapeutic approaches are urgently needed for the treatment of this disorder in children.

The authors report a documented case of hyperphosphatemia-induced nephrocalcinosis after chemotherapy of an acute lymphoblastic leukemia (ALL). Microscopic examination of the kidney showed numerous calcium deposits with concentric structure in the calyces and in the tubules. Electronic microsound analysis proved the deposits to be composed of calcium phosphate. The nephropathy mechanism is studied, and a review of the 34 similar cases of this acute tumor lysis syndrome is made. Some suggestions are put forward to present the consequences of this therapy-induced syndrome.