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Abstract 878 Introduction: We investigated, in a prospective randomized study, the place of ASCT in the frontline treatment of CLL. Patients and methods: From March 2001 to December 2007, 241 patients were included in the trial. Eligibility criteria were previously untreated stage B and C CLL patients under 66 years, characterized by Matutes score 4-5, absence of cyclin D1 expression, baseline flow assessment of ZAP 70 and CD38 expression, karyotype and FISH analysis, IgHv mutational status (centralized). Preceding randomization, initial chemotherapy consisted of 3 monthly courses of mini CHOP regimen as previously described, followed by 3 monthly courses of fludarabine, IV or oral. Patients achieving CR (NCI 1996 criteria plus normal CT scan) were randomized between observation and ASCT. Non CR patients were offered cisplatin/cytosine-arabinoside/dexamethasone (DHAP) rescue and randomized whatever the response between ASCT or 3 subsequent monthly IV courses of Fludarabine-Cyclophosphamide (FC). Conditioning regimen for ASCT consisted of cyclophosphamide IV (60 mg/sqm d-5-4) and fractionated total body irradiation (10 Gy). The primary end-point of the study was event-free survival at 3 years. Responses after initial treatment (i.e.before randomization) and after completion of therapy, overall survival, side effects, prognostic significance of clinical and biological characteristics at baseline were other endpoints. Results: Baseline characteristics were: gender (M/F: 3), age (median 56.4 years, range 33.3-66), stage B (185 patients) or C (56 patients). All enrolled cases but five (236 patients) started the treatment. Among them, 206 completed the six planned courses of initial chemotherapy. For the 236 patients, CR rate was 43.6%, and overall response was 89.8%. Forty two patients were not randomized because of treatment failure (19) or patient/physician decisions (23). After an observed median follow-up of 40.2 months (Q1-Q3, 17.9-47.9) at the reference date (1/1/2009), the overall survival for the 241 patients was 87.8% (95% CI, 83.3-92.6) at 3 years and 75.4% (95% CI, 66.2-88.6) at 5 years. For the 199 randomized patients, the overall survival was 90.9% (95% CI, 86.7-95.3) at 3 years. Among them 105 patients were in CR after initial treament and were allocated to ASCT (53 patients) or observation (52 patients) with a 3 years EFS of respectively 78.7% (95% CI, 67.7-91.4) and 31.3% (95% CI, 20.1-48.8) (p Conclusions: ASCT is a safe procedure which significantly improves response duration in patients attaining CR after a first line treatment. For patients not in CR, ASCT or consolidation with 3 FC courses provide similar results on response duration but ASCT could be considered in patients without 17p deletion or with mutated IGHV gene. Disclosures: Van Den Neste: Roche: Research Funding.

Autologous stem cell transplantation (ASCT) is widely used in relapsed or refractory low grade lymphoma with conditioning regimen including chemotherapy with or without total body irradiation (TBI). Radiolabelled immunotherapy 90Yttrium ibritumomab tiuxetan (Zevalin) is effective in B-cell lymphoma and delivers targeted radiation without TBI toxicity. To take advantage of this antilymphoma effect, conventional dose of 90Yttrium ibritumomab tiuxetan 15 MBq/kg (maximum 1200 MBq, total dose) was given without dosimetry day -14 before ASCT and combined to standard BEAM regimen starting at day -7. The goal of this phase II study was to evaluate efficacy and toxicity of Z BEAM. Patients < 65 years with CD20+ low grade B cell Lymphoma in 1st or 2nd relapses, or not achieving complete remission after first line treatment were included in the trial. They had to be chemosensitive to last salvage therapy, no more than three lines of treatment and eligible for ASCT. The primary end point was to detect a 2 yrs EFS at least 80%. Hematological reconstitution was evaluated after transplant and during the first year follow up. From 3/2005 to 8/2006, 77 patients were included. Patients characteristics at inclusion: 90% follicular lymphoma, median age 53 yr. (31–64), FLIPI 1G/L 12 days (9–35), time to platelets >20 G/L 12 days (3–42). Median number of platelets transfusions 4; red blood cell transfusions 2. Grade 3-4 toxicities were: infection 83%, mucositis 47%, pulmonary 4%. Safety data indicated 35 serious adverse events in 24 patients that did not appear to significantly differ from those usually seen after ASCT. No toxic death was observed. At week 12 and 42 after ASCT, median haemoglobin level were 11.6 g/dl and 11.3 g/dl, median platelets counts was 111G/L and 148 G/L, leucocytes counts 3.48 G/L and 4.80 G/L respectively. Only 5 events were reported. After a minimum follow up of one year for all patients, estimated 2 years EFS is 93%. Updated results on survival will be reported. Conclusion: Z BEAM is a safe conditioning regimen which can be used for B cell lymphoma. Longer follow up is necessary to evaluate long term toxicity and efficacy. Further randomized study are warranted.

The aim of this study was to evaluate the safety and efficacy of radiolabelled DTPA-chelated rabbit polyclonal antiferritin antibody (Ab) in relapsed or refractory HL. The protocol included a first intravenous injection of 111Indium-labelled antiferritin Ab followed by immunoscintigraphy at 4, 48, and 72 hours and intravenous injection of 90Yttrium-labelled antiferritin Ab in the case of tumour targeting. Ten patients were included in the study: median number of chemotherapy regimens: 3; number of autografted pts: 8; number of previously irradiated pts: 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed tumour targeting. Nine patients were treated, as the last patient died from progressive HL before therapeutic injection. Median injected activity was 12 MBq/kg (0.32 mCi/kg). Among the ten patients who were included in the study, 1 CR and 6 PR were observed (ORR 70%) with a median duration of response of 8 months (range: 7–12 months). Toxicity was mainly haematological, with grade 1 or 2 neutropenia and anaemia, and grade 2 and 3 thrombocytopenia. The pharmacokinetic study showed that the half-lives of 111Indium and 90Yttrium were almost identical. These results confirm those previously reported in the literature and show the therapeutic potential of rabbit polyclonal antiferritin Ab in relapsed or refractory HL. On the basis of all these results, MATBioPharma proposed to test a radioimmunotherapy with polyclonal antiferritin antibodies (Abs) in patients with refractory or relapsed HL. The treatment is constituted with chelated rabbit polyclonal antiferritin Abs to be loaded with 111Indium for the diagnosis of the tumour(s) by immunoscintigraphy and with 90Yttrium for the treatment of the tumour(s). A phase I study is still ongoing at the Institut Curie / Centre René Huguenin (France) to evaluate the safety and tolerability of ascending doses of 90Yttrium antiferritin until the maximum tolerated dose (MTD) is reached and to select a dose for further investigation (one dose step below MTD). A pharmacokinetics is concomitantly performed to determine dose linearity and pharmacokinetic parameters of increasing 90Y-Ab and Ab. The second dose level will be completed in the third quarter 2007 and available data on immunoscintigraphy, safety, and efficacy of included HL patients will be provided for the 49th ASH congress.

The aim of this study was to assess the efficacy of a gemcitabine-based regimen in pretreated Hodgkin’s lymphoma (HL) patients. Relapsed or refractory HL patients treated with gemcitabine, used alone or in combination with other cytotoxic agents, were retrospectively reviewed. Fifty-five patients were included in the study. Initial characteristics before gemcitabine administration were: Ann Arbor stage III–IV: 84%; International Prognostic Score less than 3 in 20/43 cases (47%); thirty-one primary refractory patients at the end of first-line therapy (56%); median number of previous chemotherapy regimens of 3. Twenty-nine patients received gemcitabine alone with a median starting dose of 750 mg/m2 per injection (range: 180–1250 mg/m2); Gemcitabine was administered at a starting dose of 1000 mg/m2 per injection (range: 500–1250) in combination with vinorelbine in 10 patients, oxaliplatin in 13 patients, and other drugs in 3 patients, with a median of 6 injections (range: 1–18). Overall response rate was 20% with 11% of complete remission. On univariate analysis, two adverse factors at progression were significant for response to gemcitabine-based regimen: stage III–IV disease and hemoglobin level less than 10.5 g/dl. In conclusion, the two identified prognostic factors for response to gemcitabine are part of the International Prognostic Score of HL, suggesting that response to gemcitabine is mainly influenced by the specific prognostic factors of HL. Moreover, with an ORR of 29%, our results of the gemcitabine administered alone regimen are not different from those reported in the literature. In contrast, the results of the various series of HL patients treated by gemcitabine-combined regimens, mainly with cisplatin or derivatives, vinorelbine, ifosfamide, doxorubicin, and prednisone, are very different due to different patient characteristics. In heavily pretreated cases, as in our study, the ORR was 26%; inversely, in patients who had received only one or two lines of chemotherapy, the ORR varied between 64% and 82% with 9% to 54% of complete remissions. This discordance can probably be explained by the prognostic impact of previous treatment lines in the response to gemcitabine. This observation emphasizes the possible interest of using gemcitabine earlier in the treatment of Hodgkin’s lymphoma, namely at the time of first relapse or after first-line treatment in primary refractory HL patients.

We previously reported an increase of tumor growth inhibition following chemotherapy combined with concomitantly administration of imatinib mesylate [Decaudin D, et al. Int J Cancer2005;113:849–856; Decaudin D, et al. Anti-Cancer drugs2006;17:685–696; Decaudin D, et al. Impact of STI571 on the pharmacokinetics of etoposide and / or ifosfamide in mice. Cancer Res (AACR Annual Meeting) 2006;abstr:5154]. Inversely, combination of imatinib and rituximab was reported in very few cases of patients and remains controversial. In order to explore this particular combination of targeted therapies, we therefore investigated the in vivo impact of rituximab plus imatinib on a B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an EBV-associated B-cell lymphoproliferative disorder xenografted into SCID or Rag2/gc −/− (B-, T-, and NK-) mice. Using SCID mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo (Figure 1A). Using alymphoid Rag2/gc −/− mice, we showed that the effect of STI571 was not dependent on the presence of NK cells (Figure 1B). In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using non immunodeficient mice, we observed an in vivo decrease of CD4-positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of NK cells. Figure Figure

18518 Background: The aim of this study was to assess the efficacy and safety of gemcitabine-based regimen in heavily pretreated HL pts. Methods: Relapsed or refractory HL pts treated with gemcitabine were retrospectively reviewed. Gemcitabine was used as a single agent or administered in combination with vinorelbine, oxaliplatine, doxorubicine, vinblastine, rituximab, and/or corticosteroids. Results: Fifty-five pts treated in 9 departments of clinical hematology between January 1999 and August 2006 were included in the study. Initial characteristics before gemcitabine administration were: nodular sclerosis in 84%; sex ratio M/F 1.1; median age 29 years (range: 15–85 years); advanced stage 84%; extranodal sites were lung, bone, liver, soft tissues, and bone marrow in 68%, 31%, 13%, 21%, and 4%, respectively; Hasenclever index lower than 3 in 20/43 cases (47%). At the end of the first front-line therapy (chemotherapy ± radiotherapy), 19 pts (35%) were in complete response (CR) in whom 13 relapsed within one year, 5 were in partial response (PR), and 31 pts were primary refractory (56%). Median number of previous chemotherapeutic regimen was 3 (range 1–8), 39 pts (71%) have received radiotherapy (RT), and 34 pts (62%) one or two autologous/allogenic stem cell transplantations (A/ASCT). Twenty-nine pts received gemcitabine alone with a median initial dose per injection of 750 mg/m2 (range: 180–1250 mg/m2); Gemcitabine was administered at an initial dose per injection of 1000 mg/m2 (range: 500–1250) in combination with vinorelbine in 10 pts, oxaliplatine in 13 pts in whom 4 with rituximab, and with others drugs in 3 pts. In both cases, the median number of combined gemcitabine regimen injections was 6 (range: 1–27). Toxicity was mainly hematological (75% of pts developed bi- or pancytopenia) or infectious (13%). Among all included pts, 6 were in CR (11%) and 5 in PR with an overall response rate of 20%. Among the 6 CR, 5 pts received thereafter A/ASCT and 2 pts RT, with 2 persistent CR at 16 and 44 months. In univariate analysis, none prognostic factor for response to gemcitabine was identified. Conclusions: This study, which constitutes one of the most important series, showed a mild efficacy of gemcitabine-based regimen in heavily pretreated HL patients. No significant financial relationships to disclose.

The recent literature shows that interest in ocular adnexal lymphomas and their biologic and clinical characteristics—along with their possible association with Chlamydia psittaci infection and therapeutic management with rituximab or anti-Chlamydia psittaci antibiotic therapy—is considerable. These new data have modified the previously reported features of this disease and have made an updated review of the literature necessary. The aims of this review are to present the current knowledge on the biology of these lymphomas, their clinical features and prognostic factors, and the panel of all available treatment options.

Using a human small cell lung cancer (SCLC) xenografted in nude mice, we previously reported an increase of tumor growth inhibition following chemotherapy in combination with STI571 (imatinib)(Int J Cancer.2005;113:849–856). This led us to study the in vivo impact of STI571 on the pharmacokinetics of chemotherapy. Plasma, urine, and fecal concentrations of etoposide were determined by a validated high performance liquid chromatography method, and plasma concentrations of ifosfamide were determined by a validated GAS chromatography assay with nitrogen-phosphorus detection. C-kit and MDR1/ABCB1 transcripts were quantified using real-time quantitative reverse transcription-PCR assays. We first observed an increase of the Cmax of both etoposide and ifosfamide on days 1 and 3 when mice were treated by chemotherapy combined with STI571 compared to chemotherapy alone. We then observed a high significant increase of the AUC 0–3h (Area Under the concentration-time Curve) of etoposide when mice were treated with etoposide + STI571, due to a decrease of its fecal excretion, without impact of concomitant administration of the CYT3A4 inhibitor fluconazole. As previously shown, this effect was observed despite the absence of c-kit receptor mRNA expression. Finally, we showed that STI571 enhanced the etoposide-induced tumor growth inhibition of a human xenografted lymphoma, but not that of an in vivo human SCLC tumor, and that this antitumor effect was correlated with the mRNA level of the MDR1/ABCB1 gene. This last observation suggests that imatinib-induced pharmacokinetic changes could be due to inhibition mediated via the MDR modulator of the P-glycoprotein transporter resulting in decreased elimination of etoposide. In conclusion, STI571 can reverse MDR1 drug resistance and potentiate the effects of etoposide in MDR1-expressing cancer cells such as lymphoma cell lines. These results show that further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib are therefore warranted in some cancer patients, such as malignant lymphoma patients, with careful toxicologic monitoring.

Breast NHL represents less than 1% of all lymphomas and 2% of lymphomatous extranodal sites. We therefore reviewed all patients treated at the Institut Curie between 1986 and 2004 for a NHL having initial breast localization to define their initial characteristics, natural history and prognostic factors. Forty-six cases were selected for the study. Pathological review according to the WHO classification showed 2 patients with lymphocytic lymphoma, 3 cases of grade I follicular NHL, 1 case of MALT lymphoma, 1 case of grade III follicular NHL, 1 Burkitt’s lymphoma, and 38 diffuse large cell lymphomas [namely, 40 cases (87%) of high-grade NHL]. A complete analysis was performed on the 40 high-grade NHL patients. Initial characteristics were: median age 62 years (range: 22–86), B symptoms 17%, PS < 2 in 92%, stages III-IV 57%, nodal involvement 57% (47% axillary sites), 2 or more extra-nodal sites 32% (15% of bone marrow involvement and 2.5% of central nervous system (CNS) involvement), elevated LDH in 37%, and IPI score of 0–1/2/3/4–5 in 45%/12%/12% and 15%, respectively. Treatment consisted of chemotherapy in all cases (chlorambucil 3, anthracycline-based regimen with (30) or without (7) intrathecal prophylaxis), breast radiotherapy in 29 cases (72%), and rituximab in 4 patients. At the end of initial therapy, 36 patients (90%) achieved CR. With a median follow-up of 96 months (range: 14–188), nineteen patients (47%) relapsed. Relapses were localized in 8 cases and diffuse in 11 cases; breast localizations were observed in 10 cases (53%), one of which included contralateral involvement, axillary in 5 cases, and CNS site involvement in 3 cases. Among relapsed patients, 8 cases achieved second CR (47 %). Among the 10 patients with breast relapses, 8 received localized radiotherapy during first-line therapy. The 2- and 5-year disease-free survivals (DFS) were 65% (95% CI: 51 to 81%) and 54 % (95% CI: 40 to 72%), respectively; the 2- and 5-year overall survivals (OS) were 74% (95% CI: 62 to 89%) and 61% (95% CI: 47 to 78%), respectively. In univariate analysis, stage IV, 2 or more extranodal sites, elevated LDH level, high IPI score, and CNS involvement were prognostic for lower DFS; moreover, age greater than 60 years, PS > 1, ESR > 30, IPI score > 2, and 2 or more extranodal sites influence adversely OS. In multivariate analysis, the presence of 2 or more extranodal sites (p = 0.0008; RR 5.48; 95% CI: 2.01–14.9) was the only one factor that had a pejorative impact on DFS (Figure 1.A). PS > 1 (p = 0.02; RR 3.63; 95% CI: 1.18–11.07) and 2 or more extranodal sites (p = 0.05; RR 2.64; 95% CI: 1.0–6.96) were associated with poor OS (Figure 1.B). Finally, high-grade selected patients were compared to a historical series of 111 patients with aggressive lymphomas treated at the Institut Curie between 1982 and 1997 with an anthracycline-based regimen. Ann Arbor stage adjusted OS was significantly lower for patients with initial breast involvement (p < 0.0383). In conclusion, initial breast localization has a pejorative impact on the outcome of NHL patients, with an impressive adverse influence of additional extranodal sites on both DFS and OS. These results suggest a specific management of NHL with breast involvement in prospective clinical trials.

17536 Background: A high prevalence of Chlamydia psittaci infection in both tumor tissues and peripheral blood mononuclear cells of Italian patients with OAL has been reported (Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell’Oro S, Fleischhauer K, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004;96(8):586–94.) This association has not been confirmed in some regions of the USA, and no data from other European countries are available. We therefore investigated the presence of DNA of C. psittaci, C. trachomatis, and C. pneumoniae DNA in French patients (pts) with OAL. Methods: Tumor samples from ophthalmologic biopsies of 16 OAL pts (10 conjunctiva, 6 orbit) were included in the study. Histologic type were MALT-type (n = 8), lymphoplasmocytic (n = 6), follicular (n = 1), and diffuse large B-cell (n = 1) lymphomas. Two other groups of lymphoproliferative disease were analyzed as controls. First, ten cases of nodal lymphomas (follicular and marginal zone B-cell lymphomas), and ten cases of reactive lymphoid hyperplasia were analyzed. A multiplex touchdown, enzyme time-release PCR designed to simultaneously detect C. psittaci, C. pneumoniae and C. trachomatis DNA sequences was performed. PCR analyses were performed in duplicate in an independent setting either inat the Curie Institut Curie in e, Paris, and in the National Cancer Institute, Aviano. Results: DNA of C. psittaci DNA was detected in the tumoral tissue of only one patient with follicular OAL. No DNA sequences of C. psittaci, C. pneumoniae and C. trachomatis DNA sequences were was detected in all any of the other OALs, or controls. Conclusions: The prevalence of C. psittaci infection in French pts with OAL was sensibly significantly lower than that reported in Italian series. Cross-controls between the two laboratories indicate that this finding is not due to different experimental conditions. Discrepancies may be explained by an heterogeneous epidemiological distribution of the bacterial infection. Large studies aimed to investigate geographical variations in the prevalence of this association are warranted. No significant financial relationships to disclose.

2534 Background: The aims of this study were to evaluate (1) the tumor targeting of 111Indium-labeled rabbit polyclonal antiferritin antibody (Ab) and (2) the therapeutic efficacy of 90Yttrium-labeled antiferritin Ab in relapsed or refractory Hodgkin’s lymphoma (HL) patients (pts). Methods: After obtention of the patients’ consent, the protocol included a first intravenous injection of 2 mg of antiferritin Ab labeled to 111 MBq (3 mCi) of 111Indium followed by immunoscintigraphy at time 24 and 48 hours and, in case of tumor targeting, one or more intravenous injections of 90Yttrium-labeled antiferritin Ab at various activities. Results: Ten patients were included in the study: median age 32 years (range: 18–43 years); sex ratio M/F 9; stages III and IV at the time of RIT 1 and 9 pts, respectively; median number of chemotherapy regimens 3 (range: 2–4); number of autografted pts 8; number of previously irradiated pts 9; response to last chemotherapy: 6 PR and 4 progressions. All immunoscintigraphies showed a tumor targeting by 111Indium-labeled antiferritin Ab. Nine patients were treated, one case died of HL evolution. Five pts received one 90Yttrium-labeled antiferritin Ab injection, three pts 2 injections (0.5, 5 et 14 months after the first one), and one pt 4 injections (3, 9 et 16 months after the first one). Median injected activity was 13 MBq/kg (0.35 mCi/kg)(range: 7–15 MBq). Among the 9 treated pts, 1 CR, 6 PR, 1 stable disease, and 1 tumor progression were observed (ORR 78%). The median duration of responses were 8 months (range: 7–12 months). Toxicity was mainly hematological, with neutropenia and anemia of grades 1 or 2, and thrombopenia of grades 2 and 3; one pt presented a generalized convulsive crisis 24 hours after the therapeutic injection, without etiologic evidence. Conclusion: These results confirmed those that have been reported by Vriesendorp and Quadri and showed that rabbit polyclonal antiferritin Ab targeted HL tumor sites and had an important therapeutic potential in this discrepancy situation. They warranted therefore further multicentric prospective trials. [Table: see text]

Patients with stage B or C CLL, under 66 years, previously untreated are included in this trial. They are scheduled to receive 3 monthly courses of mini-CHOP (3mC) followed by 3 monthly courses of Fludarabine (3F) before evaluation of the response. Patients in complete response (NCI) undergo stem cells mobilisation with G-CSF alone, then are randomized between ASCT and observation. Patients not in CR receive 1 or 2 courses of DHAP for mobilisation of stem cells and are randomized between ASCT or 3 monthly courses of Fludarabine/Cytoxan (F/C). The primary endpoint in this study is EFS at 3 years. This first interim analysis was planed after the randomisation of the first 100 patients (6 October 2004). At that time, 142 patients have been included. Among them, 16 have not completed yet the full treatment before randomization; 26 were not randomized because of early death (9), erroneous inclusion (3), autoimmune hemolytic anemia (2), cytopenia (2), investigator’s or patient’s decision (10). From these 26 patients, 14 were nevertheless assessable for response after they received 3mC+3F (1 CR, 4 PR, 2 SD, 7 PD), 6 failed and 6 were not evaluable for response. For each included patient, cytology, flow cytometry, cyclin D1 expression and biological pronostic factors (cytogenetics, IgVH, mutational status, ZAP70 expression) were centrally reviewed. At baseline, 110 patients were in Binet stage B and 32 in Binet stage C. Median age at inclusion was 55 years (min: 31, max: 65). After the six monthly courses (3mC+3F), overall response (CR + PR) was 82.5% (99/120 patients); 49 patients were in CR (41%) from which 48 were randomized between observation and ASCT. 52 patients, not in CR, (46 PR, 5 SD, 1 PD) were randomized between ASCT and F/C. After randomisation, 9 patients died from refractory disease (6), pneumonia (3), neither after ABMT. Two patients had prolonged pancytopenia: one after ASCT who was further allografted and one after F/C. Four patients experienced a Richter syndrome, 3 before ASCT, 1 in the observation arm. Two patients developed hemolytic anemia (one after DHAP, one after the first course of F/C). One patient had hepatitis B virus reactivation 6 months after ASCT. This study is ongoing until randomization of 208 patients. These preliminary results show that in advanced stage CLL (B and C Binet stages) the 3mC+3F regimen displays a very good response rate, which compares favorably with the best published ones. The study of the impact of pronostic biological parameters on response rate is on progress and will be presented at the meeting.

6722 Background:to evaluate the results of combined treatment modality with doxorubicin-based chemotherapy (C), locoregional radiotherapy (RT) and CNS prophylaxis in NHL of the breast. Methods: From 1984 to 1999, 20 female pts with diffuse large B-cell lymphoma of the breast, were treated at the Curie Institute. Following biopsy-established diagnosis, complete physical exam, CAT of the chest, abdomen, pelvis, and brain, CSF, gastric endoscopy, usual blood work, bone marrow biopsy were done. All pts were Ann Arbor stage I -II. The C protocols were: time-modified CHOP: D1, 10, 20,35,50,65 (n=14) or MACOP-B variant (n=3), both with IT MTX and araC. Three pts received ACVB P with IT MTX and 2 HD MTX infusions. All pts had RT to the breast and regional nodes, within a month after C. Total dose was 40 Gy in 20–22 fractions using megavoltage photons. RT to CNS (18 Gy/10 fr.) was delivered in the same time. Results: Median age was 62.8 yrs (ranged 26–86). All pts had a unilateral breast mass, median size 6 cm (2–...

Les recepteurs peripheriques des benzodiazepines (PBR) sont impliques dans de nombreux processus cellulaires. Les PBR ont ete initialement decouverts dans les tissus peripheriques, et ont egalement ete mis en evidence au niveau des cellules gliales du systeme nerveux central (SNC). L'etude de la liaison de plusieurs ligands synthetiques ou endogenes a permis la caracterisation tissulaire et moleculaire de ces recepteurs, ainsi que la decouverte de proteines susceptibles de leur etre associees. Les effets des ligands des PBR concernent principalement les fonctions mitochondriales. Ces ligands interviennent dans la physiologie des mitochondries, la synthese des steroides, les processus de proliferation et de differenciation cellulaires, les processus d'apoptose, et seraient impliques dans la reponse immunitaire.

Association between infectious agents and non-Hodgkin’s lymphomas, such as Hp infection and MALT-type gastric lymphomas or Chlamydia psittaci and OAL, has been previously reported. Therefore, in a large monocentric cohort of OAL patients, we investigated the prevalence of Hp infection in gastric biopsy specimens obtained during the initial staging period. The detection of Hp infection was determined by Giemsa staining of gastric biopsies and by Hp -specific PCR. Among the patients treated at the Institut Curie between 1970 and 2006 for an OAL and for whom gastric tissues were available for PCR analyses, 83 cases were selected for the study. Pathological review according to the WHO classification showed 5 patients with lymphocytic lymphoma, 14 cases with lymphoplasmocytic lymphoma, 6 patients with follicular NHL, 47 cases with MALT type lymphoma (57%), 3 patients with unclassified low-grade NHL, 2 patients with mantle-cell lymphoma, and 6 cases with diffuse large B-cell lymphomas. Initial characteristics were: median age 66 years (range: 26–90); M/F sex ratio 0.9; B symptoms 1%; PS ≥ 2 in 2%; Stages I and IV 59% and 41%, respectively; nodal involvement 24%; 2 or more extra-nodal localizations 34% (10% of bone marrow involvement, 8% of gastric involvement, and 5% of lung localizations); elevated LDH in 9%; serum albumin lower than 40g/l in 32% of patients; and IPI score of 0–1/2/3/4–5 in 60%/21%/18% and 1% of cases, respectively. Ocular localization were intra-orbital in 32 patients (39%), conjunctival in 36 (43%), palpebral in 4 cases, lacrymal in 10 patients, and intra-ocular in 1 case; bilateral ocular sites were found in 10% of cases. The research of Hp infection was performed in 51 patients by Giemsa staining of gastric biopsies with 21 positive cases (41%), and in the 83 selected patients by PCR analysis with 29 positive cases (35%), with an overall number of 37 Hp positive patients (45%). Correlation between histopathological and PCR analyses evaluated on the 51 patients for whom both analyses have been performed is presented in Table 1 (p = 0.011). Finally, we observed that the presence of gastric Hp infection did not correlate with patients’ characteristics of the overall population and of the 47 MALT-type cases. However, on the 83 studied patients, we found a trend of significant difference in Hp positive cases including low albumin levels (p = 0;09), elevated stage (p = 0.08), 2 or more extra-nodal localizations (p = 0.08), and high IPI score (p = 0.06). In conclusion, we observed a high prevalence of gastric Hp infection at the initial diagnosis of OAL, namely 45% of selected cases, with a possible but not significant association of Hp infection with pejorative clinical characteristics. In order to well define this observation and clearly evaluate the impact of Hp infection on the clinical presentation, we are now investigating the prevalence of gastric Hp infection in patients having different histopathological subtypes of nodal malignant lymphomas. | | | Hp-Histopathological anlyses | Hp-Histopathological analyses | |:--------------- | - | ---------------------------- | ----------------------------- | | | | − | + | | Hp PCR analyses | − | 22 (43%) | 8 (16%) | | Hp PCR analyses | + | 8 (16%) | 13 (25%)

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.