Investigation of fullerene cluster growth mechanisms by carbon atom addition using classical molecular dynamics.

The mechanisms of carbon sticking reactions to C36 and C-C80 fullerenes were investigated with molecular dynamics simulations (MD) using the Second-generation Reactive Empirical Bond Order (SREBO) and Adaptive Intermolecular Reactive Empirical Bond Order (AIREBO) potentials that were specifically optimized for carbon-carbon interactions. Results showed the existence of three possible sticking configurations where the projectile atom can stick either to one, two or three atoms of the target fullerene. They also showed that although the two potentials give similar magnitudes for the sticking cross-sections, they yield fairly different results as far as sticking mechanisms and configurations at thermal collision-energies, i.e., in the range 0.05-0.5 eV, are concerned. While AIREBO, that takes into account the long-range Lennard-Jones interaction, essentially results in a surface-sticking configuration with a single atom of the target fullerene, SREBO potential yields both surface- and two neighbors-sticking (2N-sticking) configurations. The fullerene structure is preserved in the last configuration while it can be recovered by a 2000 K annealing in the former configuration. Results obtained with SREBO eventually showed larger sticking probabilities for C36 as compared with C80. In spite of this, the sticking cross-sections obtained for C80 are similar to or even larger than those obtained for C36 due to the larger size of C80 that compensates for its smaller sticking probabilities.

Binary and ternary Pt-based clusters grown in a plasma multimagnetron-based gas aggregation source: electrocatalytic evaluation towards glycerol oxidation.

Platinum (Pt), platinum-bismuth (PtBi), platinum-copper (PtCu) and platinum-bismuth-copper (PtCuBi) clusters were grown in a gas aggregation source (GAS) equipped with three in-plane plasma magnetrons located in a single region of the gas aggregation zone. The X-ray diffraction results have shown that PtCu clusters form alloys as the decrease of the lattice parameter occurs when the Cu atomic content increases. PtBi clusters do not form alloys, but the presence of secondary Bi oxide phases was detected. Scanning transmission electron microscope mapping images revealed that simultaneously adding Bi and Cu to Pt leads to PtCu alloyed clusters decorated with Bi or CuBi species on the surface. The electrochemical results indicated that the shell might be composed of a metastable CuBi phase. Electrochemical measurements have shown that the addition of Bi or Cu to the Pt clusters enhances the catalytic activity for glycerol oxidation by decreasing the oxidation onset potential.

Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.

Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature.

PURPOSE: To analyze therapy-related acute myeloid leukemias (tAMLs) with t(8;21), inv(16), or t(8;16). PATIENTS AND METHODS: Twenty-five patients with tAML and t(8;21)(q22;q22), inv(16)(p13;q22), or t(8;16)(p11;p13) from seven centers, along with 23 previously published cases, were studied. RESULTS: Twenty-six, 16, and six patients, respectively, had t(8;21), inv(16), and t(8;16). Prior cancer was a solid tumor in 27 cases, and a hematologic malignancy in all other patients. Five patients had received prior radiotherapy (RT) alone, and 43 had received prior chemotherapy with or without RT. Prior chemotherapy included a drug that directly reacts with DNA (alkylating agent or cisplatin) and/or an agent that targets topoisomerase II (ATTop, an anthracycline or derivative or, less often, epipodophyllotoxin) in most patients. The interval between prior tumor and diagnosis of tAML was less than 3 years in most cases, and only seven patients had a preleukemic phase of disease. Morphology was M2 AML for t(8;21), M4eo for inv(16), and M4 or M5 for t(8;16). Sixteen of 21 (76%), 12 of 14 (86%), and zero of four patients with t(8;21), inv(16), and t(8;16), respectively, achieved complete remission (CR) with intensive chemotherapy. The actuarial disease-free survival rate at 24 months was 47% and 54% in patients with t(8;21) and inv(16), respectively. CONCLUSION: Like other tAMLs with a karyotype specific of de novo AML [balanced 11q23 rearrangement or t(15;17)], tAMLs with t(8;21), inv(16), or t(8;16) are usually characterized by a short latent period, previous treatment often combining a drug that directly reacts with DNA and an ATTop, and absence of preleukemic phase. Hematologic characteristics and response to treatment are also identical to those of de novo AML with the same karyotypes.

Autologous peripheral-blood progenitor-cell support following high-dosechemotherapy or chemoradiotherapy in patients with high-risk multiple myeloma.

PURPOSE: The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low. RESULTS: One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.

Scoring system for the prediction of successful peripheral blood stem cell (PBSC) collection in non-Hodgkin's lymphoma (NHL): application in clinical practice.

Fifty-six patients with chemosensitive NHL were studied to assess factors affecting mobilization and peripheral blood stem cell (PBSC) collection: all were mobilized with high-dose cyclophosphamide and etoposide and G-CSF 5 microg/kg/day. None of them had bone marrow involvement at the time of mobilization or a history of extended field irradiation. Previous chemotherapy regimens were divided into two groups: moderately myelotoxic chemotherapy (MMC) and highly myelotoxic chemotherapy (HMC). The adequacy of the PBSC harvest was not associated with age, gender, a past history of bone marrow involvement or disease status. In contrast, the number of MMC cycles (n(MMC)) and the number of HMC cycles (n(HMC)) were both significant (P = 0.009 and P = 0.0004, respectively) and were used to compute a score predictive of a successful PBSC harvest: SCORE = n(MMC) + 4 n(HMC). The estimated successful PBSC collection rate was greater than 80% in patients with a score ranging from 0 to 15 and dropped rapidly to below 20% in patients with a score exceeding 25. This scoring system may help to determine the timing of PBSC mobilization in patients with a score below 15 and suggests that new PBSC mobilization procedures should be investigated in other patients. Bone Marrow Transplantation (2000) 25, 495-499.

VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensification program in relapsed or refractory Hodgkin's disease.

Forty-two patients with refractory (15 patients) or relapsed (27 patients) Hodgkin's disease (HD) were included in a prospective single center study evaluating the efficacy of a regimen VIP combining etoposide 75 mg/m2/day days 1-5, ifosfamide 1.2 g/m2/day days 1-5 and cisplatinum 20 mg/m2/day days 1-5, one course every 4 weeks as salvage therapy in patients with refractory or relapsed Hodgkin's disease, potentially eligible for high-dose chemotherapy with reinjection of hematopoietic stem cells (HSC). If patients were considered chemosensitive after two courses of VIP, high-dose chemotherapy followed by the reinjection of HSC was planned. After two courses of VIP, 67% achieved an objective response including 38% complete responses. Overall, 28 patients went on to high-dose therapy with reinjection of HSC, and 46% of grafted patients are in a sustained complete remission. When the overall patient population is considered, 33% are in complete remission (CR) with a median follow-up of 37 months. A CR of less than 12 months and refractory disease were associated with a poor survival. These results showed that the VIP regimen is effective in relapsed or refractory HD and allows high-dose therapy to be given in the case of most responding patients. However, results in patients with refractory disease or a first complete remission of less than 12 months need to be further improved.

Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study.

Vaginal bleeding during aplasia can induce transfusion support, infection and discomfort. Oral and intramuscular hormonotherapy can be toxic and/or difficult to manage (mucositis). This single-center pilot study evaluated the efficacy and safety of leuprorelin (L) in preventing heavy vaginal bleeding in 20 nonmenopausal women with leukemia, lymphoma or myeloma and foreseable therapy-induced thrombocytopenia. Until platelet recovery, patients received subcutaneous injections of L, with concomitant nomegestrol acetate (NA) during the first 35 days to prevent flare-up. Median age was 33 years (18-48). Platelet nadir was < 20 x 10(9)/l in 17 patients; 103 L injections were performed (median per patient: 4 [1-14]). No moderate or severe adverse event was related to hormonal therapy. Seventeen patients did not experience any clinically or therapeutically relevant bleeding. Eleven spottings and 8 metrorrhagias (mean duration: 3 days) occurred in 11 patients, requiring enhanced NA in 3 cases (baseline platelet count was < 20 x 10(9)/l in 1 pt, premature termination of NA [the single platelet transfusion for metrorrhagia] in 1 pt, and endometrial hyperplasia (EH) in the third). In patients without EH, only 5 spottings were observed after the third injection, without neither clinical nor therapeutic impact (63 injections). In conclusion, leuprorelin administration is safe and effective in preventing vaginal bleeding. The sustained-release form and subcutaneous administration offer quality of life advantages.

Acute myelogenous leukemia with T-cell features.

From May 1985 to June 1990, 94 newly diagnosed cases of acute myelogenous leukemia (AML) were treated at the Institut Gustave-Roussy, of which four (4.3%) demonstrated mixed cell lineage. All these cases were morphologically and cytochemically considered as myelogenous leukemias according to the FAB classification. Immunophenotyping revealed in all four cases that the blast population had T-lymphoid (CD2, CD5, CD7 and cytoplasmic CD3) markers. In three of these cases, blast cells co-expressed myelogenous CD13 and CD33 markers. Cytogenetic analysis of the blast cells revealed a normal karyotype in all cases. The response to therapy has been poor. The two patients initially treated with a regimen usually used for AML did not achieve complete remission. By contrast, in three cases, complete remission was obtained with a drug combination used for lymphoblastic leukemia (in one case after failure of first line AML regimen). Only one patient remained disease-free for more than 18 months. We conclude that this form of leukemia is a distinct biological and clinical entity and may benefit form alternative therapy.

[Salvage therapy of relapsing or refractory malignant lymphoma with non-myelotoxic combined chemotherapy. Results of combination of cisplatin, bleomycin, methyl-GAG and prednisolone (Cis-BMP)]. / Traitement de rattrapage des lymphomes malins en rechute ou réfractaires par une combinaison chimiothérapique peu myélotoxique. Resultats de l'association cisplatine, bléomycine, methyl-GAG et prednisolone (Cis-BMP).

Fifty-one patients with primary refractory or relapsed malignant lymphoma (47 non-Hodgkin's lymphoma and four Hodgkin's disease) were treated with a new chemotherapeutic regimen (cisplatinum, methyl GAG, bleomocyin, methyl prednisolon). Among these 51 patients, 41 had measurable disease. Three of these 41 patients achieved complete remissions (7.3%) and 17 showed partial response (41.5%). The low hematological toxicity of this chemotherapeutic combination allowed us to give the full dose at the planned cycle date in 90% of the cycles. No major toxicity were observed (two minor neurological toxicities, one ototoxicity associated with oral mucositis toxicity, 6 febrile episodes) during 164 courses. With a median follow-up of 12 months, 18% of patients were alive without disease. We conclude that in this particular population of malignant lymphomas, Cis-BMP is an effective therapy with minimal toxicity.

Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles.

Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.