High-dose therapy and autologous hematopoietic stem cell transplantation in T-cell lymphoma : a single centre experience

Le diagnostic de lymphome représente 4% de tous les cancers et a une incidence particulièrement élevée dans les pays industrialisés. La proportion de lymphomes T, évaluée en Europe et aux Etats Unis, représente environ 5 à 10% des lymphomes. Alors que des progrès très sensibles ont été apportés dans la prise en charge et le pronostic des lymphomes B agressifs durant ces dernières décennies et en particulier depuis le début des années 2000 avec l'utilisation des anticorps anti-CD20 associés à la chimiothérapie, le pronostic des lymphomes T reste très décevant. La survie globale des lymphomes T à 5 ans est estimée entre 28% et 38%. Le bénéfice réel d'une chimiothérapie intensive suivie d'une autogreffe de cellules souches hématopoïétiques périphériques au terme d'un traitement de chimiothérapie d'induction dans le lymphome T périphérique reste débattu. Les résultats des rares études prospectives et des études rétrospectives à disposition sont discordants. Nous avons donc analysé rétrospectivement 43 patients successifs de mars 2000 à mars 2011, atteints de lymphome T, issus de notre base de données du programme autogreffe lausannois. Nos analyses statistiques permettent, sur la base d'un suivi médian de 63 mois, une estimation à 12 ans, de la survie globale de nos patients à 40%, de la survie sans progression à 34% et de la survie sans événement à 30%. Ces chiffres s'inscrivent parfaitement dans les résultats des études prospectives qui montrent un bénéfice de l'autogreffe dans le lymphome T. Parmi les différents paramètres pronostiques habituellement évalués, l'âge et l'absence de symptômes B au diagnostic sont les seuls paramètres statistiquement significatifs en analyse univariée dans notre cohorte. En effet, Les patients de moins de 50 ans et ceux qui ne présentent pas de symptômes B au diagnostic ont un meilleur pronostic. Nous concluons de cette analyse que les patients traités par chimiothérapie intensive et autogreffe de cellules souches hématopoïétiques périphériques ont une survie moyenne supérieure aux résultats rapportés dans la littérature avec des traitements de chimiothérapie conventionnelle de type CHOP. En effet, on estime à environ 50% les patients répondant à une chimiothérapie conventionnelle de type CHOP.

La stratégie thérapeutique anti-VEGF améliore le pronostic visuel de la dégénérescence maculaire liée à l'âge exsudative [Intravitreal anti-VEGF injections improve the visual prognosis of wet age related macular degeneration].

Age related macular degeneration (AMD) is an ocular disease with high prevalence among elderly persons. Two different forms exist: dry AMD, usually slowly progressive, and neovascular AMD (wet form) more aggressive. Photodynamic therapy is used to treat the wet form and anti VEGF treatments recently became available and offer a real change in the prognostic of wet AMD. Two products are registered and used in Switzerland (Macugen and Lucentis), a third "off labels product", Avastin is also currently used in clinical practice. Nevertheless, both the duration of treatment and the number of injection requested to stabilise the disease were not defined in the studies. Ongoing studies are mainly evaluating combined treatments and long acting form of the drug.

Airway epithelial IL-15 transforms monocytes into dendritic cells.

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha gene expression up to 300-fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6(+), CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1(-), CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.

Effects of neuroinflammation on demyelination and remyelination: an in vitro study in aggregating brain cell cultures

La neuroinflammation joue un rôle important dans de nombreuses maladies neurodégéneratives dont la sclérose en plaques. Les microglies et les astrocytes sont les cellules effectrices de la réponse inflammatoire dans le cerveau et sont impliquées dans les processus de démyélinisation et de remyélinisation. Dans ce travail, nous avons étudié les réactions inflammatoires accompagnant la démyélinisation et leurs conséquences sur la remyélinisation. Dans ce but, trois différents traitements démyélinisants ont été appliqués sur des cultures en agrégats de télencéphales de rats, à savoir (i) la lysophosphatidylcholine, (ii) l'interféron-γ (IFN-γ) combiné avec du lipopolysaccharide (LPS), et (iii) des anticorps dirigés contre la MOG (myelin oligodendrocyte glycoprotein) en présence de complément. Nous avons montré que ces traitements induisent différents types de démyélinisation, de réponses inflammatoires et d'effets secondaires sur les neurones. Nous avons ensuite examiné les effets de l'atténuation de la réponse inflammatoire sur la démyélinisation et la remyélinisation, en utilisant la minocycline, un antibiotique bloquant la réactivité microgiale, et le GW 5501516, un agoniste de PPAR-β (peroxisome proliferator-activated receptor-β). Nous avons montré que la minocycline prévient l'activation microgliale induite par le traitement avec l'IFN-γ et le LPS, mais qu'elle ne protège pas de la démyélinisation. Néanmoins, elle induit une remyélinisation, probablement en favorisant la maturation d'oligodendrocytes immatures. Le GW 501516 diminue l'expression de l'IFN-γ après une démyélinisation induite par les anticorps anti-MOG, mais il ne prévient pas la démyélinisation et ne favorise pas la remyélinisation. Ces résultats indiquent que la démyélinisation induite par le traitement avec l'IFN-γ et le LPS n'est pas une conséquence directe de l'activation microgliale, et que l'augmentation de l'expression de l'IFN-γ ne participe pas à la démyélinisation induite par les anticorps anti-MOG. Ces résultats suggèrent que l'atténuation de l'activation microgliale est bénéfique pour la remyélinisation.

Molecular basis of leukocyte rolling on PSGL-1. Predominant role of core-2 O-glycans and of tyrosine sulfate residue 51.

Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues. Simultaneous expression of core-2 beta1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44, strongly decreased L-selectin binding and leukocyte rolling on PSGL-1. Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor role, an observation that contrasts with the pattern seen for the interactions between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling analysis of L-selectin and P-selectin interactions with PSGL-1 further supported these observations. Additional experiments showed that core-2 O-glycans attached to Thr-57 were also of critical importance in regulating the velocity and stability of leukocyte rolling. These observations pinpoint the structural characteristics of PSGL-1 that are required for optimal interactions with L-selectin and may be responsible for the specific kinetic and mechanical bond properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.

Rhumatologie. Denosumab: le joker du rhumatologue [Denosumab, the rheumatologist's joker?]

The number of molecules acting on bone turn over rapidly increasing. The idea to use them on bones erosions is not new, however this year a new molecule confirms the suitability of such an approach with the demonstration of efficency in both postmenopausal osteoporosis as well as in the prevention of bone erosions in rheumatoid arthritis. Denosumab, a human monoclonal antibody against RANKL (Receptor Activator of Nuclear factor-KB ligand), decreases the fracture risk in postmenopausal osteoporosis and prevents new bone erosions in rheumatoid arthritis. Of simple use, it appears to act rapidly, to be efficient with a sustain benefit. The tolerance seems excellent, and now we'll have just to wait for its licensing.

Antigène carcino-embryonnaire circulant, fortement élevé et persistant, sans cancer décelable

A markedly elevated circulating CEA level was observed in January 1978 in a 40-year-old male patient who complained of functional digestive disorders consisting of 2-3 bowel movements at the end of each night. During follow-up of more than 3 years the CEA level was always found to be higher than 300 ng/ml as determined on 12 different blood samples using 3 different assays: the Hansen assay, our own inhibition radioimmunoassay performed on perchloric acid extract of serum, and a newly developed solid phase non-competitive enzyme immunoassay involving monoclonal anti-CEA antibody. The clinical evolution showed no aggravation of the persistent but mild bowel troubles, i.e. no real diarrhea or blood in the stool. The patient enjoys excellent general health and shows no weight loss. Barium enema, colonoscopy and extensive investigation by computerized axial tomography showed no evidence of primary or metastatic tumor. Apart from CEA, the blood chemistry was within normal limits. Six members of the patient's family have normal CEA levels. A possible explanation for this unique case of marked and persistent elevation of circulating CEA without evidence of cancer is discussed.

Different behaviour of mouse-human chimeric antibody F(ab')2 fragments of IgG1, IgG2 and IgG4 sub-class in vivo.

Mouse-human chimeric monoclonal antibodies (MAbs) of 3 different human IgG sub-classes directed against carcinoembryonic antigen (CEA) have been produced in SP-0 cells transfected with genomic chimeric DNA. F(ab')2 fragments were obtained by pepsin digestion of the purified chimeric MAbs of human IgG1, IgG2 and IgG4 sub-class and of parental mouse MAb IgG1. The 4 F(ab')2 fragments exhibit similar molecular weight by SDS-PAGE. They were labelled with 125I or 131I and high binding (80 to 87%) to purified unsolubilized CEA was observed. In vivo, double labelling experiments indicate that the longest biological half-life and the highest tumour-localization capacity is obtained with F(ab')2 from chimeric MAb of human IgG2 sub-class, whereas F(ab')2 from chimeric MAb IgG4 give very low values for these 2 parameters. F(ab')2 from chimeric MAb IgG1 and from parental mouse MAb yield intermediate results in vivo. Our findings should help to select the appropriate human IgG sub-class to produce chimeric or reshaped MAb F(ab')2 to be used for tumour detection by immunoscintigraphy and for radioimmunotherapy.

Therapeutic drug monitoring in cancer - Are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

The BAFF/APRIL system in SLE pathogenesis.

Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.

Schweizerisches Register für TNF-alpha-Blocker bei Kindern und Jugendlichen mit rheumatologischen Erkrankungen [Swiss registry for TNF-alpha blockers in children and adolescents with rheumatological diseases].

We created a registry to evaluate long term outcome, efficacy and adverse events for children treated wit TNF-alpha inhibitors in Switzerland. 106 patients (68 female/38 male) were included. 61 patients were treated with Etanercept (Enbrel) and 45 with Infliximab (Remicade). Concomitant treatment at baseline included corticosteroids in 26% and Methotrexate in 75% of the patients. Subjective disease activity three months after initiation of TNF-alpha was better in 81%, worse in 4% and stable in 15% of the patients. In total 24 adverse events in 21 patients were reported. Treatment with TNF-alpha inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases.

MHC class I-related chain A conjugated to antitumor antibodies can sensitize tumor cells to specific lysis by natural killer cells.

PURPOSE: As a first step for the development of a new cancer immunotherapy strategy, we evaluated whether antibody-mediated coating by MHC class I-related chain A (MICA) could sensitize tumor cells to lysis by natural killer (NK) cells. EXPERIMENTAL DESIGN: Recombinant MICA (rMICA) was chemically conjugated to Fab' fragments from monoclonal antibodies specific for tumor-associated antigens, such as carcinoembryonic antigen, HER2, or CD20. RESULTS: Flow cytometry analysis showed an efficient coating of MICA-negative human cancer cell lines with the Fab-rMICA conjugates. This was strictly dependent on the expression of the appropriate tumor-associated antigens in the target cells. Importantly, preincubation of the tumor cells with the appropriate Fab-rMICA conjugate resulted in NK cell-mediated tumor cell lysis. Antibody blocking of the NKG2D receptor in NK cells prevented conjugate-mediated tumor cell lysis. CONCLUSIONS: These results open the way to the development of immunotherapy strategies based on antibody-mediated targeting of MICA.

Dosimetry of 90Y-ibritumomab tiuxetan as consolidation of first remission in advanced-stage follicular lymphoma: results from the international phase 3 first-line indolent trial.

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). METHODS: The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. RESULTS: Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. CONCLUSION: In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.

Early production of IL-4 in susceptible mice infected with Leishmania major rapidly induces IL-12 unresponsiveness.

Previous results have documented a burst of IL-4 mRNA that peaks in draining lymph nodes of susceptible BALB/c mice 16 h after infection with Leishmania major. The importance of this early IL-4 response in subsequent Th2 cell maturation is supported by observations showing that 1) neutralization of IL-4 at the initiation of infection or 2) administration of IL-12, which results in an inhibition of the 16 h IL-4 mRNA burst, inhibits Th2 cell development. However, both treatments are effective in hampering Th2 cell development only if given at a time when IL-4 has been produced for &lt;48 h. At this time after infection, lymph node CD4+ T cells from BALB/c mice no longer respond to IL-12. This IL-12 unresponsiveness is prevented in mice treated with anti-IL-4 Abs at the initiation of infection. Finally, the inhibition of Th2 development in BALB/c mice treated with anti-IL-4 Abs at the onset of infection results from maintenance of IL-12 responsiveness, since it requires IL-12. Together, these results reveal a narrow window of time, between 16 h and &lt;48 h after infection, during which IL-4 produced rapidly in BALB/c mice renders T cells unresponsive to IL-12, allowing their differentiation toward the Th2 phenotype.