Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability.

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE <sup>-/-</sup> mice transplanted with AT1aR <sup>-/-</sup> or AT1aR <sup>+/+</sup> BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR <sup>-/-</sup> BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR <sup>-/-</sup> BM 2K1C mice (-79% in the aortic sinus and -71% in whole aorta compared to controls). Plaques from AT1aR <sup>-/-</sup> BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (-82% and -88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR <sup>-/-</sup> BM 2K1C mice. No significant differences in either the number of circulating Ly6C <sup>high</sup> inflammatory monocytes and Ly6C <sup>low</sup> resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability

A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.

BACKGROUND: CD19 is a B cell lineage specific surface receptor whose broad expression, from pro-B cells to early plasma cells, makes it an attractive target for the immunotherapy of B cell malignancies. In this study we present the generation of a novel humanized anti-CD19 monoclonal antibody (mAb), GBR 401, and investigate its therapeutic potential on human B cell malignancies. METHODS: GBR 401 was partially defucosylated in order to enhance its cytotoxic function. We analyzed the in vitro depleting effects of GBR 401 against B cell lines and primary malignant B cells from patients in the presence or in absence of purified NK cells isolated from healthy donors. In vivo, the antibody dependent cellular cytotoxicity (ADCC) efficacy of GBR 401 was assessed in a B cell depletion model consisting of SCID mice injected with healthy human donor PBMC, and a malignant B cell depletion model where SCID mice are xenografted with both primary human B-CLL tumors and heterologous human NK cells. Furthermore, the anti-tumor activity of GBR 401 was also evaluated in a xenochimeric mouse model of human Burkitt lymphoma using mice xenografted intravenously with Raji cells. Pharmacological inhibition tests were used to characterize the mechanism of the cell death induced by GBR 401. RESULTS: GBR 401 exerts a potent in vitro and in vivo cytotoxic activity against primary samples from patients representing various B-cell malignancies. GBR 401 elicits a markedly higher level of ADCC on primary malignant B cells when compared to fucosylated similar mAb and to Rituximab, the current anti-CD20 mAb standard immunotherapeutic treatment for B cell malignancies, showing killing at 500 times lower concentrations. Of interest, GBR 401 also exhibits a potent direct killing effect in different malignant B cell lines that involves homotypic aggregation mediated by actin relocalization. CONCLUSION: These results contribute to consolidate clinical interest in developing GBR 401 for treatment of hematopoietic B cell malignancies, particularly for patients refractory to anti-CD20 mAb therapies

Suivi thérapeutique de l'imatinib

* Le monitoring (suivi) joue un rôle important pour un traitement et son évaluation - pour autant qu'il se base sur la mesure de marqueurs cliniques adéquats ou de substituts validés. * Pour ce qui est du traitement d'imatinib, le «therapeutic drug monitoring» (TDM) semble être une option utile pour le contrôle du traitement de la LMC. Il utilise la concentration plasmatique de ce médicament comme marqueur. * Les concentrations plasmatiques d'imatinib varient considérablement d'un patient à l'autre sous un même schéma posologique, en raison de la variabilité interindividuelle de sa pharmacocinétique. Il a été démontré que l'exposition plasmatique était en corrélation avec le résultat clinique des patients LMC - aussi bien pour la réponse au traitement que pour le profil d'effets indésirables. * Il n'est pas encore établi si le TDM de l'imatinib doit être utilisé que dans le cas de problèmes cliniques ou si les patients LMC peuvent déjà profiter d'un contrôle préventif systématique «de routine» - de manière à garder la concentration plasmatique dans des marges thérapeutiques. Cela est toujours plus recommandé ces derniers temps. * Pour répondre à cette question, une étude suisse prospective, randomisée et contrôlée recrute des patients LMC traités par imatinib depuis moins de 5 ans et propose en outre le TDM pour tous les patients en cas de problèmes cliniques. - * Monitoring spielt eine wichtige Rolle zur Therapieevaluierung und Behandlungsentscheidung - solange es auf der Basis der Messung von entsprechenden klinischen oder validierten Surrogat-Markern stattfindet. * Im Hinblick auf die Imatinib-Therapie scheint das «Therapeutische Drug-Monitoring» (TDM) ein nützlicher Ansatz zum Therapie-Monitoring der CML-Behandlung zu sein, welches die Plasmakonzentration des Arzneimittels als Marker zur Therapieüberwachung verwendet. * Imatinib-Plasmakonzentrationen variieren beträchtlich von Patient zu Patient unter dem gleichen Dosierungsschema, aufgrund der interindividuell unterschiedlichen Pharmakokinetik des Arzneimittels. Für die Plasmaexposition wurde gezeigt, dass sie mit dem klinischen Outcome von CML-Patienten korreliert - sowohl im Bezug auf das Therapieansprechen als auch auf das Nebenwirkungsprofil. * Es ist noch unklar, ob das TDM von Imatinib nur im Falle von klinischen Problemen Verwendung finden sollte oder ob CML-Patienten bereits von einem systematischen, präventiven «Routine»-Monitoring zur Therapieindividualisierung - zur Steuerung der Plasmakonzentration in einen therapeutischen Bereich - profitieren könnten, welches in letzter Zeit immer häufiger empfohlen wird. * Um diese Fragestellung zu beantworten, nimmt eine prospektive, randomisiert kontrollierte Schweizer Studie CML-Patienten auf, die seit weniger als 5 Jahren mit Imatinib behandelt werden, und bietet das TDM zudem für alle Patienten im Falle von klinischen Problemen an

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents

Patients' experiences with cancer care in Switzerland: Results of a multicentre cross-sectional survey.

The objectives were to describe patients' experiences of cancer care in Switzerland and explore the variation of these experiences by type of cancer. The Swiss Cancer Patient Experiences (SCAPE) study was a cross-sectional, multicentre survey conducted in 2018. Adult patients (n = 7145) with breast, prostate, lung, colorectal, skin or haematological cancer from four large hospitals in French-speaking Switzerland were invited to complete a survey. Logistic regressions were used to assess whether experiences varied according to cancer type, adjusting for confounders. Of the 3121 persons who returned the survey (44% response rate), 2755 reporting an eligible cancer were included in the analyses. Participants' average score for overall care was 8.5 out of a maximum score of 10. Higher rates of positive experiences were found for nurse consultations (94%), diagnostic tests (85%) and inpatient care (82%). Lower positive responses were reported for support for people with cancer (70%), treatment decisions (66%), diagnosis (65%) and home care (55%). We observed non-systematic differences in experiences of care by cancer type. This large study identified that cancer patient experiences can be improved in relation to communication, information and supportive care aspects. Improvement efforts should target these areas of care to enhance responsiveness of cancer care

Transfer of human systemic lupus erythematosus in severe combined immunodeficient (SCID) mice

To study the role of peripheral blood leukocytes (PBL) in the pathogenesis of human systemic lupus erythematosus (SLE), we transferred PBL from 5 SLE patients into 15 severe combined immunodeficiency (SCID) mice. Such reconstituted mice showed long-term presence of auto-antibodies characteristic of the donor in their sera, as well as human immunoglobulin deposition, and in some cases mouse C3, in the renal glomeruli. SCID mice repopulated with PBLs from normal donors do not develop serologic abnormalities or immunodeposits. It is concluded that human SLE serology and some associated renal changes can be reproduced solely by PBL transferred from afflicted patients, and that SCID-human-SLE mice may serve as an in vivo laboratory model for the study of human SLE

Current status and updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland

The availability of drugs such as thalidomide, bortezomib and lenalidomide changed the landscape in myeloma treatment and has extended the median survival up to 10 years with a substantial improvement in quality of life. This development prompted a Swiss expert panel to re-evaluate the current status and formulate updated clinical recommendations for the diagnosis and treatment of plasma cell myeloma. These recommendations should help clinicians in their decision making to achieve the best outcome based on currently available data

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial

Purpose: This study assessed whether a cycle of "routine” therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000ng/ml (tolerance: 750-1,500ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue” TDM). Methods: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5years. Patients were allocated 1:1 to "routine TDM” or "rescue TDM.” The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). Results: Among 56 patients (55 evaluable), 14/27 (52%) receiving "routine TDM” remained event-free versus 16/28 (57%) "rescue TDM” controls (P=0.69). In the "routine TDM” arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895ng/ml), who had fewer unfavorable events (28%) than the 13 not receiving the advised dosage (77%; P=0.03; median C min: 648ng/ml). Conclusions: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM” because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents