Single agent rituximab in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research (SAKK)

Background: Predictive factors of rituximab efficacy and its effect on the immune system are still not defined. Patients and methods: Three hundred and six patients with follicular or mantle cell lymphoma received four weekly doses of rituximab (induction) and no further treatment (arm A) or four more doses at 2-month intervals (arm B). Results: Response rate to induction was 44%. Independent predictive factors for response were disease bulk <5 cm, follicular histology, normal hemoglobin and low lymphocyte count. Factors associated with event-free survival (EFS) were having responded to induction, having received not more than one line of therapy, Ann Arbor stage I-III, high lymphocyte count, disease bulk <5 cm, Fc-gamma receptor genotype VV and receiving prolonged treatment. B cells were suppressed by treatment but recovered after a median of 12 months in arm A and 18 months in arm B. The median IgM level after 1 year was normal in arm A but was decreased to 73% of baseline in arm B. We observed 24 serious adverse events, equally distributed between arms. Ten patients receiving induction only and six patients receiving prolonged treatment developed a second tumor. Conclusions: We defined the characteristics predicting response and EFS to rituximab. Prolonged treatment results in longer EFS at the cost of a longer reduction in B cell and IgM levels, but without additional clinical toxicit

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

Sociodemographic and clinical predictors of depression in children and adolescents: results of a two-year follow-up study

Depressive disorders are a main cause of disability-adjusted life years already in children and adolescents, in whom the clinical picture somewhat differs from adult-onset depression. Thus, we studied sociodemographic and clinical predictors of depression/dysthymia in a sample of minors. Our baseline sample (N=676) included patients at clinical high-risk for psychosis (CHR-P, n=183), inpatients admitted for non-psychotic, non-affective disorders (n=277), and community participants (n=216) of age 7.0 to 17.9 years (43.8% male). They were assessed by clinical psychologists for mental disorders and symptoms with various clinical interviews including the Mini International Neuropsychiatric Interview for Children and Adolescents, which was also used to assess depression/dysthymia in the CHR-P group at 1- and 2-year-follow up (n=117 and 73, respectively). Analyses followed a stepwise procedure at baseline with stepwise logistic regression analyses to identify the final baseline model that was tested in the follow-up samples. The final cross-sectional model included nationality and 13 clinical variables Mild depressive symptoms in particular played a decisive role here. Variables contributing significantly to the prediction varied over time, indicating that CAD depression/dysthymia may require different predictors depending on the follow-up time. Furthermore, the prospective accuracy of ruling out depression/dysthymia was superior to the accuracy of ruling it in. This lower positive likelihood ratio might be overcome in future by stepwise approaches that further stratify risk in those initially identified as at increased risk of depression/dysthymia

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

Protein C anticoagulant system—anti-inflammatory effects

Activated protein C (APC) plays active roles in preventing progression of a number of disease processes. These include thrombosis due to its direct anticoagulant activity which is likely augmented by its cytoprotective activity, thereby limiting exposure of procoagulant cellular membrane surfaces on cells. Beyond that, the pathway signals the cells to prevent apoptosis, to dampen inflammation, to increase endothelial barrier function, and to selectively downregulate some genes implicated in disease progression. Most of these functions are manifested to APC binding to endothelial protein C receptor (EPCR) allowing PAR1 activation, but activation of other PARS is also implicated in some cases. In addition to EPCR orchestrating these changes, CD11b is also capable of supporting APC signaling. Selective control of these pathways offers potential in new therapeutic approaches to disease

Transcriptome analysis revealed unique genes as targets for the anti-inflammatory action of activated protein C in human macrophages

BACKGROUND: Activated protein C (APC) has been introduced as a therapeutic agent for treatment of patients with severe sepsis due to its unique anticoagulant and anti-inflammatory properties in the vascular system. In this study we investigated novel targets for the anti-inflammatory action of APC in human macrophages. METHODS: Using a genome-wide approach, effects of APC on the expression profile in inflammatory activated human macrophages were analyzed. RESULTS: We identified, for the first time, genes that are specifically regulated by APC under inflammatory conditions, such as chromatin binding protein 4B (CHMP4B) and p300/CBP-associated factor (PCAF), thus indicating a role of APC in the epigenetic control of gene transcription. A functional assay showed the influence of APC in the acetyltransferase/deacetylase activity of nuclear extracts from inflamed macrophages. CONCLUSION: Our data sheds new light on APC targets in inflammation and opens new lines of investigation that may be explored in order to further elucidate its unique molecule properties