Outcome of patients with newly diagnosed AML admitted to the ICU, including preemptive admission - a multi-center study.

Acute myeloid leukemia (AML) can lead to life-threatening complications that may require intensive care unit (ICU) management. It has been advocated that early preemptive (ePE) ICU admission, before the onset of organ failure, could benefit some high-risk patients such as those with hyperleukocytosis. The aim of this study was to retrospectively analyze the outcome of newly diagnosed AML patients who required ICU admission in five academic centers with a special focus on patients with an ePE admission strategy, i.e., those transferred to the ICU without any organ failure (modified SOFA score ≤ 2 [omitting thrombocytopenia] and no life-sustaining intervention in the first 24 h following ICU admission) before the start of induction therapy. Between January 2017 and December 2019, 428 patients were included among which 101 were admitted to the ICU. Among patients requiring life-sustaining interventions (n = 83), 18 (22%) died while in the ICU but ICU survivors had the same survival as those not admitted to the ICU. Patients with an ePE admission (n = 18) had more comorbidities and high-risk disease features such as hyperleukocytosis but required no life-sustaining interventions while in the ICU. In a subgroup analysis of patients with hyperleukocytosis ≥ 50 G/l at diagnosis (n = 85), patients not admitted to the ICU and those admitted with an ePE strategy had similar outcomes. This study provides encouraging results about ICU outcome in AML patients during induction therapy but the potential benefit of an ePE strategy must be confirmed prospectively.

[The need for a better definition of therapeutic indications of carboxypeptidase in delayed elimination of methotrexate]. / Les critères d'utilisation de la carboxypeptidase dans les surexpositions au méthotrexate doivent être mieux définis.

OBJECTIVES: High dose methotrexate (HD-MTX) may cause nonhaematological and haematological toxicities. MTX overexposure may be subsequent to administration errors or to delayed renal elimination resulting from MTX nephrotoxicity. The rescue agent carboxypeptidase rapidly hydrolyses MTX to inactive metabolites. However, current criteria for carboxypeptidase use are not well defined. We retrospectively evaluated the number of patients how should have received the drug if the criteria were applied, but who didn't receive it, and analysed their toxicities. METHODS: Patients treated at our institution in 2004 and 2005 and presenting the following criteria: concentrations of MTX at H48 >or= 3 microM, or impaired renal function, were considered. Post-course tolerance was recorded and graded. Recovery of renal function was followed-up periodically up to the 3rd month following the end of treatment. RESULTS: Twenty courses over 301 (7%) and 18 patients over 120 exhibited at least one criterion. Grade 3-4 toxicity was observed in 30% of the courses, including 2 severe acute renal impairment. Renal function decreased in most patients but had recovered upon the 3rd month in all but 2 patients. CONCLUSION: Despite a higher rate of toxicity than in general population, most of the patients recovered from it. Considering the cost of this treatment, the criteria for its therapeutic use could be restricted to concentration of MTX at H48 superior at 10 microM, associated with renal impairment.

[Not Available]. / Les critères d'utilisation de la carboxypeptidase dans les surexpositions au méthotrexate doivent être mieux définis.

OBJECTIVES: High dose methotrexate (HD-MTX) may cause nonhaematological and haematological toxicities. MTX overexposure may be subsequent to administration errors or to delayed renal elimination resulting from MTX nephrotoxicity. The rescue agent carboxypeptidase rapidly hydrolyses MTX to inactive metabolites. However, current criteria for carboxypeptidase use are not well defined. We retrospectively evaluated the number of patients how should have received the drug if the criteria were applied, but who didn't receive it, and analysed their toxicities. METHODS: Patients treated at our institution in 2004 and 2005 and presenting the following criteria: concentrations of MTX at H48 ≥ 3 µM, or impaired renal function, were considered. Post-course tolerance was recorded and graded. Recovery of renal function was followed-up periodically up to the 3rd month following the end of treatment. RESULTS: Twenty courses over 301 (7%) and 18 patients over 120 exhibited at least one criterion. Grade 3-4 toxicity was observed in 30% of the courses, including 2 severe acute renal impairment. Renal function decreased in most patients but had recovered upon the 3rd month in all but 2 patients. CONCLUSION: Despite a higher rate of toxicity than in general population, most of the patients recovered from it. Considering the cost of this treatment, the criteria for its therapeutic use could be restricted to concentration of MTX at H48 superior at 10| M, associated with renal impairment.

Detergent binding as a sensor of hydrophobicity and polar interactions in the binding cavities of proteins.

To evaluate the role of hydrophobic and electrostatic or other polar interactions for protein-ligand binding, we studied the interaction of human serum albumin (HSA) and beta-lactoglobulin with various aliphatic (C10-C14) cationic and zwitterionic detergents. We find that cationic detergents, at levels that do not cause unfolding, interact with a single site on beta-lactoglobulin and with two primary and five to six secondary sites on HSA with an affinity that is approximately the same as that with which zwitterionic (dimethylamineoxide) detergents interact, suggesting the absence of significant electrostatic interactions in the high-affinity binding of these compounds. The binding affinity for all of the groups of compounds was dependent upon hydrocarbon chain length, suggesting the predominant role of hydrophobic forces, supported by polar interactions at the protein surface. A distinct correlation between the binding energy and the propensity for micelle formation within the group of cationic or noncharged (nonionic and zwitterionic) detergents indicated that the critical micellar concentration (CMC) for each of these detergent groups, rather than the absolute length of the hydrocarbon chain, can be used to compare their hydrophobicities during their interaction with protein. Intrinsic fluorescence data suggest that the two primary binding sites on serum albumin for the zwitterionic and cationic compounds are located in the C-terminal part of the albumin molecule, possibly in the Sudlow II binding region. Comparisons with previous binding data on anionic amphiphiles emphasize the important contribution of ion bond formation and other polar interactions in the binding of fatty acids and dodecyl sulfate (SDS) by HSA but not by beta-lactoglobulin. Electrostatic interactions by cationic detergents played a significant role in destabilizing the protein structure at high binding levels, with beta-lactoglobulin being more susceptible to unfolding than HSA. Zwitterionic detergents, in contrast to the cationic detergents, had no tendency to unfold the proteins at high concentrations.