Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Should We Worry About Nutrition Of Adults With Minor Burns? An Audit Of Their Intakes.

Small burn injuries are managed in an outpatient setting by surgeons and/or nurses. Nutrition in minor burn patients is rarely investigated. This observational study aimed to quantify their nutritional intakes, and o compare them to theoretical adequate values. Their average daily food intakes since injury were evaluated by a dietician using a ten-point visual assessment of consumed portions during the last meal (SEFI tool) and a food anamnesis. Macro- and micronutrient intakes were compared to national recommended dietary allowances (RDA) for healthy subjects: intakes <66% RDA were considered inadequate. Forty-two patients with a median age of 45 (34-56) years, BMI of 25.9 (23.5-28.9) kg/m2, and burn surface area (BSA) of 2 (1-3) % were included. Energy and protein RDA were reached in 28.6 and 71.4% of the patients, respectively. Intakes of n-3 fatty acids were inadequate in 80.9% of the patients. A SEFI <7 was associated with insufficient intakes regards both energy and proteins. Inadequate intakes of different micronutrients were frequently observed, but no risk factors could be detected. Vitamin A and C were the most impacted: 71.4% of the patients had inadequate intakes. Vitamin D intake was low: 225 (56-431) UI/d. In contrast, intakes of iron, selenium and zinc were adequate in at least 61.9% of the patients. In conclusion, this audit highlighted that a majority of macronutrient and micronutrient intakes did not reach the levels recommended by the RDA. Such data should help in designing further studies aimed at assessing the impact of optimized nutrition on outcomes.

Certains patients, souffrant de brûlures mineures, sont suivis en externe par des chirurgiens et/ou des infirmières. La nutrition de tels patients est rarement étudiée. Cette étude observationnelle a pour but de quantifier leurs apports nutritionnels et de les comparer aux apports théoriques nécessaires. Leurs apports moyens depuis la brûlure ont été évalués par une diététicienne en utilisant une échelle visuelle (0 à 10) d'évaluation des portions consommées lors du dernier repas (échelle SEFI) et un historique de leurs repas. Les apports macro- et micronutritionnels réels ont été comparés aux apports recommandés aux sujets sains, un apport <66 % étant considéré comme insuffisant. Quarante deux patients d'âge médian de 45 ans (34- 56), à l'IMC de 25,9 (23,5- 28,9) kg/m² et brûlés sur 2 % (1- 3) SCT ont été inclus. Les apports en énergie et protéines étaient suffisants dans 28,6 et 71,4 % des cas. Ceux en acides gras 3 étaient insuffisants dans 80,9 % des cas. Un SEFI < 7 était associé à des apports insuffisants aussi bien en calories qu'en protéines. Des apports insuffisants en micronutriments étaient fréquemment observés, sans facteur de risque particulier, les apports en vitamines A et C étant ceux ayant été le plus souvent considérés comme insuffisants (dans 71,4 % des cas). Les apports de vitamine D (225- 56/431) UI/j étaient faibles eux aussi. À l'opposé, les apports en Fe, Se et Zn étaient considérés comme satisfaisants chez au moins 61,9 % des patients. En conclusion, cette étude montre que les patients, dans leurs majorité, n'ingèrent pas les quantités de macro- et micronutriments recommandés. Elle peut servir de point de départ à des études évaluant l'impact d'une optimisation nutritionnelle dans cette situation.

Cleavage of the actin-capping protein alpha -adducin at Asp-Asp-Ser-Asp633-Ala by caspase-3 is preceded by its phosphorylation on serine 726 in cisplatin-induced apoptosis of renal epithelial cells.

Decreased phosphorylation of focal adhesion kinase and paxillin is associated with loss of focal adhesions and stress fibers and precedes the onset of apoptosis (van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The cortical actin cytoskeletal network is also lost during apoptosis, yet little is known about the temporal relationship between altered phosphorylation of proteins that are critical in the regulation of this network and their potential cleavage by caspases during apoptosis. Adducins are central in the cortical actin network organization. Cisplatin caused apoptosis of renal proximal tubular epithelial cells, which was associated with the cleavage of alpha-adducin into a 74-kDa fragment; this was blocked by a general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk). Hemagglutinin-tagged human alpha-adducin was cleaved into a similar 74-kDa fragment by caspase-3 in vitro but not by caspase-6 or -7. Asp-Arg-Val-Asp(29)-Glu, Asp-Ile-Val-Asp(208)-Arg, and Asp-Asp-Ser-Asp(633)-Ala were identified as the principal caspase-3 cleavage sites; Asp-Asp-Ser-Asp(633)-Ala was key in the formation of the 74-kDa fragment. Cisplatin also caused an increased phosphorylation of alpha-adducin and gamma-adducin in the MARCKS domain that preceded alpha-adducin cleavage and was associated with loss of adducins from adherens junctions; this was not affected by z-VAD-fmk. In conclusion, the data support a model in which increased phosphorylation of alpha-adducin due to cisplatin leads to dissociation from the cytoskeleton, a situation rendered irreversible by caspase-3-mediated cleavage of alpha-adducin at Asp-Asp-Ser-Asp(633)-Ala.