Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.

Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.

Whole body deletion of Gpr68 does not change hematopoietic stem cell function.

G protein-coupled receptor 68 (GPR68) responds to extracellular protons, thus called the proton-sensing G protein-coupled receptor (GPCR), leading to activation of the phospholipase C-ß (PLCß)/calcium (Ca2+) pathway or the adenylyl cyclase (AC)/cyclic AMP (cAMP) pathway. We recently found that whole body deletion of Gpr68 (Gpr68-/- mice) reduced the number of B lymphocytes with age and during hematopoietic regeneration, such as in response to fluorouracil (5-FU) administration. This prompted us to characterize the hematopoietic stem cell (HSC) phenotype in Gpr68-/- mice. Despite high level of Gpr68 protein expression on HSC in bone marrow (BM), the pool size of HSC was unaltered in Gpr68-/- mice either under steady state or upon stress, including aging and 5-FU treatment. HSC from Gpr68-/- mice exhibited comparable cellular features, such as cell cycle quiescence and cell survival. HSC from Gpr68-/- mice also exhibited comparable competitiveness after serial transplantation. Surprisingly, cytosolic Ca2+ accumulation was increased in HSC from Gpr68-/- mice. In contrast, cAMP levels were reduced in hematopoietic stem and progenitor cells (HSPC) from Gpr68-/- mice. Intriguingly, we found high level of Gpr68 protein expression on non-hematopoietic cells in BM, especially endothelial cells that function as HSC niche. In addition, expression of other proton-sensing GPCR was upregulated in HSPC from Gpr68-/- mice. Our studies suggest that Gpr68-/- mice display insignificant phenotype on HSC biology, possibly due to the function of Gpr68 in non-hematopoietic cells and/or the compensatory effects from other proton-sensing GPCR.

Use and effectiveness of a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) in a real-world population with type 2 diabetes: Results from a European, multicentre, retrospective chart review study.

AIMS: To describe the real-world use and effectiveness of IDegLira, a fixed-ratio combination of the basal insulin degludec, and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide. MATERIALS AND METHODS: This European, multicentre, retrospective chart review comprised adults (n = 611) with type 2 diabetes, who started IDegLira ≥6 months before data collection. Clinical characteristics were assessed at baseline (defined as the most recent recording during the 6 months before the first IDegLira prescription) and 3, 6, 9 and 12 months (± 45 days for each time point) after commencing IDegLira, where data were available. RESULTS: Baseline regimens included non-injectable medications (19%), basal insulin (19%), GLP-1RA (10%), free combination therapy (insulin/GLP-1RA, 24%) and multiple daily-dose insulin injections (MDI, 28%), all ± oral antidiabetic drugs. After 6 months, significant glycated haemoglobin (HbA1c) reductions were observed in patients overall and in all subgroups (-10 mmol/mol [-0.9%] overall; P < .0001), and a significant reduction in mean body weight (-0.7 kg; P < .05) was observed in patients overall and in patients receiving MDI (-2.4 kg; P < .0001). The mean IDegLira dose was 22, 30 and 32 dose steps at initiation, and at 6 and 12 months follow-up, respectively. In total, only 67 patients reached the maximum 50 dose steps, with most coming from the free combination therapy (n = 31) or MDI (n = 15) baseline regimen groups. Hypoglycaemia rates were reduced by 82% (rate ratio 0.18; P < .0001) in the 6-month period after vs before IDegLira initiation. Overall, a total of 12 patients experienced 15 events in the 6 months after IDegLira initiation. CONCLUSION: In real-world practice, after 6 months and at a moderate dose, IDegLira resulted in substantial reductions in HbA1c and body weight, with a reduced risk of hypoglycaemia.

A European, multicentre, retrospective, non-interventional study (EU-TREAT) of the effectiveness of insulin degludec after switching basal insulin in a population with type 1 or type 2 diabetes.

AIMS: To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care. MATERIALS AND METHODS: This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI]. RESULTS: T1DM (n = 1717): HbA1c decreased by -2.2 [-2.6; -2.0] mmol/mol (-0.20 [-0.24; -0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by -4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by -5.6 [-6.3; -4.7] mmol/mol (-0.51 [-0.58; -0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non-severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period. Total daily insulin dose decreased by -2.48 [-4.24; -0.71] U (-3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months. CONCLUSIONS: This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice.

Validation in daily clinical situations of Diascope®, a software developed to help healthcare professionals individualize antidiabetic treatment in type 2 diabetes. / Validación en situaciones clínicas reales del DiaScope®, un software de ayuda al profesional sanitario en la individualización del tratamiento antidiabético en la diabetes tipo 2.

INTRODUCTION: DiaScope® is a software to help in individualized prescription of antidiabetic treatment in type 2 diabetes. This study assessed its value and acceptability by different professionals. MATERIAL AND METHODS: DiaScope® was developed based on the ADA-EASD 2012 algorithm and on the recommendation of 12 international diabetes experts using the RAND/UCLA appropriateness method. The current study was performed at a single session. In the first phase, 5 clinical scenarios were evaluated, selecting the most appropriated therapeutic option among 4 possibilities (initial test). In a second phase, the same clinical cases were evaluated with DiaScope® (final test).Opinion surveys on DiaScope® were also performed (questionnaire). RESULTS: DiaScope® changed the selected option 1 or more times in 70.5% of cases. Among 275 evaluated questionnaires, 54.0% strongly agree that DiaScope® allowed finding easily a similar therapeutic scenario to the corresponding patient, and 52.5 among the obtained answers were clinically plausible. Up to 58.3% will recommend it to a colleague. In particular, primary care physicians with >20 years of professional dedication found with DiaScope® the most appropriate option for a particular situation against specialists or those with less professional dedication (p<.05). DISCUSSION: DiaScope® is an easy to use tool for antidiabetic drug prescription that provides plausible solutions and is especially useful for primary care physicians with more years of professional practice.

Validación en situaciones clínicas reales del DiaScope(R), un software de ayuda al profesional sanitario en la individualización del tratamiento antidiabético en la diabetes tipo 2 / Validation in daily clinical situations of Diascope(R), a software developed to help healthcare professionals individualize antidiabetic treatment in type 2 diabetes

Introducción: DiaScope(R) es un software de ayuda a la prescripción individualizada del tratamiento antidiabético en la diabetes tipo 2. Este estudio evalúa la utilidad y aceptabilidad de dicha aplicación entre diferentes profesionales. Material y métodos: DiaScope(R) fue desarrollado en base al algoritmo de la ADA-EASD 2012 y con las recomendaciones de 12 expertos en diabetes internacionales, usando el método RAND/UCLA Appropriateness Method. El presente estudio se llevó a cabo en una sola reunión. En una primera fase, se evaluaron de 5 escenarios clínicos, eligiendo la opción terapéutica más adecuada entre 4 posibilidades (test inicial). En una segunda fase, estos mismos casos clínicos fueron evaluados con DiaScope(R) (test final). Además, se realizaron encuestas de opinión sobre DiaScope(R) (cuestionario). Resultados: DiaScope(R) modificó la opinión una o más veces en un 70,5% de los casos. De los 276 cuestionarios evaluados, un 54,0% estuvieron muy de acuerdo en que DiaScope(R) permitía encontrar con facilidad un escenario terapéutico similar al de un paciente determinado, y un 52,5% en que las respuestas obtenidas eran clínicamente plausibles. Hasta un 58,3% se lo recomendaría a un compañero. En particular, los médicos de Atención Primaria y>20 años de ejercicio profesional encontraron con DiaScope(R) la opción terapéutica más adecuada para una situación concreta, frente a médicos de Atención Especializada o con menos años de ejercicio profesional (p<0,05). Discusión: DiaScope(R) es una herramienta de ayuda en la prescripción de antidiabéticos, de uso sencillo, con soluciones plausibles, especialmente útil en profesionales de Atención Primaria, con más años de ejercicio profesional (AU)

Introduction: DiaScope(R) is a software to help in individualized prescription of antidiabetic treatment in type 2 diabetes. This study assessed its value and acceptability by different professionals. Material and methods: DiaScope(R) was developed based on the ADA-EASD 2012 algorithm and on the recommendation of 12 international diabetes experts using the RAND/UCLA appropriateness method. The current study was performed at a single session. In the first phase, 5 clinical scenarios were evaluated, selecting the most appropriated therapeutic option among 4 possibilities (initial test). In a second phase, the same clinical cases were evaluated with DiaScope(R) (final test).Opinión surveys on DiaScope(R) were also performed (questionnaire). Results: DiaScope(R) changed the selected option 1 or more times in 70.5% of cases. Among 275 evaluated questionnaires, 54.0% strongly agree that DiaScope(R) allowed finding easily a similar therapeutic scenario to the corresponding patient, and 52.5 among the obtained answers were clinically plausible. Up to 58.3% will recommend it to a colleague. In particular, primary care physicians with >20 years of professional dedication found with DiaScope(R) the most appropriate option for a particular situation against specialists or those with less professional dedication (p<.05). Discussion: DiaScope(R) is an easy to use tool for antidiabetic drug prescription that provides plausible solutions and is especially useful for primary care physicians with more years of professional practice (AU)

A decision support tool for appropriate glucose-lowering therapy in patients with type 2 diabetes.

BACKGROUND: Optimal glucose-lowering therapy in type 2 diabetes mellitus requires a patient-specific approach. Although a good framework, current guidelines are insufficiently detailed to address the different phenotypes and individual needs of patients seen in daily practice. We developed a patient-specific decision support tool based on a systematic analysis of expert opinion. MATERIALS AND METHODS: Based on the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 position statement, a panel of 12 European experts rated the appropriateness (RAND/UCLA Appropriateness Method) of treatment strategies for 930 clinical scenarios, which were permutations of clinical variables considered relevant to treatment choice. These included current treatment, hemoglobin A1c difference from individualized target, risk of hypoglycemia, body mass index, life expectancy, and comorbidities. Treatment options included addition of a second or third agent, drug switches, and replacement by monotherapies if the patient was metformin-intolerant. Treatment costs were not considered. Appropriateness (appropriate, inappropriate, uncertain) was based on the median score and expert agreement. The panel recommendations were embedded in an online decision support tool (DiaScope(®); Novo Nordisk Health Care AG, Zürich, Switzerland). RESULTS: Treatment appropriateness was associated with (combinations of) the patient variables mentioned above. As second-line agents, dipeptidyl peptidase-4 inhibitors were considered appropriate in all scenarios, followed by glucagon-like peptide-1 receptor agonists (50%), insulins (33%), and sulfonylureas (25%), but not pioglitazone (0%). Ratings of third-line combinations followed a similar pattern. Disagreement was highest for regimens including pioglitazone, sulfonylureas, or insulins and was partly due to differences in panelists' opinions and in drug availability and reimbursement across European countries (although costs were disregarded in the rating process). CONCLUSIONS: A novel decision support tool based on the ADA/EASD 2012 position statement and a systematic analysis of expert opinion has been developed to help healthcare professionals to individualize glucose-lowering therapy in daily clinical situations.

A decision tool to support appropriate referral for deep brain stimulation in Parkinson's disease.

BACKGROUND AND OBJECTIVE: Although Deep Brain Stimulation (DBS) has been proven to be an effective treatment for patients with advanced Parkinson's disease (PD), it may be difficult for general neurologists to identify appropriate candidates for this procedure. We developed an electronic decision tool that can assist neurologists in deciding which PD patients should be referred for DBS consideration. METHODS: Using the RAND/UCLA Appropriateness Method, an international expert panel assessed the appropriateness of referral for 972 theoretical patient profiles. Panel results were embedded in an electronic decision support tool which displays the panel statement on referral (appropriate, inappropriate and uncertain) after completion of the patient profile. RESULTS: Referral was considered appropriate for 33% of the theoretical profiles. Logistic regression showed excellent internal consistency of the ratings (predictive value 92%). Symptom severity (OFF-symptoms, dyskinesias, refractory tremor) and PD duration were positively associated with the panel judgment that referral is appropriate. Presence of levodopa-resistant axial symptoms, age >or= 70 years and presence of cognitive impairment showed the strongest negative impact. CONCLUSIONS: The RAND/UCLA method proved to be useful in determining the appropriate criteria for DBS referral. Validity and applicability of the decision tool (accessible via http://test.stimulus-dbs.org) in clinical practice need to be further determined.