Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies.

PURPOSE: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. PATIENTS AND METHODS: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. RESULTS: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. CONCLUSION: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.     

Prediction intervals for future BMI values of individual children - a non-parametric approach by quantile boosting

Background  

The construction of prediction intervals (PIs) for future body mass index (BMI) values of individual children based on a recent German birth cohort study with n = 2007 children is problematic for standard parametric approaches, as the BMI distribution in childhood is typically skewed depending on age.     

Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria

At the end of 2012, more than 300 participants discussed and agreed on the update of the international guidelines on urticaria at the 4th International Consensus Meeting (URTICARIA 2012). Currently, the recommendations are in the final process of international coordination. In preparation for the update, questions were prepared by an expert panel; this was followed by a systematic literature search. The questions and the resulting recommendations were discussed by the participants and decided upon in an open vote. Consensus was defined as at least 75% agreement. The updated guidelines will modify and improve the currently available guidelines in various areas, especially in therapy. For the treatment of chronic urticaria, the new algorithm recommends a three‐step process starting with a standard dose of a non‐sedating H1 antihistamine. If there is an insufficient treatment response, the dosage should be increased up to four times. In, therapy refractory patients, omalizumab, cyclosporine A, or montelukast are advised in the third step. Short‐term corticosteroid treatment for a maximum of 10 days may be considered. H2 antihistamines and dapsone, which were included in the previous version of the guidelines, are absent in the updated and revised version because of changes in the evidence level.     

Transplant ethics under scrutiny – responsibilities of all medical professionals

In this text, we present and elaborate ethical challenges in transplant medicine related to organ procurement and organ distribution, together with measures to solve such challenges. Based on internationally acknowledged ethical standards, we looked at cases of organ procurement and distribution practices that deviated from such ethical standards. One form of organ procurement is known as commercial organ trafficking, while in China the organ procurement is mostly based on executing prisoners, including killing of detained Falun Gong practitioners for their organs. Efforts from within the medical community as well as from governments have contributed to provide solutions to uphold ethical standards in medicine. The medical profession has the responsibility to actively promote ethical guidelines in medicine to prevent a decay of ethical standards and to ensure best medical practices.     

Tissue Distribution of P32-Labeled Parathion

Repeated inhalation of the vapors of bis(chloromethyl) ether and chloromethyl methyl ether at one and two ppm, respectively, and of the aerosol of urethan at approximately 138 ppm, resulted in an increase in incidence of pulmonary adenomas in strain A mice. In addition, the high toxicity of the two haloethers and the general lack of properties irritating to the upper respiratory tract in all three compounds pose an insidious industrial handling hazard.     

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.     

Parahydrogen‐induced polarization of carboxylic acids: a pilot study of valproic acid and related structures

Parahydrogen‐induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non‐Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. ¹³C), thus improving the signal‐to‐noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the ¹H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized ¹³C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP‐based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd.     

Was ist gesichert in der Therapie der rheumatoiden Arthritis?

Rheumatoid arthritis (RA) is the most important chronic inflammatory joint disease with a prevalence of 1%. When untreated the disease leads to joint destruction and therefore to functional restrictions of the patients and also to increased rates of cardiovascular and malignant diseases. After the pathophysiology of rheumatoid arthritis was better understood, in the last 20 years biologics could be developed, which are directed against targets involved in the inflammatory process in RA. Since then the remission rates of RA have substantially increased. In 2017 Janus kinase (JAK) inhibitors were additionally approved for the treatment of RA in Germany. They further broaden the therapeutic options and, in contrast to biologics, are administered orally. The response rates to therapy are better the earlier the disease is diagnosed and treated. Patients in whom RA is suspected due to a new onset of polyarthritis, should therefore be promptly referred to a rheumatologist.