Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia : RATIFY study results

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3 -ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3 -ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin

Lehrbuch zu spektroskopischen, chromatographischen, elektrochemischen und thermischen Analysenmethoden

Das Rückgrat der Analytik Die Bedeutung der instrumentellen Methoden in der Arzneimittelanalytik wächst, die Verfahren werden ständig weiterentwickelt und verbessert. Die Neuauflage dieses bewährten Lehrbuchs passt alle instrumentellen Analysenmethoden dem Stand der Wissenschaft und der aktuellen Ausgabe des Arzneibuchs an. Neue oder erweiterte Themen sind unter Anderem: - Emissionsspektroskopie und Massenspektrometrie mit induktiv gekoppeltem Plasma (ICP-OES und ICP-MS) - Kopplungsverfahren der IR-Spektroskopie - Raman-Spektroskopie - Massenspektrometrische Ionisationsverfahren Durch die fokussierte Behandlung von bekannten sowie neuen Anwendungen bietet dieses Lehrbuch einen aktuellen und modernen Einblick in die Möglichkeiten der pharmazeutischen Analytik. Die Verknüpfung mit der aktuellen Ausgabe des Arzneibuchs stellt den Praxisbezug her. Das Buch wendet sich gleichermaßen an Studierende und Praktiker, sei es in der Pharmazie, der Biologie oder der Chemie/Biochemie.5., überarbeitete Auflage 201

Unknown primary of the head and neck: A long-term follow-up

BACKGROUND: A diagnosis of squamous cell carcinoma of an unknown primary (CUP) is a major burden for patients. Because the location of the primary tumor is unclear, patients remain fearful of recurrence, which aggravates the uncertain prognosis of the disease. This study evaluates factors associated with long-term recurrence-free and overall survival of patients with CUP of the head and neck. Additionally, patient survival rates are compared with those of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 293 consecutive patients operated on between January 1999 and December 2009 with at least a 5-year follow-up (survival permitting), were evaluated retrospectively. RESULTS: Twenty-six patients with a CUP of the head and neck were identified. Patients with CUP had a low overall survival rate, comparable with that of patients with pN + HNSCC, and recurrent disease occurred with a similar likelihood as in patients with pN + HNSCC. The median recurrence-free survival in the CUP group was 28.5 months compared with 48 months in the whole of the HNSCC group. The median overall survival of the CUP group was 56 months versus 65 months for the HNSCC group. Extracapsular spread was the only independent prognostic factor for overall survival for CUP patients. CONCLUSION: Patients diagnosed with CUP syndrome have a poorer prognosis for overall survival compared with other HNSCC patients. Postoperative radiotherapy diminished disease recurrence and improved overall survival. Omission of postoperative radiotherapy resulted in a very high recurrence rate (75%) for CUP patients. Based on these results we suggest postoperative radiotherapy including the oral mucosa for all patients, regardless of histopathological results, possible favorable nodal disease, or favorable lymph node ratios

DNA Self-Assembly Mediated by Programmable Soft-Patchy Interactions

Adding shape and interaction anisotropy to a colloidal particle offers exquisitely tunable routes to engineer a rich assortment of complex-architected structures. Inspired by the hierarchical self-assembly concept with block copolymers and DNA liquid crystals and exploiting the unique assembly properties of DNA, we report here the construction and self-assembly of DNA-based soft-patchy anisotropic particles with a high degree of modularity in the system’s design. By programmable positioning of thermoresponsive polymeric patches on the backbone of a stiff DNA duplex with linear and star-shaped architecture, we reversibly drive the DNA from a disordered ensemble to a diverse array of long-range ordered multidimensional nanostructures with tunable lattice spacing, ranging from lamellar to bicontinuous double-gyroid and double-diamond cubic morphologies, through the alteration of temperature. Our results demonstrate that the proposed hierarchical self-assembly strategy can be applied to any kind of DNA nanoarchitecture, highlighting the design principles for integration of self-assembly concepts from the physics of liquid crystals, block copolymers, and patchy colloids into the continuously growing interdisciplinary research field of structural DNA nanotechnology

Pilot Study on Mass Spectrometry–Based Analysis of the Proteome of CD34+CD123+ Progenitor Cells for the Identification of Potential Targets for Immunotherapy in Acute Myeloid Leukemia

Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia. As a reference, CD34+CD123+ normal hematopoietic progenitor cells from five healthy, granulocyte-colony stimulating factor (G-CSF) mobilized stem cell donors were analyzed. In this Tandem Mass Tag (TMT) 10-plex labelling–based approach, 2070 proteins were identified with 171 proteins differentially abundant in one or both cellular compartments. This proof-of-principle-study demonstrates the potential of mass spectrometry to detect differentially expressed proteins in two compartment fractions of the entire proteome of leukemic stem cells, compared to their non-malignant counterparts. This may contribute to future immunotherapeutic target discoveries and individualized AML patient characterization

Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 1

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature

Background!#!Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates.!##!Methods!#!We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia.!##!Results!#!With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever.!##!Conclusions!#!Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011