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Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.

Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3-ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell-like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification. SIGNIFICANCE: Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes. This article is highlighted in the In This Issue feature, p. 549.

Tin sulfide (SnS) is an analog of tin selenide (SnSe) and is a promising thermoelectric material. However, a stable and effective doping of this compound has still not been achieved. According to our observations, this is mainly due to the very low equilibrium solubility of dopants and formation of extraneous phases, which is also an important issue for photovoltaic (PV) applications. Achieving a reasonable (60%) doping efficiency of thallium (Tl) in a cation sublattice of SnSe, we explored the same doping for SnS. Hot-pressed polycrystalline (PC) samples were prepared along with their single-crystalline (SC) counterparts. Samples were examined for extraneous phases by X-ray diffraction (XRD), and energy-dispersive spectroscopy (EDS). Thermal stability was determined by thermogravimetric analysis (TGA). Measurements of the Seebeck and Hall coefficient, and electrical and thermal conductivity were conducted over a temperature range of 80-775 K. The experiments suggested a very low solubility of Tl ( approximate to 0.1%). Slight Tl doping resulted in a substantial improvement of the thermoelectric efficiency (ZT) of SnS and enhanced crystal quality in terms of carrier mobility. We found, however, that attempts to prepare material with a high concentration of Tl or the examination of samples at temperatures above 600 K led to chemical instability. (C) 2019 Elsevier B.V. All rights reserved., Sulfid cínatý (SnS) je analogem selenidu cínatého (SnSe) a je slibným termoelektrickým materiálem. Stále však nebylo dosaženo stabilního a efektivního dopování této sloučeniny. Podle našich pozorování je tomu tak hlavně kvůli velmi nízké rovnovážné rozpustnosti dopantů a tvorbě cizích fází, což je také důležitý problém pro fotovoltaické (PV) aplikace. Dosažením rozumné (60%) dopovací účinnosti thalia (Tl) v kationtové podmřížce SnSe, zkoumali jsme stejné dopování v případě SnS. Byly připraveny za tepla lisované polykrystalické (PC) vzorky spolu s jejich monokrystalickými (SC) protějšky. Vzorky byly vyšetřeny na přítomnost cizích fází rentgenovou difrakcí (XRD) a energiově-dispersní spektroskopií (EDS). Termická stabilita byla stanovena termogravimetrickou analýzou (TGA). Měření Seebeckova a Hallova koeficientu a elektrické a tepelné vodivost byla provedena v teplotním rozsahu 80-775 K. Experimenty naznačily velmi nízkou rozpustnost Tl (≈0,1%). Mírné dopování Tl vedlo k podstatnému zlepšení termoelektrické účinnosti (ZT) SnS a ke zlepšení kvality krystalů z hlediska pohyblivosti nositelů. Zjistili jsme však, že pokusy připravit materiál a vysokou koncentrací Tl nebo vyšetření vzorků při teplotách nad 600 K vedly k chemické nestabilitě.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or breakapart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.

Three parental neuroblastoma cell lines and nine derived lines resistant to Vincristin, Doxorubicin and Cisplatin, respectively, using CGH were studied. CGH profiles of all three parental cell lines were obtained using DNA from a healthy volunteer as reference DNA. Labeled DNA from each of the drug resistant daughter cell lines and labeled DNA from their parental sensitive cell lines were hybridized to obtain a comparison of gains and losses that accompanied the development of resistance for that particular drug. All three parental cell lines were characterized by typical findings for high risk neuroblastoma: N-myc amplification, gain of 17q, and loss of 1p36.2-36.3. Acquired drug resistance in the neuroblastoma cell lines appeared to be accompanied by a large array of DNA sequence copy number changes. The regions frequently affected in chemo-resistant cell lines included gains of 13q14.1-32, and 7q11.2-31.3, 4 q. Amplifications were seen at 7q 21.1 consistent with MDR1 amplification in UKF-NB-2 VCR, UKF-NB-3 DOXO, UKF-NB-4 VCR, and UKF-NB-4 DOXO, but not in any Cisplatin resistant line. All Cisplatin and Doxorubicin and two Vincristin resistant line (UKF-NB-2 VCR and UKF-NB-4 VCR) had a deletion of part of 19q or the whole 19 chromosome. All lines resistant to Vincristin or Doxorubicin and two Cisplatin resistant lines (UKF-NB-2 CDDP and UKF-NB-4 CDDP) had a deletion of at least part of 17q, UKF-NB-4 DOXO had deletion of the whole chromosome 17. The loss of 17q may cause chemoresistance by deletion of topoisomerase IIalpha gene. Deletion of 19 q in all but one chemo-resistant lines may influence of cytochromes P450 genes which are located on 19q13.2. Also gains of 15q 22, which were detected in UKF-NB-4 VCR, UKF-NB-2 DOXO and UKF-NB-4 DO X O, may affect other cytochromes P450 genes.