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Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance.

This paper describes the ginkgoaleans (Ginkgoites) and conifers (Palissya, Stachyotaxus, Schizolepis) of the Rhaetian flora from Wustenwelsberg, as well as a new species of the cycad Becklesia. The ginkgophyte leaf fragments are very abundant in certain levels (‘Blatterkohle‘) whereas conifers are common in the main fossiliferous bed. The Wustenwelsberg specimens extend the range for Ginkgoites taeniatus from the Hettangian to the Rhaetian and for the genus Becklesia from the Cretaceous to the Rhaetian. The other elements are typical for the Rhaetian floras of Bavaria and often also of the Northern Hemisphere. A comparison with other Northern Hemisphere plant assemblages demonstrates a high similarity with the Rhaetian floras from Jameson Land (Greenland) and Scania (Sweden) but significant differences to the Hettangian floras from adjacent areas in Franconia, especially at species and sometimes at generic level. A comparison with the microflora from the same sections shows a hidden diversity that is highest in small herbaceous plants (mosses, lycophytes, ferns) and in the conifers. Wustenwelsberg reflects, thus, an articulated landscape with a high water and nutrients availability (stagnant water bodies and/or river systems) covered by a complex and multi-storeyed vegetation shown, among others, by the general abundance in hygrophytic spores and high diversity among the various plant groups. This must have corresponded to one of the humid episodes that characterized the generally warm and arid climate of the Rhaetian of Europe.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified. © 2021 American Society of Hematology

Desmiophyllum harrisii was described from the Hettangian of Poland based on specimens yielding dispersed leaf fragments only, albeit with cuticle. Here, we record a shoot with attached leaves assignable to Desmiophyllum harrisii from the Rhaetian of Bavaria, besides a few specimens with dispersed leaf fragments. The leaves yielded also a thin and fragmentary cuticle with stomata arranged in characteristic single, short longitudinal files. This record does not only expand the temporal range of the species but also necessitates emending the specific diagnosis accordingly. The affinity of Desmiophyllum among gymnosperms is still uncertain, and the epidermal anatomy resembles that of Czekanowskiales and of some fossil taxa that have been assigned to Ginkgoales and Coniferales. The thin cuticle points to a habitat in moist environments.

Background: In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. Results: The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. Conclusions: Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features. © 2019 The Author(s).

Recently collected material of the monotypic schizaeaceous fern genus Phialopteris is described including for the first time the in situ spores. The complex nomenclatural history of the type species is discussed, resulting in the designation of the new combination Phialopteris heterophylla (Sternberg ex Göppert, 1836) comb. nov. as type. This delicate fern has so far only been found in the Hettangian of Bavaria (Germany). Along with a comparison with contemporary schizaeaceous ferns and extant members of Schizaeaceae, and with dispersed spores, the possibility that this fern might have been a climbing fern, similar to some living Lygodium species, is briefly discussed.

To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.

Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. © 2016 by The American Society of Hematology.

The diverse seed fern and cycad plant remains from the Rhaetian of Wustenwelsberg (Franconia, southern Germany) are described by means of macromorphological anatomy and cuticular characteristics. The study is part of the ongoing examination of this recently excavated and excellently preserved fossil plant assemblage. In total, six species of seed ferns have been identified including Lepidopteris (1 species with male and female reproductive organs; Peltaspermales), Pachypteris (1 species; Umkomasiales), Rhaphidopteris (1 species), Ptilozamites (2 species) and Hydropterangium (1 species, a male reproductive organ); some dispersed seeds were described as Carpolithes sp. Cycads (including Nilssoniales) contain Nilssonia (1 species), Doratophyllum (1 species), Ctenis (1 species), Pseudoctenis (2 species). Four Thinnfeldia species have to be recombined into Pachypteris species in the course of the study for reasons of nomenclatorial priority. The comparison of the flora from Wustenwelsberg with adjacent Rhaetian floras revealed distinct local differences in the seed fern and cycad portion of the respective floras, which are discussed in the light of palaeogeography involving dispersal patterns or mechanisms and adaptations of the plants.

Mississippian plant fossils are generally rare, and in central and northwestern Europe especially Tournaisian to middle Visean fossil floras are restricted to isolated occurrences. While sphenophytes and lycophytes generally are represented by only a few widespread and long-ranging taxa such as Archaeocalamites radiatus, Sphenophyllum tenerrimum and several species of Lepidodendropsis and Lepidodendron, Visean floras in particular show a remarkably high diversity of fern-like foliage, including filiform types (Rhodea, Diplotmema), forms with bipartite fronds (Sphenopteridium, Diplopteridium, Spathulopteris, Archaeopteridium), others with monopodial, pinnate fronds (Anisopteris, Fryopsis) and still others characterized by several-times pinnate fronds (e.g., Adiantites, Triphyllopteris, Sphenopteris, Neuropteris). Most of these leaf types have been interpreted as belonging to early seed ferns, whereas true ferns seem to have been rare or lacking in impression/compression floras. In the upper Visean, two types of plant assemblages can be distinguished, i.e., the northern Kohlenkalk-type and the south-eastern Kulm-type assemblage. Although several compression/impression taxa have been revised in recent years to provide a more uniform classification, additional parameters such as different modes of preservation and imprecise information on stratigraphic age hamper detailed interregional comparisons of Mississippian floras., Pflanzenfossilien aus dem Mississippium sind generell selten. Floren aus dem Tournaisium bis Mittel-Viseum hat man in Zentral- und Nordwesteuropa nur in wenigen isolierten Lokalitäten gefunden. Diese Floren sind von Sphenophyten und Lycophyten (z.B. Archaeocalamites radiatus, Sphenophyllum tenerrimum sowie Taxa aus den Gattungen Lepidodendropsis und Lepidodendron) dominiert, welche alle eine weite geographische Verbreitung und lange geologische Reichweite aufweisen. Demgegenüber weisen die Floren des jüngeren Viseum eine bemerkenswerte Diversität an Pteridophyllen auf. Neben filiformen Wedeln (Rhodea, Diplotmema) kennt man aus diesen Floren unterschiedliche Typen einfach gegabelter (Sphenopteridium, Diplopteridium, Spathulopteris, Archaeopteridium) sowie einfach (Anisopteris, Fryopsis) und mehrfach gefiederter Wedel (e.g., Adiantites, Triphyllopteris, Sphenopteris, Neuropteris). Der überwiegende Teil dieser Wedel wird den frühen Samenfarnen zugeordnet; Nachweise von echten Farnen sind ausgesprochen selten. Im oberen Viseum können zwei unterschiedliche Pflanzenassoziationen unterschieden werden: eine nördliche Kohlenkalk-Assoziation und eine südöstliche Kulm-Assoziation. Obwohl mehrere Pflanzentaxa des Mississippiums in Europa in den vergangenen Jahren revidiert worden sind, bleiben doch überregionale Vergleiche sowie die Erstellung einer einheitlichen Klassifikation durch die z.T. großen Unterschiede in der Erhaltung der Fossilien aus den einzelnen Fundpunkten sowie durch Probleme bei der Bestimmung des exakten stratigraphischen Alters der jeweiligen Fundschichten schwierig.

In this paper we test the effectiveness of explanations as mandated by the revised ISA 700 auditor's report in reducing the audit expectation gap. German auditors and financial statement users participated in an experiment where they read a summary of a firm's financial statements and an auditor's report, the latter of which we manipulated as being the auditor's report including the explanations as mandated by ISA 700 versus a mere audit opinion-only version. We elicited participants' perceptions about auditor versus management responsibilities and financial statement reliability. We find strong evidence for a persistent expectation gap with respect to the auditor's responsibilities. Meanwhile, auditors and users reach a reasonable belief consensus regarding management's responsibilities and financial statement reliability. Most notably, explanations of the ISA 700 auditor's report do not result in a smaller expectation gap. Our findings suggest that the audit opinion alone may signal sufficient relevant information to users. © 2012 Blackwell Publishing Ltd.

We report on the results of an experiment, in which experienced auditors and users (financial analysts as sophisticated users and students as unsophisticated users) read a brief company description, a summary of the firm¿s financial statements, and an audit report, the latter of which we manipulated as being either the complete auditor¿s report according to the revised ISA 700 or a short-form audit opinion-only version. Participants then responded to questions related to the perceived responsibility of the auditor versus management for producing the financial statements, detecting and preventing fraud, the soundness of the firm¿s internal control structure, etc.; and to the reliability of the financial statements with respect to misstatements, fraud, errors, etc. We find strong evidence for a persisting audit expectation gap between auditors and financial statement users under the revised ISA 700 auditor¿s report. Also, results are robust in indicating that the detailed explanations of the ISA 700 auditor¿s report of auditor versus management responsibilities and the task and scope of the audit are not effective in reducing this expectation gap, and partially even have a detrimental effect.

Twelve vineyards of cv 'Centennial Seedless' (v. vinifera L.) were chosen for leaf (Iamina + petiole), lamina and petiole mineral analysis, over a two year period, in lales, São Paulo State, Brazil. Twenty vine canes from each vineyard were sampled for bud fertility evaluation using a stereomicroscope. The relationship between bud fertility or bud necrosis and mineral contents were investigated. The correlations determined were weak when other factors were involved in bud fertility, such as temperature, light, shoot vigor and water deficiency. Nitrogen and potassium contents showed an inverse relationship with the percentage of bud necrosis. Iron and boron contents presented a quadratic relationship between the percentage of fertile buds and the percentage of bud necrosis. The possible involvement of these elements in root growth and, therefore, in cytokinin biosynthesis, could explain their influence on floral stimulus. (Bulletin 0.1.V., 2005, vol. 78, n? 897-898, pp. 737-749). Made available in DSpace on 2019-08-17T00:37:58Z (GMT). No. of bitstreams: 1 79862005p.737749.pdf: 6048803 bytes, checksum: c0542cedf5241599121230c1f722ab63 (MD5) Previous issue date: 2005

The t(11;14) (q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (Ig-H) loci in mantle cell lymphomy (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14;18) in follicular lymphoma. We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BC-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides)...

International audience; Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0–14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0–14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.

Current diagnostic standards for lymphoproliferative disorders include multiple tests for detection of clonal immunoglobulin (IG) and/or T-cell receptor (TCR) rearrangements, translocations, copy-number alterations (CNAs), and somatic mutations. The EuroClonality-NGS DNA Capture (EuroClonality-NDC) assay was designed as an integrated tool to characterize these alterations by capturing IGH switch regions along with variable, diversity, and joining genes of all IG and TCR loci in addition to clinically relevant genes for CNA and mutation analysis. Diagnostic performance against standard-of-care clinical testing was assessed in a cohort of 280 B- and T-cell malignancies from 10 European laboratories, including 88 formalin-fixed paraffin-embedded samples and 21 reactive lesions. DNA samples were subjected to the EuroClonality-NDC protocol in 7 EuroClonality-NGS laboratories and analyzed using a bespoke bioinformatic pipeline. The EuroClonality-NDC assay detected B-cell clonality in 191 (97%) of 197 B-cell malignancies and T-cell clonality in 71 (97%) of 73 T-cell malignancies. Limit of detection (LOD) for IG/TCR rearrangements was established at 5% using cell line blends. Chromosomal translocations were detected in 145 (95%) of 152 cases known to be positive. CNAs were validated for immunogenetic and oncogenetic regions, highlighting their novel role in confirming clonality in somatically hypermutated cases. Single-nucleotide variant LOD was determined as 4% allele frequency, and an orthogonal validation using 32 samples resulted in 98% concordance. The EuroClonality-NDC assay is a robust tool providing a single end-to-end workflow for simultaneous detection of B- and T-cell clonality, translocations, CNAs, and sequence variants.

No abstract available

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies., This work was supported by Ministry of Health of the Czech Republic, grant no. 16-34272A; computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures”. Analyses in Prague (JT, EF and MS) were supported by Ministry of Health, Czech Republic, grant no. 00064203, and by PRIMUS/17/MED/11. Analyses in the Monza (Centro Ricerca Tettamanti, SS, AG and GC) laboratory were supported by the Italian Association for Cancer Research (AIRC) and Comitato Maria Letizia Verga.

Analysis and interpretation of Ig and TCR gene rearrangements in the conventional, low-throughput way have their limitations in terms of resolution, coverage, and biases. With the advent of high-throughput, next-generation sequencing (NGS) technologies, a deeper analysis of Ig and/or TCR (IG/TR) gene rearrangements is now within reach, which impacts on all main applications of IG/TR immunogenetic analysis. To bridge the generation gap from low- to high-throughput analysis, the EuroClonality-NGS Consortium has been formed, with the main objectives to develop, standardize, and validate the entire workflow of IG/TR NGS assays for 1) clonality assessment, 2) minimal residual disease detection, and 3) repertoire analysis. This concerns the preanalytical (sample preparation, target choice), analytical (amplification, NGS), and postanalytical (immunoinformatics) phases. Here we critically discuss pitfalls and challenges of IG/TR NGS methodology and its applications in hemato-oncology and immunology.

SEA0400 ist ein Na+/Ca2+-Austauscher (NCX1)-Inhibitor der als Therapie bei Herzrhythmusstörungen diskutiert wird. Inwieweit ein verändertes NCX1-Expressionsniveau, wie bei Herzinsuffizienz, die Wirkung von SEA0400 beeinflusst, wurde an Herzmuskelzellen von NCX1-Überexpressor(OE)- und -Knockout(KO)-Mausmodellen untersucht. SEA0400 verminderte in allen Genotypen die NCX1-Aktivität und erhöhte gleichsinnig die Beladung des sarkoplasmatischen Retikulums. Diese resultierte aber nur in den Wildtypen (WTOE, WTKO) und im KO in einem positiv inotropen Effekt. SEA0400 reduzierte die Häufigkeit von spontanen Kalziumfreisetzungen (sCR) als Maß für Proarrhythmie im OE. In WTOE, WTKO und im KO stiegen die sCR jedoch an und es wurden vermehrt Hyperkontraktionen mit Ca2+-induzierten Zelltod beobachtet.

Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma which is characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in almost all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of 15% long-term survivors has been identified with a rather indolent clinical course. Targeted strategies include the proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and especially inhibitors of the B-cell receptor pathway. Our recent annual conference focused on the molecular pathogenesis of the disease and how these underlying molecular alterations may guide the selection and integration of innovative approaches for therapy. This review of the meeting covers in particular the identification of indolent cases, and deals with the role of the B-cell receptor pathway in MCL, as well as the detection of minimal residual disease and implementation of molecular approaches in current clinical trials.

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network ( http://www.european-mcl.net ) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.

We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095) We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eighty-four of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23. Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095)

Breve profilo dell'autrice e curatrice di una delle riviste femminili più di successo del Settecento tedesco. L'esame del concetto di 'Denkerin' come concetto-guida per la formazione femminile diretta non a sviluppare ambizioni intellettuali, ma a svolgere mansioni di casalinga, madre e compagna con un certo giudizio.