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Jan A Burger, Susan O'Brien
During the past 5 years, a number of highly active novel agents, including kinase inhibitors targeting BTK or PI3Kδ, an antagonist of the antiapoptotic protein BCL-2, and new anti-CD20 monoclonal antibodies, have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). In these exciting times, care is needed to optimally integrate these novel agents into the traditional treatment algorithm without overlooking or compromising the benefits of established treatments, especially chemoimmunotherapy...
May 18, 2018: Nature Reviews. Clinical Oncology
Philip A Thompson, Christine B Peterson, Paolo Strati, Jeff Jorgensen, Michael J Keating, Susan M O'Brien, Alessandra Ferrajoli, Jan A Burger, Zeev Estrov, Nitin Jain, Tapan M Kadia, Gautam Borthakur, Courtney D DiNardo, Naval Daver, Elias Jabbour, William G Wierda
Achieving undetectable MRD (U-MRD) status after chemoimmunotherapy predicts longer progression-free and overall survival. The predictive factors and timing of relapse in patients with U-MRD and value of interim MRD analysis are ill-defined. This was a prospective study of 289 patients with CLL treated first-line with FCR. MRD analysis was performed after course 3 (C3) and at end of therapy (EOT) in bone marrow using 4-color flow cytometry (sensitivity 10-4 ). Eighteen percent of patients had U-MRD after C3 and 48% at EOT...
April 17, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Uri Rozovski, David M Harris, Ping Li, Zhiming Liu, Preetesh Jain, Alessandra Ferrajoli, Jan Burger, Phillip Thompson, Nitin Jain, William Wierda, Michael J Keating, Zeev Estrov
Although several studies established that unlike normal B cells chronic lymphocytic leukemia (CLL) cells metabolize fatty acids (FA), how CLL cells internalize FA is poorly understood. Because in various cell types CD36 facilitates FA uptake, we wondered whether a similar mechanism is operative CLL. We found that CD36 levels are higher in CLL cells than in normal B cells, and that small interfering RNA, CD36 neutralizing antibodies or sulfosuccinimidyl oleate (SSO) that inhibits CD36 significantly reduced the oxygen consumption of CLL cells incubated with FA...
April 20, 2018: Oncotarget
Jan A Burger
No abstract text is available yet for this article.
May 3, 2018: Blood
Kiran Naqvi, Elias Jabbour, Jeffrey Skinner, Musa Yilmaz, Alessandra Ferrajoli, Prithviraj Bose, Philip Thompson, Yesid Alvarado, Nitin Jain, Koichi Takahashi, Jan Burger, Zeev Estrov, Gautam Borthakur, Naveen Pemmaraju, Shilpa Paul, Jorge Cortes, Hagop M Kantarjian
BACKGROUND: Dasatinib is a potent BCR-ABL1 and Src family tyrosine kinase inhibitor. It is approved at a dose of 100 mg orally daily for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). This dose schedule is associated with myelosuppression and pleural effusions. Anecdotal data suggest that lower doses may be as effective and less toxic. The aim of this study was to assess the efficacy and safety of a lower dose of dasatinib (50 mg daily) in patients with newly diagnosed CML-CP...
May 3, 2018: Cancer
Michael Gierth, Florian Zeman, Stefan Denzinger, Malte W Vetterlein, Margit Fisch, Patrick J Bastian, Isabella Syring, Jörg Ellinger, Stephan C Müller, Edwin Herrmann, Christian Gilfrich, Matthias May, Armin Pycha, Florian M Wagenlehner, Stefan Vallo, Georg Bartsch, Axel Haferkamp, Marc-Oliver Grimm, Jan Roigas, Chris Protzel, Oliver W Hakenberg, Hans-Martin Fritsche, Maximilian Burger, Atiqullah Aziz, Roman Mayr
Background/Aims/Objectives: To evaluate the influence of body mass index (BMI) on complications and oncological outcomes in patients undergoing radical cystectomy (RC). METHODS: Clinical and histopathological parameters of patients have been prospectively collected within the "PROspective MulticEnTer RadIcal Cystectomy Series 2011". BMI was categorized as normal weight (<25 kg/m2), overweight (≥25-29.9 kg/m2) and obesity (≥30 kg/m2). The association between BMI and clinical and histopathological endpoints was examined...
May 2, 2018: Urologia Internationalis
Eric-Jan J A A van Gorp, Onno Teernstra, Hans J Aukes, Tanja Hamm-Faber, Katja Bürger, Jan Willem Kallewaard, Geert Spincemaille, Johannes W L C Schapendonk, Leon Vonhögen, Ewald Bronkhorst, Kris C P Vissers
OBJECTIVE: Different approaches in neuromodulation have been used to treat chronic low back pain in failed back surgery syndrome (FBSS) patients. We previously randomized 52 FBSS patients to be treated with spinal cord stimulation (SCS) and additional peripheral nerve field stimulation (PNFS) or SCS alone. At three months, we found a significant reduction of back pain in the PNFS-SCS group compared to the SCS group. In the subsequent open phase part of the study, all patients received optimal SCS and PNFS simultaneously...
April 2, 2018: Neuromodulation: Journal of the International Neuromodulation Society
Kristína Záhonová, Romana Petrželková, Matus Valach, Euki Yazaki, Denis V Tikhonenkov, Anzhelika Butenko, Jan Janouškovec, Štěpánka Hrdá, Vladimír Klimeš, Gertraud Burger, Yuji Inagaki, Patrick J Keeling, Vladimír Hampl, Pavel Flegontov, Vyacheslav Yurchenko, Marek Eliáš
Rheb is a conserved and widespread Ras-like GTPase involved in cell growth regulation mediated by the (m)TORC1 kinase complex and implicated in tumourigenesis in humans. Rheb function depends on its association with membranes via prenylated C-terminus, a mechanism shared with many other eukaryotic GTPases. Strikingly, our analysis of a phylogenetically rich sample of Rheb sequences revealed that in multiple lineages this canonical and ancestral membrane attachment mode has been variously altered. The modifications include: (1) accretion to the N-terminus of two different phosphatidylinositol 3-phosphate-binding domains, PX in Cryptista (the fusion being the first proposed synapomorphy of this clade), and FYVE in Euglenozoa and the related undescribed flagellate SRT308; (2) acquisition of lipidic modifications of the N-terminal region, namely myristoylation and/or S-palmitoylation in seven different protist lineages; (3) acquisition of S-palmitoylation in the hypervariable C-terminal region of Rheb in apusomonads, convergently to some other Ras family proteins; (4) replacement of the C-terminal prenylation motif with four transmembrane segments in a novel Rheb paralog in the SAR clade; (5) loss of an evident C-terminal membrane attachment mechanism in Tremellomycetes and some Rheb paralogs of Euglenozoa...
March 27, 2018: Scientific Reports
Martijn H Hulsmans, Mark van Heijl, Roderick M Houwert, Bart J Burger, Egbert Jan M Verleisdonk, Dirk Jan Veeger, Olivier A van der Meijden
PURPOSE: Surgical treatment of displaced midshaft clavicle fractures requires a decision between plate fixation and intramedullary (IM) fixation. Numerous studies report on the biomechanical properties of various repair constructs. The goal of this systematic review was to provide an overview of studies describing the biomechanical properties of the most commonly used surgical fixations of midshaft clavicle fractures. Additionally, we aimed to translate these biomechanical results into clinically relevant conclusions...
April 2018: Injury
Grazia Zulian, Erik Stange, Helen Woods, Laurence Carvalho, Jan Dick, Christopher Andrews, Francesc Baró, Pilar Vizcaino, David N Barton, Megan Nowel, Graciela M Rusch, Paula Autunes, João Fernandes, Diogo Ferraz, Rui Ferreira Dos Santos, Réka Aszalós, Ildikó Arany, Bálint Czúcz, Joerg A Priess, Christian Hoyer, Gleiciani Bürger-Patricio, David Lapola, Peter Mederly, Andrej Halabuk, Peter Bezak, Leena Kopperoinen, Arto Viinikka
Ecosystem service (ES) spatial modelling is a key component of the integrated assessments designed to support policies and management practices aiming at environmental sustainability. ESTIMAP ("Ecosystem Service Mapping Tool") is a collection of spatially explicit models, originally developed to support policies at a European scale. We based our analysis on 10 case studies, and 3 ES models. Each case study applied at least one model at a local scale. We analyzed the applications with respect to: the adaptation process; the "precision differential" which we define as the variation generated in the model between the degree of spatial variation within the spatial distribution of ES and what the model captures; the stakeholders' opinions on the usefulness of models...
February 2018: Ecosystem Services
Paolo Strati, Alessandra Ferrajoli, William G Wierda, Nitin Jain, Philip A Thompson, Susan M O'Brien, Katy Rezvani, Hagop M Kantarjian, Jan A Burger, Christina O Hinojosa, Michael J Keating, Zeev Estrov
No abstract text is available yet for this article.
February 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Uri Rozovski, David M Harris, Ping Li, Zhiming Liu, Preetesh Jain, Alessandra Ferrajoli, Jan Burger, Phillip Thompson, Nitin Jain, William Wierda, Michael J Keating, Zeev Estrov
Unlike normal B-cells, and similar to fat cells, chronic lymphocytic leukemia (CLL) cells aberrantly express lipoprotein lipase (LPL), which contributes to free fatty acids (FFAs) metabolism. Here we show that, in CLL cells, the B-cell receptor (BCR) inhibitor ibrutinib reduced LPL mRNA and protein levels and inhibited FFA metabolism in vitro. Likewise, in CLL cells from ibrutinib-treated patients, FFA metabolism was reduced and eventually stopped. Because ibrutinib disrupts CLL cells' ability to use FFAs for energy production, and because various BCR-dependent cellular functions rely on a continuous supply of chemical energy, ibrutinib interrupts several pathways imperative for cellular function in CLL cells...
February 21, 2018: Leukemia & Lymphoma
Susan O'Brien, Richard R Furman, Steven Coutre, Ian W Flinn, Jan A Burger, Kristie Blum, Jeff Sharman, William Wierda, Jeffrey Jones, Weiqiang Zhao, Nyla A Heerema, Amy J Johnson, Ying Luan, Danelle F James, Alvina D Chu, John C Byrd
We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients...
April 26, 2018: Blood
Gerard M H Swaen, Miranda Langendam, Joost Weyler, Huibert Burger, Sabine Siesling, Willem Jan Atsma, Lex Bouter
OBJECTIVES: To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste. SETTING: A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology...
February 10, 2018: Journal of Clinical Epidemiology
Guillemette E Benoist, Eric van der Meulen, Inge M van Oort, Jan H Beumer, Diederik M Somford, Jack A Schalken, David M Burger, Nielka P van Erp
BACKGROUND: Enzalutamide is a potent androgen-signaling receptor inhibitor and is licensed for the treatment of metastatic castration-resistant prostate cancer. N-desmethylenzalutamide is the active metabolite of enzalutamide. A method to quantitate enzalutamide and its active metabolite was developed and validated according to the European Medicine Agency guidelines. METHODS: Enzalutamide and N-desmethylenzalutamide were extracted by protein precipitation, separated on a C18 column with gradient elution and analyzed with tandem quadrupole mass spectrometry in positive ion mode...
April 2018: Therapeutic Drug Monitoring
Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A Burger, William G Wierda, P Andrew Futreal, Alessandra Ferrajoli
Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients...
April 19, 2018: Blood
Hagop Kantarjian, Farhad Ravandi, Nicholas J Short, Xuelin Huang, Nitin Jain, Koji Sasaki, Naval Daver, Naveen Pemmaraju, Joseph D Khoury, Jeffrey Jorgensen, Yesid Alvarado, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Musa Yilmaz, Gautam Bortakhur, Jan Burger, Steven Kornblau, William Wierda, Courtney DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Elias Jabbour
BACKGROUND: Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia. METHODS: We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower...
February 2018: Lancet Oncology
Jan A Burger, Adrian Wiestner
B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling...
March 2018: Nature Reviews. Cancer
Kristina M Wolf, Emma E Torbert, Dennis Bryant, Martin Burger, R Ford Denison, Israel Herrera, Jan Hopmans, Will Horwath, Stephen Kaffka, Angela Y Y Kong, R F Norris, Johan Six, Thomas P Tomich, Kate M Scow
The Century Experiment at the Russell Ranch Sustainable Agriculture Facility at the University of California, Davis provides long-term agroecological data from row crop systems in California's Central Valley starting in 1993. The Century Experiment was initially designed to study the effects of a gradient of water and nitrogen availability on soil properties and crop performance in ten different cropping systems to measure tradeoffs and synergies between agricultural productivity and sustainability. Currently systems include 11 different cropping systems-consisting of four different crops and a cover crop mixture-and one native grass system...
February 2018: Ecology
Erika Tissino, Dania Benedetti, Sarah E M Herman, Elisa Ten Hacken, Inhye E Ahn, Kari G Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre Chigaev, Larry A Sklar, Jan A Burger, Alessandra Ferrajoli, Tait D Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells...
February 5, 2018: Journal of Experimental Medicine
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