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SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer.

16 min 14 s sitten
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SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer.

Front Pharmacol. 2017;8:956

Authors: Magistri P, Battistelli C, Strippoli R, Petrucciani N, Pellinen T, Rossi L, Mangogna L, Aurello P, D'Angelo F, Tripodi M, Ramacciato G, Nigri G

Abstract
HIGHLIGHTS Preliminary results of this work were presented at the 2016 Academic Surgical Congress, Jacksonville (FL), February 2-4 2016 (Original title: Selective Smo-Inhibition Interferes With Cellular Energetic Metabolism In Colorectal Cancer)This study was funded by "Sapienza-University of Rome" (Funds for young researchers) and "AIRC" (Italian Association for Cancer Research)Hedgehog inhibitor was kindly provided by Genentech, Inc.®. Colon Cancer (CC) is the fourth most frequently diagnosed tumor and the second leading cause of death in the USA. Abnormalities of Hedgehog pathway have been demonstrated in several types of human cancers, however the role of Hedgehog (Hh) in CC remain controversial. In this study, we analyzed the association between increased mRNA expression of GLI1 and GLI2, two Hh target genes, and CC survival and recurrence by gene expression microarray from a cohort of 382 CC patients. We found that patients with increased expression of GLI1 showed a statistically significant reduction in survival. In order to demonstrate a causal role of Hh pathway activation in the pathogenesis of CC, we treated HCT 116, SW480 and SW620 CC cells lines with GDC-0449, a pharmacological inhibitor of Smoothened (SMO). Treatment with GDC-0449 markedly reduced expression of Hh target genes GLI1, PTCH1, HIP1, MUC5AC, thus indicating that this pathway is constitutively active in CC cell lines. Moreover, GDC-0449 partially reduced cell proliferation, which was associated with upregulation of p21 and downregulation of CycD1. Finally, treatment with the same drug reduced migration and three-dimensional invasion, which were associated with downregulation of Snail1, the EMT master gene, and with induction of the epithelial markers Cytokeratin-18 and E-cadherin. These results were confirmed by SMO genetic silencing. Notably, treatment with 5E1, a Sonic Hedgehog-specific mAb, markedly reduced the expression of Hedgehog target genes, as well as inhibited cell proliferation and mediated reversion toward an epithelial phenotype. This suggests the existence of a Hedgehog autocrine signaling loop affecting cell plasticity and fostering cell proliferation and migration/invasion in CC cell lines. These discoveries encourage future investigations to better characterize the role of Hedgehog in cellular plasticity and invasion during the different steps of CC pathogenesis.

PMID: 29456503 [PubMed]

Preclinical evaluation of a semi-automated and rapid commercial electrophoresis assay for von Willebrand factor multimers.

Ma, 19/02/2018 - 00:48
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Preclinical evaluation of a semi-automated and rapid commercial electrophoresis assay for von Willebrand factor multimers.

J Clin Lab Anal. 2018 Feb 17;:

Authors: Pikta M, Zemtsovskaja G, Bautista H, Nouadje G, Szanto T, Viigimaa M, Banys V

Abstract
BACKGROUND: The von Willebrand factor (VWF) multimer test is required to correctly subtype qualitative type 2 von Willebrand disease (VWD). The current VWF multimer assays are difficult, nonstandardized, and time-consuming. The purpose of this study was to evaluate the clinical utility of the commercial VWF multimer kit by Sebia (Lisses, France), an electrophoresis technique yielding same-day results.
METHODS: Ten healthy volunteer plasma samples, in-house reference plasma (IRP) and commercial normal plasma (CNP) samples, 10 plasma samples from patients with a known VWD type, 1 hemophilia A plasma sample, and 7 external quality assurance (EQA) samples were analyzed using the commercial VWF multimer kit. Additional coagulation testing included measurements of VWF antigen (VWF:Ag), VWF activity (VWF:Ac), and FVIII activity (FVIII:C).
RESULTS: The CNP results revealed a relative loss of the highest molecular weight multimers; therefore, IRP was preferred as the reference sample. The interpretations of 10 patients with a known VWD type could be successfully reproduced and agreed with previous VWF multimer results. In all EQA surveys, the multimer results and final VWD diagnosis agreed with expert opinion.
CONCLUSIONS: The VWF multimer assay by Sebia is easy to perform and can be successfully implemented in any clinical laboratory for second-stage evaluation of VWD. The resolution power of multimer distribution is adequate to correctly classify VWD types 1, 2A, 2B, and 3.

PMID: 29453814 [PubMed - as supplied by publisher]

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

Su, 18/02/2018 - 00:47
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Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

Nat Commun. 2018 Feb 15;9(1):697

Authors: Schrader A, Crispatzu G, Oberbeck S, Mayer P, Pützer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmüller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brümmendorf TH, Nürnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, Herling M

Abstract
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

PMID: 29449575 [PubMed - in process]

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

La, 17/02/2018 - 00:47
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Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

Thromb Haemost. 2018 Feb 15;:

Authors: Carcao M, Altisent C, Castaman G, Fukutake K, Kerlin BA, Kessler C, Lassila R, Nugent D, Oldenburg J, Garly ML, Rosholm A, Inbal A

Abstract
Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A2 dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A2 efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A2; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A2 was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A2 prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A2 dose, and four were performed 10 to 21 days after the last dose.

PMID: 29448295 [PubMed - as supplied by publisher]

Optogenetics in cancer drug discovery.

La, 17/02/2018 - 00:47
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Optogenetics in cancer drug discovery.

Expert Opin Drug Discov. 2018 Feb 15;:1-14

Authors: Kiełbus M, Czapiński J, Odrzywolski A, Stasiak G, Szymańska K, Kałafut J, Kos M, Giannopoulos K, Stepulak A, Rivero-Müller A

Abstract
INTRODUCTION: The discovery and domestication of biomolecules that respond to light has taken a light of its own, providing new molecular tools with incredible spatio-temporal resolution to manipulate cellular behavior. Areas covered: The authors herein analyze the current optogenetic tools in light of their current, and potential, uses in cancer drug discovery, biosafety and cancer biology. Expert opinion: The pipeline from drug discovery to the clinic is plagued with drawbacks, where most drugs fail in either efficacy or safety. These issues require the redesign of the pipeline and the development of more controllable/personalized therapies. Light is, aside from inexpensive, almost harmless if used appropriately, can be directed to single cells or organs with controllable penetration, and comes in a variety of wavelengths. Light-responsive systems can activate, inhibit or compensate cell signaling pathways or specific cellular events, allowing the specific control of the genome and epigenome, and modulate cell fate and transformation. These synthetic molecular tools have the potential to revolutionize drug discovery and cancer research.

PMID: 29447015 [PubMed - as supplied by publisher]

Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations.

La, 17/02/2018 - 00:47
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Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations.

Hum Mutat. 2018 Feb 15;:

Authors: Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, Leslie G, Aalfs CM, Abugattas J, Adlard J, Agata S, Aittomäki K, Andrews L, Andrulis IL, Arason A, Arnold N, Arun BK, Asseryanis E, Auerbach L, Azzollini J, Balmaña J, Barile M, Barkardottir RB, Barrowdale D, Benitez J, Berger A, Berger R, Blanco AM, Blazer KR, Blok MJ, Bonadona V, Bonanni B, Bradbury AR, Brewer C, Buecher B, Buys SS, Caldes T, Caliebe A, Caligo MA, Campbell I, Caputo S, Chiquette J, Chung WK, Claes KBM, Collée JM, Cook J, Davidson R, de la Hoya M, De Leeneer K, de Pauw A, Delnatte C, Diez O, Ding YC, Ditsch N, Domchek SM, Dorfling CM, Velazquez C, Dworniczak B, Eason J, Easton DF, Eeles R, Ehrencrona H, Ejlertsen B, EMBRACE, Engel C, Engert S, Evans DG, Faivre L, Feliubadaló L, Ferrer SF, Foretova L, Fowler J, Frost D, Galvão HCR, Ganz PA, Garber J, Gauthier-Villars M, Gehrig A, GEMO Study Collaborators, Gerdes AM, Gesta P, Giannini G, Giraud S, Glendon G, Godwin AK, Greene MH, Gronwald J, Gutierrez-Barrera A, Hahnen E, Hauke J, HEBON, Henderson A, Hentschel J, Hogervorst FBL, Honisch E, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jensen UB, John EM, Joseph V, Kaczmarek K, Karlan BY, Kast K, Investigators K, Kim SW, Konstantopoulou I, Korach J, Laitman Y, Lasa A, Lasset C, Lázaro C, Lee A, Lee MH, Lester J, Lesueur F, Liljegren A, Lindor NM, Longy M, Loud JT, Lu KH, Lubinski J, Machackova E, Manoukian S, Mari V, Martínez-Bouzas C, Matrai Z, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Mickys U, Miller A, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Neuhausen SL, Nevanlinna H, Ngeow J, Nguyen HP, Niederacher D, Nielsen HR, Nielsen FC, Nussbaum RL, Offit K, Öfverholm A, Ong KR, Osorio A, Papi L, Papp J, Pasini B, Pedersen IS, MSc AP, MSc NP, Peterlongo P, Pohl E, Ba NP, Prajzendanc K, Prieur F, Pujol P, Radice P, Ramus SJ, Rantala J, Rashid MU, Rhiem K, Robson M, Rodriguez GC, Rogers MT, Rudaitis V, Schmidt AY, Schmutzler RK, Senter L, Shah PD, Sharma P, Side LE, Simard J, Singer CF, Skytte AB, Slavin TP, Snape K, Sobol H, Southey M, Steele L, Steinemann D, Sukiennicki G, Sutter C, Szabo CI, Tan YY, Teixeira MR, Terry MB, Teulé A, Thomas A, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Topka S, Trainer AH, Tung N, van Asperen CJ, van der Hout AH, van der Kolk LE, van der Luijt RB, Van Heetvelde M, Varesco L, Varon-Mateeva R, Vega A, Villarreal-Garza C, von Wachenfeldt A, Walker L, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Yoon SY, Zanzottera C, Zidan J, Zorn KK, Selkirk CGH, Hulick PJ, Chenevix-Trench G, Spurdle AB, Antoniou AC, Nathanson KL, CIMBA Consortium

Abstract
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on 6 continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. This article is protected by copyright. All rights reserved.

PMID: 29446198 [PubMed - as supplied by publisher]

Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing.

La, 17/02/2018 - 00:47
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Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing.

Cell Death Differ. 2017 May;24(5):832-843

Authors: Garg AD, Vandenberk L, Fang S, Fasche T, Van Eygen S, Maes J, Van Woensel M, Koks C, Vanthillo N, Graf N, de Witte P, Van Gool S, Salven P, Agostinis P

Abstract
Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H2O2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.

PMID: 28234357 [PubMed - indexed for MEDLINE]

Sex bias in MHC I-associated shaping of the adaptive immune system.

Pe, 16/02/2018 - 00:47
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Sex bias in MHC I-associated shaping of the adaptive immune system.

Proc Natl Acad Sci U S A. 2018 Feb 12;:

Authors: Schneider-Hohendorf T, Görlich D, Savola P, Kelkka T, Mustjoki S, Gross CC, Owens GC, Klotz L, Dornmair K, Wiendl H, Schwab N

Abstract
HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.

PMID: 29440397 [PubMed - as supplied by publisher]

Inadvertent completely HLA-mismatched allogeneic unrelated bone marrow transplant: lessons learned.

To, 15/02/2018 - 00:46
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Inadvertent completely HLA-mismatched allogeneic unrelated bone marrow transplant: lessons learned.

Bone Marrow Transplant. 2016 07;51(7):1016-8

Authors: Sorensen BS, Szer J, Shaw B, Korhonen M, Mengling T, Fechter M, Elmoazzen H, Lindberg B, Chapman J, Nørgaard JM, Foeken L, Hwang WY, Nielsen B

PMID: 26974269 [PubMed - indexed for MEDLINE]

Left ventricular mass and ambulatory blood pressure are increased in long-term survivors of childhood cancer after autologous SCT.

To, 15/02/2018 - 00:46
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Left ventricular mass and ambulatory blood pressure are increased in long-term survivors of childhood cancer after autologous SCT.

Bone Marrow Transplant. 2016 06;51(6):853-5

Authors: Vatanen A, Ojala TH, Sarkola T, Turanlahti M, Jahnukainen T, Saarinen-Pihkala UM, Jahnukainen K

PMID: 26828907 [PubMed - indexed for MEDLINE]

Mast cell-neural interactions contribute to pain and itch.

Ke, 14/02/2018 - 00:45

Mast cell-neural interactions contribute to pain and itch.

Immunol Rev. 2018 Mar;282(1):168-187

Authors: Gupta K, Harvima IT

Abstract
Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer.

PMID: 29431216 [PubMed - in process]

A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma.

Ke, 14/02/2018 - 00:45

A New Model to Predict Benign Histology in Residual Retroperitoneal Masses After Chemotherapy in Nonseminoma.

Eur Urol Focus. 2018 Feb 07;:

Authors: Leão R, Nayan M, Punjani N, Jewett MAS, Fadaak K, Garisto J, Lewin J, Atenafu EG, Sweet J, Anson-Cartwright L, Boström P, Chung P, Warde P, Bedard PL, Bagrodia A, Freifeld Y, Power N, Winquist E, Hamilton RJ

Abstract
BACKGROUND: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is indicated in testicular cancer patients with normalised or plateaued serum tumour markers and residual retroperitoneal lesions >1cm. Challenges remain in predicting postchemotherapy residual mass (pcRM) histology, which may lead to unnecessary surgery.
OBJECTIVE: To develop an accurate model to predict pcRM histology in patients with nonseminomatous germ cell tumours (NSGCTs).
DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 335 patients undergoing pcRPLND for metastatic NSGCTs to develop a model to predict benign histology in retroperitoneal pcRM. Our model was compared with others and externally validated.
INTERVENTION: Chemotherapy and pcRPLND.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression to evaluate the presence of benign histology, and fractional polynomials to allow for a nonlinear association between continuous variables and the outcome. The final Princess Margaret model (PMM) was selected based on the number of variables used, reliability, and discriminative capacity to predict benign pcRM.
RESULTS AND LIMITATIONS: PMM included the presence of teratoma in the orchiectomy, prechemotherapy α-fetoprotein, prechemotherapy mass size, and change in mass size during chemotherapy. Model specificity was 99.3%. Compared with Vergouwe et al's model, PMM had significantly better accuracy (C statistic 0.843 vs 0.783). PMM appropriately identified a larger number of patients for whom pcRPLND can safely be avoided (13.9% vs 0%). Validated in external cohorts, the model retained high discrimination (C statistic 0.88 and 0.80). Larger and prospective studies are needed to further validate this model.
CONCLUSIONS: Our clinical model, externally validated, showed improved discriminative ability in predicting pcRM histology when compared with other models. The higher accuracy and reduced number of variables make this a novel and appealing model to use for patient counselling and treatment strategies.
PATIENT SUMMARY: Princess Margaret model accurately predicted postchemotherapy benign histology. These results might have clinical impact by avoiding unnecessary retroperitoneal lymph node dissection and consequently changing the paradigm of advanced testicular cancer treatment.

PMID: 29428550 [PubMed - as supplied by publisher]

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Ke, 14/02/2018 - 00:45
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Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

Oncotarget. 2016 Dec 06;7(49):80140-80163

Authors: Hamdi Y, Soucy P, Adoue V, Michailidou K, Canisius S, Lemaçon A, Droit A, Andrulis IL, Anton-Culver H, Arndt V, Baynes C, Blomqvist C, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borresen-Dale AL, Brand JS, Brauch H, Brenner H, Broeks A, Burwinkel B, Chang-Claude J, NBCS Collaborators, Couch FJ, Cox A, Cross SS, Czene K, Darabi H, Dennis J, Devilee P, Dörk T, Dos-Santos-Silva I, Eriksson M, Fasching PA, Figueroa J, Flyger H, García-Closas M, Giles GG, Goldberg MS, González-Neira A, Grenaker-Alnæs G, Guénel P, Haeberle L, Haiman CA, Hamann U, Hallberg E, Hooning MJ, Hopper JL, Jakubowska A, Jones M, Kabisch M, Kataja V, Lambrechts D, Le Marchand L, Lindblom A, Lubinski J, Mannermaa A, Maranian M, Margolin S, Marme F, Milne RL, Neuhausen SL, Nevanlinna H, Neven P, Olswold C, Peto J, Plaseska-Karanfilska D, Pylkäs K, Radice P, Rudolph A, Sawyer EJ, Schmidt MK, Shu XO, Southey MC, Swerdlow A, Tollenaar RA, Tomlinson I, Torres D, Truong T, Vachon C, Van Den Ouweland AM, Wang Q, Winqvist R, kConFab/AOCS Investigators, Zheng W, Benitez J, Chenevix-Trench G, Dunning AM, Pharoah PD, Kristensen V, Hall P, Easton DF, Pastinen T, Nord S, Simard J

Abstract
There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

PMID: 27792995 [PubMed - indexed for MEDLINE]

Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms - clinical practice among Nordic specialists.

Ma, 12/02/2018 - 00:45

Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms - clinical practice among Nordic specialists.

Eur J Haematol. 2018 Feb 10;:

Authors: Bjerrum OW, Samuelsson J, Ghanima W, Kauppila M, Andersen CL, Nordic Myeloproliferative Neoplasm Study Group

Abstract
BACKGROUND: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting and access to therapy, however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs.
OBJECTIVES: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar health care systems.
RESULTS: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining anti-aggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients.
CONCLUSIONS: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary health care sector. This article is protected by copyright. All rights reserved.

PMID: 29427461 [PubMed - as supplied by publisher]

Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function.

Ma, 12/02/2018 - 00:45

Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function.

Int J Lab Hematol. 2018 Feb 10;:

Authors: Nummi V, Lassila R, Joutsi-Korhonen L, Armstrong E, Szanto T

Abstract
INTRODUCTION: Diagnosis of von Willebrand disease (VWD) is challenging, particularly for type 1. The current diagnostic guidelines emphasize simultaneous bleeding symptoms and von Willebrand factor (VWF) levels of <30-40 IU/dL. Historical diagnoses require updated evaluation. We assessed the accuracy of past VWD diagnoses in our comprehensive care center with the standardized bleeding score (BS) and central laboratory analysis, focusing on VWF-dependent platelet functions in whole blood.
METHODS: Our study comprised 83 adults with prior VWD who were diagnosed a median of 20 years ago. We assessed BS, VWF antigen and activity (minimum of 3 measurements), FVIII, PFA-100® , and platelet aggregation via Multiplate® . Genetic testing was targeted to types 3, 2N, 2B, and equivocal cases.
RESULTS: All 13/13 (100%) type 3 and 29/32 (90%) type 2, but only 10/38 (26%) of type 1 (overall 52/83 (63%)) patients met the current criteria for VWD. All confirmed cases had abnormal BS, impaired PFA-100® , and decreased or absent ristocetin-induced platelet aggregation (RIPA), except subtype 2B. VWF, FVIII, RIPA, and PFA correlated with BS including all study subjects. Ten of the 38 patients with previous type 1 had low VWF (35-50 IU/dL) and variable VWF-dependent platelet function. Altogether, 21/83 patients (25%) had repeatedly normal VWF:RCo (>50 IU/dL).
CONCLUSION: von Willebrand disease is associated with impaired VWF-dependent whole blood platelet functions that match traditional VWF measurements. We detected normal VWF in 25% of historically diagnosed patients, mainly type 1 patients, implying that there is a need to systematically re-evaluate historical VWD diagnoses.

PMID: 29427305 [PubMed - as supplied by publisher]

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Su, 11/02/2018 - 00:44

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Nat Commun. 2018 Feb 08;9(1):556

Authors: Klein AP, Wolpin BM, Risch HA, Stolzenberg-Solomon RZ, Mocci E, Zhang M, Canzian F, Childs EJ, Hoskins JW, Jermusyk A, Zhong J, Chen F, Albanes D, Andreotti G, Arslan AA, Babic A, Bamlet WR, Beane-Freeman L, Berndt SI, Blackford A, Borges M, Borgida A, Bracci PM, Brais L, Brennan P, Brenner H, Bueno-de-Mesquita B, Buring J, Campa D, Capurso G, Cavestro GM, Chaffee KG, Chung CC, Cleary S, Cotterchio M, Dijk F, Duell EJ, Foretova L, Fuchs C, Funel N, Gallinger S, M Gaziano JM, Gazouli M, Giles GG, Giovannucci E, Goggins M, Goodman GE, Goodman PJ, Hackert T, Haiman C, Hartge P, Hasan M, Hegyi P, Helzlsouer KJ, Herman J, Holcatova I, Holly EA, Hoover R, Hung RJ, Jacobs EJ, Jamroziak K, Janout V, Kaaks R, Khaw KT, Klein EA, Kogevinas M, Kooperberg C, Kulke MH, Kupcinskas J, Kurtz RJ, Laheru D, Landi S, Lawlor RT, Lee IM, LeMarchand L, Lu L, Malats N, Mambrini A, Mannisto S, Milne RL, Mohelníková-Duchoňová B, Neale RE, Neoptolemos JP, Oberg AL, Olson SH, Orlow I, Pasquali C, Patel AV, Peters U, Pezzilli R, Porta M, Real FX, Rothman N, Scelo G, Sesso HD, Severi G, Shu XO, Silverman D, Smith JP, Soucek P, Sund M, Talar-Wojnarowska R, Tavano F, Thornquist MD, Tobias GS, Van Den Eeden SK, Vashist Y, Visvanathan K, Vodicka P, Wactawski-Wende J, Wang Z, Wentzensen N, White E, Yu H, Yu K, Zeleniuch-Jacquotte A, Zheng W, Kraft P, Li D, Chanock S, Obazee O, Petersen GM, Amundadottir LT

Abstract
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

PMID: 29422604 [PubMed - in process]

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Su, 11/02/2018 - 00:44
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Oncotarget. 2016 Oct 11;7(41):66328-66343

Authors: Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, Hautman C, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, Kamineni A, Kolonel LN, Kulke MH, Malats N, Olson SH, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Brais L, Bueno-de-Mesquita HB, Basso D, Berndt SI, Boutron-Ruault MC, Bijlsma MF, Brenner H, Burdette L, Campa D, Caporaso NE, Capurso G, Cavestro GM, Cotterchio M, Costello E, Elena J, Boggi U, Gaziano JM, Gazouli M, Giovannucci EL, Goggins M, Gross M, Haiman CA, Hassan M, Helzlsouer KJ, Hu N, Hunter DJ, Iskierka-Jazdzewska E, Jenab M, Kaaks R, Key TJ, Khaw KT, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, Landi MT, Landi S, Le Marchand L, Mambrini A, Mannisto S, Milne RL, Neale RE, Oberg AL, Panico S, Patel AV, Peeters PH, Peters U, Pezzilli R, Porta M, Purdue M, Quiros JR, Riboli E, Rothman N, Scarpa A, Scelo G, Shu XO, Silverman DT, Soucek P, Strobel O, Sund M, Małecka-Panas E, Taylor PR, Tavano F, Travis RC, Thornquist M, Tjønneland A, Tobias GS, Trichopoulos D, Vashist Y, Vodicka P, Wactawski-Wende J, Wentzensen N, Yu H, Yu K, Zeleniuch-Jacquotte A, Kooperberg C, Risch HA, Jacobs EJ, Li D, Fuchs C, Hoover R, Hartge P, Chanock SJ, Petersen GM, Stolzenberg-Solomon RS, Wolpin BM, Kraft P, Klein AP, Canzian F, Amundadottir LT

Abstract
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

PMID: 27579533 [PubMed - indexed for MEDLINE]

Harmonemia: a universal strategy for flow cytometry immunophenotyping-A European LeukemiaNet WP10 study.

Su, 11/02/2018 - 00:44
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Harmonemia: a universal strategy for flow cytometry immunophenotyping-A European LeukemiaNet WP10 study.

Leukemia. 2016 08;30(8):1769-72

Authors: Lacombe F, Bernal E, Bloxham D, Couzens S, Porta MG, Johansson U, Kern W, Macey M, Matthes T, Morilla R, Paiva A, Palacio C, Preijers F, Ratei R, Siitonen S, Allou K, Porwit A, Béné MC

PMID: 26922887 [PubMed - indexed for MEDLINE]

Antibody persistence after pneumococcal conjugate vaccination in patients with chronic lymphocytic leukemia.

La, 10/02/2018 - 00:44

Antibody persistence after pneumococcal conjugate vaccination in patients with chronic lymphocytic leukemia.

Hum Vaccin Immunother. 2018 Feb 08;:0

Authors: Lindström V, Aittoniemi J, Salmenniemi U, Käyhty H, Huhtala H, Itälä-Remes M, Sinisalo M

Abstract
Patients with chronic lymphocytic leukemia (CLL) are at a high risk for infections caused by Streptococcus pneumoniae. A pneumococcal conjugate vaccine (PCV) can induce a significant antibody response for some CLL patients. In this study we investigated antibody persistence after PCV7 in patients with CLL. The study material comprised 24 patients with CLL and 8 immunocompetent controls. The median antibody concentrations five years after PCV7 were lower for six pneumococcal serotypes in patients with CLL compared to controls, but the difference was not statistically significant. Depending on the serotype, the percentage of the CLL patients with antibody levels suggested to provide protection against invasive pneumococcal disease (IPD) varied from 29 to 71% five years after vaccination. This data suggests that PCV could result in antibody persistence at least five years in CLL patients.

PMID: 29420116 [PubMed - as supplied by publisher]

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

La, 10/02/2018 - 00:44

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

Haematologica. 2018 Feb 01;:

Authors: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V

Abstract
MABLE (NCT01056510) investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every 4 weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs. 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.

PMID: 29419437 [PubMed - as supplied by publisher]