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https://www.readbyqxmd.com/read/29024776/update-on-tumor-infiltrating-lymphocytes-tils-in-breast-cancer-including-recommendations-to-assess-tils-in-residual-disease-after-neoadjuvant-therapy-and-in-carcinoma-in-situ-a-report-of-the-international-immuno-oncology-biomarker-working-group-on-breast-cancer
#1
REVIEW
Maria Vittoria Dieci, Nina Radosevic-Robin, Susan Fineberg, Gert van den Eynden, Nils Ternes, Frederique Penault-Llorca, Giancarlo Pruneri, Timothy M D'Alfonso, Sandra Demaria, Carlos Castaneda, Joselyn Sanchez, Sunil Badve, Stefan Michiels, Veerle Bossuyt, Federico Rojo, Baljit Singh, Torsten Nielsen, Giuseppe Viale, Seong-Rim Kim, Stephen Hewitt, Stephan Wienert, Sybille Loibl, David Rimm, Fraser Symmans, Carsten Denkert, Sylvia Adams, Sherene Loi, Roberto Salgado
Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research...
October 9, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28947417/combined-cdk4-6-and-pi3k%C3%AE-inhibition-is-synergistic-and-immunogenic-in-triple-negative-breast-cancer
#2
Zhi Ling Teo, Stephanie Versaci, Sathana Dushyanthen, Franco Caramia, Peter Savas, Chris Mintoff, Magnus Zethoven, Balaji Virassamy, Stephen J Luen, Grant A McArthur, Wayne A Phillips, Phillip K Darcy, Sherene Loi
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy...
September 25, 2017: Cancer Research
https://www.readbyqxmd.com/read/28928458/agonist-immunotherapy-restores-t-cell-function-following-mek-inhibition-improving-efficacy-in-breast-cancer
#3
Sathana Dushyanthen, Zhi Ling Teo, Franco Caramia, Peter Savas, Christopher P Mintoff, Balaji Virassamy, Melissa A Henderson, Stephen J Luen, Mariam Mansour, Michael H Kershaw, Joseph A Trapani, Paul J Neeson, Roberto Salgado, Grant A McArthur, Justin M Balko, Paul A Beavis, Phillip K Darcy, Sherene Loi
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923573/neoadjuvant-buparlisib-plus-trastuzumab-and-paclitaxel-for-women-with-her2-primary-breast-cancer-a-randomised-double-blind-placebo-controlled-phase-ii-trial-neophoebe
#4
Sibylle Loibl, Lorena de la Pena, Valentina Nekljudova, Dimitrios Zardavas, Stefan Michiels, Carsten Denkert, Mahdi Rezai, Begoña Bermejo, Michael Untch, Soo Chin Lee, Sabine Turri, Patrick Urban, Sherko Kümmel, Guenther Steger, Andrea Gombos, Michael Lux, Martine J Piccart, Gunter Von Minckwitz, José Baselga, Sherene Loi
AIM: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. METHODS: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel...
November 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28855210/cd73-promotes-resistance-to-her2-erbb2-antibody-therapy
#5
Martin Turcotte, David Allard, Deepak Mittal, Yacine Bareche, Laurence Buisseret, Vinu José, Sandra Pommey, Vincent Delisle, Sherene Loi, Heikki Joensuu, Pirkko-Liisa Kellokumpu-Lehtinen, Christos Sotiriou, Mark J Smyth, John Stagg
Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome...
October 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28777143/assessing-tumor-infiltrating-lymphocytes-in-solid-tumors-a-practical-review-for-pathologists-and-proposal-for-a-standardized-method-from-the-international-immuno-oncology-biomarkers-working-group-part-2-tils-in-melanoma-gastrointestinal-tract-carcinomas-non
#6
Shona Hendry, Roberto Salgado, Thomas Gevaert, Prudence A Russell, Tom John, Bibhusal Thapa, Michael Christie, Koen van de Vijver, M V Estrada, Paula I Gonzalez-Ericsson, Melinda Sanders, Benjamin Solomon, Cinzia Solinas, Gert G G M Van den Eynden, Yves Allory, Matthias Preusser, Johannes Hainfellner, Giancarlo Pruneri, Andrea Vingiani, Sandra Demaria, Fraser Symmans, Paolo Nuciforo, Laura Comerma, E A Thompson, Sunil Lakhani, Seong-Rim Kim, Stuart Schnitt, Cecile Colpaert, Christos Sotiriou, Stefan J Scherer, Michail Ignatiadis, Sunil Badve, Robert H Pierce, Giuseppe Viale, Nicolas Sirtaine, Frederique Penault-Llorca, Tomohagu Sugie, Susan Fineberg, Soonmyung Paik, Ashok Srinivasan, Andrea Richardson, Yihong Wang, Ewa Chmielik, Jane Brock, Douglas B Johnson, Justin Balko, Stephan Wienert, Veerle Bossuyt, Stefan Michiels, Nils Ternes, Nicole Burchardi, Stephen J Luen, Peter Savas, Frederick Klauschen, Peter H Watson, Brad H Nelson, Carmen Criscitiello, Sandra O'Toole, Denis Larsimont, Roland de Wind, Giuseppe Curigliano, Fabrice André, Magali Lacroix-Triki, Mark van de Vijver, Federico Rojo, Giuseppe Floris, Shahinaz Bedri, Joseph Sparano, David Rimm, Torsten Nielsen, Zuzana Kos, Stephen Hewitt, Baljit Singh, Gelareh Farshid, Sibylle Loibl, Kimberly H Allison, Nadine Tung, Sylvia Adams, Karen Willard-Gallo, Hugo M Horlings, Leena Gandhi, Andre Moreira, Fred Hirsch, Maria V Dieci, Maria Urbanowicz, Iva Brcic, Konstanty Korski, Fabien Gaire, Hartmut Koeppen, Amy Lo, Jennifer Giltnane, Marlon C Rebelatto, Keith E Steele, Jiping Zha, Kenneth Emancipator, Jonathan W Juco, Carsten Denkert, Jorge Reis-Filho, Sherene Loi, Stephen B Fox
Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma...
November 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/28777142/assessing-tumor-infiltrating-lymphocytes-in-solid-tumors-a-practical-review-for-pathologists-and-proposal-for-a-standardized-method-from-the-international-immunooncology-biomarkers-working-group-part-1-assessing-the-host-immune-response-tils-in-invasive-breast
#7
Shona Hendry, Roberto Salgado, Thomas Gevaert, Prudence A Russell, Tom John, Bibhusal Thapa, Michael Christie, Koen van de Vijver, M V Estrada, Paula I Gonzalez-Ericsson, Melinda Sanders, Benjamin Solomon, Cinzia Solinas, Gert G G M Van den Eynden, Yves Allory, Matthias Preusser, Johannes Hainfellner, Giancarlo Pruneri, Andrea Vingiani, Sandra Demaria, Fraser Symmans, Paolo Nuciforo, Laura Comerma, E A Thompson, Sunil Lakhani, Seong-Rim Kim, Stuart Schnitt, Cecile Colpaert, Christos Sotiriou, Stefan J Scherer, Michail Ignatiadis, Sunil Badve, Robert H Pierce, Giuseppe Viale, Nicolas Sirtaine, Frederique Penault-Llorca, Tomohagu Sugie, Susan Fineberg, Soonmyung Paik, Ashok Srinivasan, Andrea Richardson, Yihong Wang, Ewa Chmielik, Jane Brock, Douglas B Johnson, Justin Balko, Stephan Wienert, Veerle Bossuyt, Stefan Michiels, Nils Ternes, Nicole Burchardi, Stephen J Luen, Peter Savas, Frederick Klauschen, Peter H Watson, Brad H Nelson, Carmen Criscitiello, Sandra O'Toole, Denis Larsimont, Roland de Wind, Giuseppe Curigliano, Fabrice André, Magali Lacroix-Triki, Mark van de Vijver, Federico Rojo, Giuseppe Floris, Shahinaz Bedri, Joseph Sparano, David Rimm, Torsten Nielsen, Zuzana Kos, Stephen Hewitt, Baljit Singh, Gelareh Farshid, Sibylle Loibl, Kimberly H Allison, Nadine Tung, Sylvia Adams, Karen Willard-Gallo, Hugo M Horlings, Leena Gandhi, Andre Moreira, Fred Hirsch, Maria V Dieci, Maria Urbanowicz, Iva Brcic, Konstanty Korski, Fabien Gaire, Hartmut Koeppen, Amy Lo, Jennifer Giltnane, Marlon C Rebelatto, Keith E Steele, Jiping Zha, Kenneth Emancipator, Jonathan W Juco, Carsten Denkert, Jorge Reis-Filho, Sherene Loi, Stephen B Fox
Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment...
September 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/28694034/insertion-and-deletion-derived-tumour-specific-neoantigens-and-the-immunogenic-phenotype-a-pan-cancer-analysis
#8
Samra Turajlic, Kevin Litchfield, Hang Xu, Rachel Rosenthal, Nicholas McGranahan, James L Reading, Yien Ning S Wong, Andrew Rowan, Nnennaya Kanu, Maise Al Bakir, Tim Chambers, Roberto Salgado, Peter Savas, Sherene Loi, Nicolai J Birkbak, Laurent Sansregret, Martin Gore, James Larkin, Sergio A Quezada, Charles Swanton
BACKGROUND: The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype. METHODS: We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas...
August 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28685159/the-aurora-pilot-study-for-molecular-screening-of-patients-with-advanced-breast-cancer-a-study-of-the-breast-international-group
#9
Marion Maetens, David Brown, Alexandre Irrthum, Philippe Aftimos, Giuseppe Viale, Sibylle Loibl, Jean-François Laes, Peter J Campbell, Alastair Thompson, Javier Cortes, Sabine Seiler, Sara Vinnicombe, Mafalda Oliveira, Françoise Rothé, Yacine Bareche, Debora Fumagalli, Dimitrios Zardavas, Christine Desmedt, Martine Piccart, Sherene Loi, Christos Sotiriou
Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28668293/mechanisms-of-resistance-of-chemotherapy-in-early-stage-triple-negative-breast-cancer-tnbc
#10
Lironne Wein, Sherene Loi
Triple negative breast cancer (TNBC) a clinically aggressive subtype of breast cancer with poor outcomes. Chromosomal instability is a hallmark of many TNBCs, and likely underlies its ability to adapt and rapidly become resistant to chemotherapy. A study of residual disease after neoadjuvant chemotherapy have identified biological mechanisms driving this resistance to chemotherapy. Copy number amplifications such as MCL1, MYC and JAK2, as well as PTEN deletions or mutations have all been identified at a higher frequency in residual disease, suggesting they may play a role in de novo or acquired chemotherapy resistance...
August 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28652278/palbociclib-combined-with-fulvestrant-in-premenopausal-women-with-advanced-breast-cancer-and-prior-progression-on-endocrine-therapy-paloma-3-results
#11
Sibylle Loibl, Nicholas C Turner, Jungsil Ro, Massimo Cristofanilli, Hiroji Iwata, Seock-Ah Im, Norikazu Masuda, Sherene Loi, Fabrice André, Nadia Harbeck, Sunil Verma, Elizabeth Folkerd, Kathy Puyana Theall, Justin Hoffman, Ke Zhang, Cynthia Huang Bartlett, Mitchell Dowsett
BACKGROUND: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). PATIENTS AND METHODS: One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo...
September 2017: Oncologist
https://www.readbyqxmd.com/read/28592566/combined-immune-checkpoint-blockade-as-a-therapeutic-strategy-for-brca1-mutated-breast-cancer
#12
Emma Nolan, Peter Savas, Antonia N Policheni, Phillip K Darcy, François Vaillant, Christopher P Mintoff, Sathana Dushyanthen, Mariam Mansour, Jia-Min B Pang, Stephen B Fox, Charles M Perou, Jane E Visvader, Daniel H D Gray, Sherene Loi, Geoffrey J Lindeman
Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model...
June 7, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28561712/novel-targeted-agents-and-immunotherapy-in-breast-cancer
#13
Ingrid A Mayer, Rebecca Dent, Tira Tan, Peter Savas, Sherene Loi
The treatment of breast cancer is generally determined according to breast cancer subtype: hormone receptor-positive (luminal), triple-negative (basal-like), and HER2-overexpressing breast cancer. Recent years have seen the development of exciting novel and potent therapeutics based on molecular pathways, immune modulation, and antibody conjugates. In this article, we cover new and emerging therapeutic areas and ongoing clinical trials that may result in further improvements in breast cancer outcomes.
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28534250/advancing-immunotherapy-in-metastatic-breast-cancer
#14
REVIEW
Mariam Mansour, Zhi Ling Teo, Stephen J Luen, Sherene Loi
Despite many advances in the treatment of breast cancer, the development of metastatic disease remains an incurable and frequent cause of cancer death for women worldwide. An improved understanding of the role of host immunosurveillance in modulating breast cancer disease biology, as well as impressive survival benefits seen to checkpoint blockade in other malignancies have provided great hope for an expanding role of immunotherapies in breast cancer management. While these novel therapies are currently being investigated in clinical trials, signals of efficacy, and tolerability in early phase studies suggest these will eventually make their way into standard practice algorithms...
June 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28430863/fgfr2-amplification-in-metastatic-hormone-positive-breast-cancer-and-response-to-an-mtor-inhibitor
#15
L Wein, P Savas, C Van Geelen, F Caramia, K Moodie, S Joshi, S Loi
No abstract text is available yet for this article.
August 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28430777/correction-the-subclonal-architecture-of-metastatic-breast-cancer-results-from-a-prospective-community-based-rapid-autopsy-program-cascade
#16
Peter Savas, Zhi Ling Teo, Christophe Lefevre, Christoffer Flensburg, Franco Caramia, Kathryn Alsop, Mariam Mansour, Prudence A Francis, Heather A Thorne, Maria Joao Silva, Nnennaya Kanu, Michelle Dietzen, Andrew Rowan, Maik Kschischo, Stephen Fox, David D Bowtell, Sarah-Jane Dawson, Terence P Speed, Charles Swanton, Sherene Loi
[This corrects the article DOI: 10.1371/journal.pmed.1002204.].
April 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28338653/breast-ductal-carcinoma-in-situ-carry-mutational-driver-events-representative-of-invasive-breast-cancer
#17
Jia-Min B Pang, Peter Savas, Andrew P Fellowes, Gisela Mir Arnau, Tanjina Kader, Ravikiran Vedururu, Chelsee Hewitt, Elena A Takano, David J Byrne, David Yh Choong, Ewan Ka Millar, C Soon Lee, Sandra A O'Toole, Sunil R Lakhani, Margaret C Cummings, G Bruce Mann, Ian G Campbell, Alexander Dobrovic, Sherene Loi, Kylie L Gorringe, Stephen B Fox
The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30)...
July 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28165340/targeting-the-adenosine-2a-receptor-enhances-chimeric-antigen-receptor-t-cell-efficacy
#18
Paul A Beavis, Melissa A Henderson, Lauren Giuffrida, Jane K Mills, Kevin Sek, Ryan S Cross, Alexander J Davenport, Liza B John, Sherly Mardiana, Clare Y Slaney, Ricky W Johnstone, Joseph A Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H Kershaw, Phillip K Darcy
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs)...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28049579/tumour-infiltrating-lymphocytes-and-the-emerging-role-of-immunotherapy-in-breast-cancer
#19
Stephen J Luen, Peter Savas, Stephen B Fox, Roberto Salgado, Sherene Loi
Breast cancer has not previously been considered a highly immunogenic cancer. Observations of tumour-infiltrating lymphocytes (TILs) in and around neoplastic cells in tumour samples, and associations with improved pathological complete response and clinical survival end points have changed our perspective on this. Lymphocytic infiltrates have long been observed in breast cancer; however, more recently, retrospective analysis of prospectively collected tissue samples from clinical trials has demonstrated the potential role of host immunosurveillance in influencing the biology of breast cancer...
February 2017: Pathology
https://www.readbyqxmd.com/read/28027521/correlation-between-severe-infection-and-breast-cancer-metastases-in-the-eortc-10994-big-1-00-trial-investigating-innate-immunity-as-a-tumour-suppressor-in%C3%A2-breast-cancer
#20
RANDOMIZED CONTROLLED TRIAL
Nathan Touati, Konstantinos Tryfonidis, Franco Caramia, Hervé Bonnefoi, David Cameron, Leen Slaets, Belinda S Parker, Sherene Loi
BACKGROUND: Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether 'severe infection' can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones...
February 2017: European Journal of Cancer
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