La Jolla, CA, United States
La Jolla, CA, United States

Time filter

Source Type

Thiele J.-A.,Charles University | Bethel K.,Scripps Clinic Medical Group | Kralickova M.,Charles University | Kuhn P.,University of Southern California
Annual Review of Pathology: Mechanisms of Disease | Year: 2017

Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further clinical utility and widespread adoption have been limited. However, immense efforts have been undertaken to further the understanding of the mechanisms behind the biology and kinetics of these rare cells, and progress continues toward better applicability in the clinic. This review describes recent advances within the field, with a particular focus on understanding the biological significance of CTCs, and summarizes emerging methods for identifying, isolating, and interrogating the cells that may provide technical advantages allowing for the discovery of more specific clinical applications. Included is an atlas of high-definition images of CTCs from various cancer types, including uncommon CTCs captured only by broadly inclusive nonenrichment techniques. © 2017 by Annual Reviews. All rights reserved.


Newton P.K.,University of Southern California | Mason J.,University of Southern California | Bethel K.,Scripps Clinic Medical Group | Bazhenova L.,University of California at San Diego | And 3 more authors.
Cancer Research | Year: 2013

The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, although not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as "spreaders" or "sponges" and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting the potential significance of self-seeding of primary tumors, we use a Markov chain Monte Carlo (MCMC) approach, based on large autopsy data sets, to quantify the stochastic, systemic, and often multidirectional aspects of cancer progression. We quantify three types of multidirectional mechanisms of progression: (i) self-seeding of the primary tumor, (ii) reseeding of the primary tumor from a metastatic site (primary reseeding), and (iii) reseeding of metastatic tumors (metastasis reseeding). The model shows that the combined characteristics of the primary and the first metastatic site to which it spreads largely determine the future pathways and timescales of systemic disease. Cancer Res; 73(9); 2760-9. © 2013 AACR.


Sigal D.S.,Scripps Clinic Medical Group | Miller H.J.,Scripps Clinic Medical Group | Schram E.D.,Scripps Clinic Medical Group | Saven A.,Scripps Clinic Medical Group | Saven A.,Ida d Cecil een Cancer Center
Blood | Year: 2010

Before the contemporary development of rationally designed antineoplastic therapies, cladribine was identified as a lymphocyte-specific agent. Its profound impact on the natural history of hairy cell leukemia, with responses approaching 100% and a median duration of response of nearly a decade after only a single 7-day course, is well known and revolutionized the treatment of hairy cell leukemia. However, cladribine's impressive activity in other lymphoproliferative disorders has been generally underappreciated. Multiple single-arm phase 2 trials have demonstrated cladribine's potency across the full spectrum of lymphoid malignancies. In a limited number of phase 3 trials and cross-study analyses, cladribine compared favorably with fludarabine, another purine nucleoside analog that is more commonly used in the treatment of indolent lymphoid malignancies. Cladribine has been noted to have particular activity among lymphoid disorders with few effective therapies, specifically, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Recently approved novel agents may act in synergy with cladribine for these conditions and should be incorporated into future clinical studies. © 2010 by The American Society of Hematology.


Kowalski M.L.,Medical University of Lódz | Woessner K.,Scripps Clinic Medical Group | Sanak M.,Jagiellonian University
Journal of Allergy and Clinical Immunology | Year: 2015

Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema. © 2015 American Academy of Allergy, Asthma & Immunology.


Chen W.C.,Scripps Research Institute | Sigal D.S.,Scripps Clinic Medical Group | Saven A.,Scripps Clinic Medical Group | Paulson J.C.,Scripps Research Institute
Leukemia and Lymphoma | Year: 2012

CD22 is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family expressed on B cells that recognizes glycans of glycoproteins as ligands. Because siglecs exhibit restricted expression on one or a few leukocyte cell types, they have gained attention as attractive targets for cell-directed therapies. Several antibody-based therapies targeting CD22 (Siglec-2) are currently in clinical trials for the treatment of hairy cell leukemia and other B cell lymphomas. As an alternative to antibodies we have developed liposomal nanoparticles decorated with glycan ligands of CD22 that selectively target B cells. Because CD22 is an endocytic receptor, ligand-decorated liposomes are bound by CD22 and rapidly internalized by the cell. When loaded with a toxic cargo such as doxorubicin, they are efficacious in prolonging life in a Daudi B cell lymphoma model. These B cell targeted nanoparticles have been demonstrated to bind and kill malignant B cells from patients with hairy cell leukemia, marginal zone lymphoma and chronic lymphocytic leukemia. The results demonstrate the potential of using CD22 ligand-targeted liposomal nanoparticles as an alternative approach for the treatment of B cell malignancies. © 2012 Informa UK, Ltd.


Bloss C.S.,Scripps Research Institute | Darst B.F.,Scripps Research Institute | Topol E.J.,Scripps Research Institute | Topol E.J.,Scripps Clinic Medical Group | Schork N.J.,Scripps Research Institute
Human Molecular Genetics | Year: 2011

Over the past 18 months, there have been notable developments in the direct-to-consumer (DTC) genomic testing arena, in particular with regard to issues surrounding governmental regulation in the USA. While commentaries continue to proliferate on this topic, actual empirical research remains relatively scant. In terms of DTC genomic testing for disease susceptibility, most of the research has centered on uptake, perceptions and attitudes toward testing among health care professionals and consumers. Only a few available studies have examined actual behavioral response among consumers, and we are not aware of any studies that have examined response to DTC genetic testing for ancestry or for drug response. We propose that further research in this area is desperately needed, despite challenges in designing appropriate studies given the rapid pace at which the field is evolving. Ultimately, DTC genomic testing for common markers and conditions is only a precursor to the eventual cost-effectiveness and wide availability of whole genome sequencing of individuals, although it remains unclear whether DTC genomic information will still be attainable. Either way, however, current knowledge needs to be extended and enhanced with respect to the delivery, impact and use of increasingly accurate and comprehensive individualized genomic data. © The Author 2011. Published by Oxford University Press. All rights reserved.


Sigal D.S.,Scripps Clinic Medical Group | Sharpe R.,Scripps Clinic Medical Group | Burian C.,Scripps Green Hospital | Saven A.,Scripps Clinic Medical Group
Blood | Year: 2010

Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin-stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses. © 2010 by The American Society of Hematology.


Bloss C.S.,Scripps Research Institute | Topol E.J.,Scripps Research Institute | Topol E.J.,Scripps Clinic Medical Group | Schork N.J.,Scripps Research Institute
Genetic Epidemiology | Year: 2012

The ongoing controversy surrounding direct-to-consumer (DTC) personal genomic tests intensified last year when the U.S. Government Accountability Office released results of an undercover investigation of four companies that offer such testing. Among their findings, they reported that some of their donors received DNA-based predictions that conflicted with their actual medical histories. We aimed to more rigorously evaluate the relationship between DTC genomic risk estimates and self-reported disease by leveraging data from the Scripps Genomic Health Initiative. We prospectively collected selfreported personal and family health history data for 3,416 individuals, who went on to purchase a commercially available DTC genomic test. For 5 out of 15 total conditions studied, we found that risk estimates from the test were significantly associated with self-reported family and/or personal health history. The five conditions included Graves' disease, Type 2 Diabetes, Lupus, Alzheimer's disease, and Restless Leg Syndrome. To further investigate these findings, we ranked each of the 15 conditions based on published heritability estimates and conducted post hoc power analyses, based on the number of individuals in our sample who reported significant histories of each condition. We found that high heritability, coupled with high prevalence in our sample and thus adequate statistical power, explained the pattern of associations observed. Our study represents one of the first evaluations of the relationship between risk estimates from a commercially available DTC personal genomic test and self-reported health histories in the consumers of that test. © 2011 Wiley Periodicals, Inc.


Woessner K.M.,Scripps Clinic Medical Group
Current Opinion in Allergy and Clinical Immunology | Year: 2015

Purpose of review The use of aspirin in coronary artery disease and address the unmet need of aspirin therapy in patients with history of hypersensitivity reactions to aspirin (acetylsalicylic acid; ASA) or other nonsteroidal inflammatory drugs (NSAIDs). Recent findings Aspirin hypersensitivity is reported in 1.5% of patients with cardiovascular disease. However, many of those labeled as allergic to aspirin had experienced side-effects and could be safely treated with aspirin. Those with true hypersensitivity reactions were often not placed on appropriate antiplatelet therapy. A number of protocols of varying complexity exist in the literature for aspirin desensitization. The focus of this review is to identify the types of aspirin reactions that can occur and provide a rational approach to oral aspirin challenge and desensitization. Summary In summary, with rare exceptions, patients with a history of 'aspirin/NSAID allergy' who need ASA for cardiovascular issues will be able to safely take aspirin either after a graded challenge or desensitization providing a central role of the allergist in the management of these patients. © 2015 Wolters Kluwer Health, Inc.


Chen W.C.,Scripps Research Institute | Completo G.C.,Scripps Research Institute | Sigal D.S.,Scripps Clinic Medical Group | Crocker P.R.,University of Dundee | And 2 more authors.
Blood | Year: 2010

Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell-specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes α2-6-linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition-based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies. © 2010 by The American Society of Hematology.

Loading Scripps Clinic Medical Group collaborators
Loading Scripps Clinic Medical Group collaborators