Publications by authors named "Amanda Wong"

42 Publications

Impact of Treatment Parameters on Racial Survival Differences in Oropharyngeal Cancer: National Cancer Database Study.

Otolaryngol Head Neck Surg 2021 Aug 17:1945998211035056. Epub 2021 Aug 17.

Department of Otolaryngology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.

Objective: To investigate how differences in treatment parameters account for survival differences between races of patients with oropharyngeal squamous cell carcinoma (OPSCC).

Study Design: Retrospective cohort study.

Setting: National Cancer Database.

Methods: Data of patients with OPSCC undergoing radiation therapy (RT) or concurrent chemoradiation therapy as primary treatment were obtained from the National Cancer Database from 2004 to 2016. We analyzed 4 treatment-related time intervals to determine their impact on survival between races when controlling for human papilloma virus (HPV) status. Cox proportional hazards models, stepwise logistic regressions, covariate adjustments, and propensity score matching were performed.

Results: A total of 3152 patients were identified (2877 White, 275 Black). In HPV- cases, Black patients with prolonged radiation duration had a significantly worse overall survival as compared with White patients (hazard ratio, 1.77; 95% CI, 1.03-3.05; = .039). In a logistic regression model, the only covariate that was significantly associated with prolonged RT was facility type. When further adjusted for facility type, the survival difference between Black and White patients with HPV- status and prolonged RT times was no longer significant (hazard ratio, 1.55; 95% CI, 0.90-2.69; = .116).

Conclusions: There is a significant disparity in overall survival between Black and White patients with HPV- OPSCC when RT duration is prolonged. Clinicians should be aware of the negative impact of prolonged RT, especially in Black patients, so that they can attempt to decrease treatment-related time intervals. Facility type was also found to affect the outcomes of patients with OPSCC, and efforts should be made to improve patient access to well-equipped, high-volume facilities.
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http://dx.doi.org/10.1177/01945998211035056DOI Listing
August 2021

Macrophage inflammatory state influences susceptibility to lysosomal damage.

J Leukoc Biol 2021 Jul 14. Epub 2021 Jul 14.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomes against damage. This property, termed inducible renitence, was previously observed in murine macrophages stimulated with LPS, peptidoglycan, IFNγ, or TNFα, which suggested roles for renitence in macrophage resistance to infection by membrane-damaging pathogens. This study analyzed additional inducers of macrophage differentiation for their ability to increase resistance to lysosomal damage by membrane-damaging particles. Renitence was evident in macrophages activated with LPS plus IFNγ, PGE , or adenosine, and in macrophages stimulated with IFN-β, but not in macrophages activated with IL-4 or IL-10. These responses indicated roles for macrophage subtypes specialized in host defense and suppression of immune responses, but not those involved in wound healing. Consistent with this pattern, renitence could be induced by stimulation with agonists for TLR, which required the signaling adaptors MyD88 and/or TRIF, and by infection with murine norovirus-1. Renitence induced by LPS was dependent on cytokine secretion by macrophages. However, no single secreted factor could explain all the induced responses. Renitence induced by the TLR3 agonist Poly(I:C) was mediated in part by the type I IFN response, but renitence induced by Pam3CSK4 (TLR2/1), LPS (TLR4), IFNγ, or TNFα was independent of type 1 IFN signaling. Thus, multiple pathways for inducing macrophage resistance to membrane damage exist and depend on the particular microbial stimulus sensed.
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http://dx.doi.org/10.1002/JLB.3A0520-325RRDOI Listing
July 2021

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

Clin Cancer Res 2021 Aug 3;27(16):4610-4623. Epub 2021 Jun 3.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.

Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).

Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the gene, with an average 50% increase in copy number, changes in mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.

Conclusions: Our data show that the dominant genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1625DOI Listing
August 2021

The jaw-dropping costs of oral cavity cancer malpractice.

Head Neck 2021 Oct 29;43(10):2869-2875. Epub 2021 May 29.

New York Head and Neck Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, New York, New York, USA.

Background: Medical litigation is different than it was 20 years ago due to changes in health care. This study provides an updated analysis of oral cavity malpractice litigation from the past two decades (2000-2010 and 2011-2019).

Methods: Verdict reviews from the Westlaw database were analyzed from January 2000 to August 2019. Data were collected and analyzed with the Statistical Package for the Social Sciences.

Results: Sixty-five lawsuits were evaluated across 24 states. Failure to diagnose was the most common allegation in both decades. Adjusting for inflation, the average amount awarded from 2000 to 2010 was $1 721 068 and $3 925 504 from 2011 to 2019.

Conclusions: There has been a significant rise in allegations of failure to biopsy and failure to refer (p < 0.05). In addition, while award amounts appear different between decades, the difference is not statistically significant (p = 0.248). Education should focus on early diagnosis, biopsy, and referral to physicians who routinely care for this patient population.
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http://dx.doi.org/10.1002/hed.26764DOI Listing
October 2021

, , and Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression.

Clin Cancer Res 2021 Mar 7;27(6):1650-1662. Epub 2021 Jan 7.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.

Experimental Design: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.

Results: , and were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous deletions. Tumor suppressors , and were controlled via disruptive chromosomal rearrangements in defective samples, but via oncogene amplification in context of defects. mutations were rare in cases with defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of and , but not , was associated with poor clinical outcomes.

Conclusions: , and defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3708DOI Listing
March 2021

Novel techniques for intraoperative parathyroid gland identification: a comprehensive review.

Expert Rev Endocrinol Metab 2020 11 19;15(6):439-457. Epub 2020 Oct 19.

St. Paul's Hospital Department of Surgery, The University of British Columbia Department of Surgery , Vancouver, British Columbia, Canada.

Introduction: The parathyroid glands (PGs) are critical for calcium regulation and homeostasis. The preservation of PGs during neck surgery is crucial to avoid postoperative hypoparathyroidism. There are no existing guidelines for intraoperative PG identification, and the current approach relies heavily on the experience of the operating surgeon. A technique that accurately and rapidly identifies PGs would represent a useful intraoperative adjunct.

Areas Covered: This review aims to assess common dye and fluorescence-based PG imaging techniques and examine their utility for intraoperative PG identification. A literature search of published data on methylene blue (MB), indocyanine green (ICG) angiography, near-infrared autofluorescence (NIRAF), and the PGs between 1971 and 2020 was conducted on PubMed.

Expert Opinion: NIRAF and near-infrared (NIR) parathyroid angiography have emerged as promising and reliable techniques for intraoperative PG identification. NIRAF may aid with real-time identification of both normal and diseased PGs and reduce the risk of postoperative complications such as hypocalcemia. Further large prospective multicenter studies should be conducted in thyroid and parathyroid surgical patient populations to confirm the clinical efficacy of these intraoperative NIR-based PG detection techniques.
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http://dx.doi.org/10.1080/17446651.2020.1831913DOI Listing
November 2020

The paralyzing legal costs of facial nerve injury in head and neck tumors.

Am J Otolaryngol 2020 Nov - Dec;41(6):102693. Epub 2020 Aug 19.

New York Head and Neck Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, New York, NY, United States of America. Electronic address:

Purpose: Facial nerve paralysis from head and neck tumors can result from disease progression or iatrogenic causes, leading to litigation. The aim of this study was to investigate lawsuits regarding facial paralysis as a consequence of these tumors to understand and better educate physicians behind the reasons for litigation.

Methods: Jury verdict reviews were obtained from the Westlaw database from 1985 to 2018. Gathered data, including verdicts, litigation reasons, defendant specialties, and amounts awarded, were analyzed via Statistical Package for the Social Sciences.

Results: Of the 26 lawsuits analyzed, the leading reason for litigation was failure to diagnose (53.8%), followed by iatrogenic injury (34.6%). The average award was $2,704,470. Otolaryngologists were the most common defendants. Defendants that included an otolaryngologist had shorter delays of diagnosis compared to those that did not (p < 0.05).

Conclusion: Failure to diagnose parotid injury was the leading cause of litigation. In instances where the jury found for the plaintiff, the amount was material. There were equivalent incidences of cases in favor of plaintiffs and defendants.
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http://dx.doi.org/10.1016/j.amjoto.2020.102693DOI Listing
January 2021

Response to Alfonso Santamaría-Gadea and Colleagues.

Otolaryngol Head Neck Surg 2021 02 11;164(2):456-457. Epub 2020 Aug 11.

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http://dx.doi.org/10.1177/0194599820951135DOI Listing
February 2021

The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis.

Otolaryngol Head Neck Surg 2020 07 5;163(1):3-11. Epub 2020 May 5.

Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.

Objective: To determine the pooled global prevalence of olfactory and gustatory dysfunction in patients with the 2019 novel coronavirus (COVID-19).

Data Sources: Literature searches of PubMed, Embase, and Scopus were conducted on April 19, 2020, to include articles written in English that reported the prevalence of olfactory or gustatory dysfunction in COVID-19 patients.

Review Methods: Search strategies developed for each database contained keywords such as , and . Resulting articles were imported into a systematic review software and underwent screening. Data from articles that met inclusion criteria were extracted and analyzed. Meta-analysis using pooled prevalence estimates in a random-effects model were calculated.

Results: Ten studies were analyzed for olfactory dysfunction (n = 1627), demonstrating 52.73% (95% CI, 29.64%-75.23%) prevalence among patients with COVID-19. Nine studies were analyzed for gustatory dysfunction (n = 1390), demonstrating 43.93% (95% CI, 20.46%-68.95%) prevalence. Subgroup analyses were conducted for studies evaluating olfactory dysfunction using nonvalidated and validated instruments and demonstrated 36.64% (95% CI, 18.31%-57.24%) and 86.60% (95% CI, 72.95%-95.95%) prevalence, respectively.

Conclusions: Olfactory and gustatory dysfunction are common symptoms in patients with COVID-19 and may represent early symptoms in the clinical course of infection. Increased awareness of this fact may encourage earlier diagnosis and treatment, as well as heighten vigilance for viral transmission. To our knowledge, this is the first meta-analysis to report on the prevalence of these symptoms in COVID-19 patients.
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http://dx.doi.org/10.1177/0194599820926473DOI Listing
July 2020

Radiologically Defined Sarcopenia Affects Survival in Head and Neck Cancer: A Meta-Analysis.

Laryngoscope 2021 02 27;131(2):333-341. Epub 2020 Mar 27.

Department of Otolaryngology - Head and Neck Surgery, Zucker School of Medicine at Hofstra/Northwell, New York, USA.

Objective: To determine whether radiologically defined sarcopenia at the C3 or L3 level as measured by computed tomography or magnetic resonance imaging is prognostic of overall survival (OS) in head and neck cancers (HNCs).

Methods: Literature searches of PubMed, Embase, and Scopus were conducted on July 12, 2019, to include articles written in the English language with no constraints on publication date. To be included in the analysis, articles had to report the prognostic impact of skeletal muscle mass measured radiologically at the C3 or L3 vertebral level in HNC patients; hazard ratios (HRs) for OS; 95% confidence intervals (CIs); be from a clinical trial, cohort, or case-control study; and have English full-text availability. Articles were reviewed in consensus by two reviewers, with disagreements reviewed by a third reviewer. Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology Checklist guidelines were used for reporting. Study quality assessment was performed using Quality In Prognosis Studies tool. The random-effects DerSimonian and Laird method was used for meta-analysis.

Results: Ten articles, nine retrospective and one prospective, were included in this meta-analysis (n = 2,181 patients). Significant differences were found in OS for HNC patients with sarcopenia (HR = 1.98; 95% CI: 1.64-2.39; P < .00001). No heterogeneity was detected in either the overall or subgroup analyses.

Conclusions: Radiologically defined sarcopenia is a negative predictor of OS in patients with HNC. Early detection of sarcopenia in cancer patients may help guide nutritional and adjuvant support to improve treatment outcomes.

Level Of Evidence: NA Laryngoscope, 131:333-341, 2021.
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http://dx.doi.org/10.1002/lary.28616DOI Listing
February 2021

Deep Phenotyping by Mass Cytometry and Single-Cell RNA-Sequencing Reveals LYN-Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan.

Circ Res 2020 05 10;126(10):e61-e79. Epub 2020 Mar 10.

From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada.

Rationale: Monocytes are key effectors of the mononuclear phagocyte system, playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into 2 major subsets termed conventional monocytes and patrolling monocytes (pMo) but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology; however, LYN's role in regulating specific monocyte subset homeostasis has not been investigated.

Objective: We sought to comprehensively profile monocytes to elucidate the underlying heterogeneity within monocytes and dissect how deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis.

Methods And Results: Mass cytometric analysis of monocyte subsets and signaling pathway activation patterns in conventional monocytes and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN's role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of -deficient pMos. Furthermore, single-cell RNA sequencing revealed marked perturbations in the gene expression profiles of monocytes with upregulation of genes involved in pMo development, survival, and function. deficiency also led to a significant increase in aorta-associated pMos and protected mice from high-fat diet-induced atherosclerosis.

Conclusions: Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315708DOI Listing
May 2020

CD151 in Respiratory Diseases.

Front Cell Dev Biol 2020 7;8:64. Epub 2020 Feb 7.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

The tetraspanin, Cluster of Differentiation 151 (CD151), is ubiquitously expressed in adult tissue, especially in the lungs where it has been implicated in lung cancer, asthma, influenza, and idiopathic pulmonary fibrosis (IPF). CD151 interacts with laminin-binding integrins and growth factor receptors, and is reported in cancer-promoting processes such as tumor initiation, metastasis, and angiogenesis. In asthma, CD151 was shown to promote airways hyperresponsiveness through calcium signaling whereas in influenza, CD151 was shown to be a novel host factor for nuclear viral export signaling. Furthermore, CD151 was shown to be associated with increased disease severity and poorer survival outcome in asthma and lung cancer, respectively. In this review, we provide an update on the current understanding of CD151 with regards to its contribution to lung pathophysiology. We also summarize factors that have been shown to regulate CD151 expression and identify key areas that need to be taken into consideration for its utility as a screening or prognostic tool in disease management and/or as a therapeutic target for the treatment of lung diseases.
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http://dx.doi.org/10.3389/fcell.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020194PMC
February 2020

Acquisition time, radiation dose, subjective and objective image quality of dual-source CT scanners in acute pulmonary embolism: a comparative study.

Eur Radiol 2020 May 5;30(5):2712-2721. Epub 2020 Feb 5.

Department of Radiology, University of British Columbia/ Vancouver General Hospital, 899 W 12th Ave, Vancouver, BC, V5Z 1M9, Canada.

Objectives: To compare the scan acquisition time, radiation dose, subjective and objective image quality of two dual-source CT scanners (DSCT) for detection of acute pulmonary embolism.

Methods: Two hundred twenty-one scans performed on the 2nd-generation DSCT and 354 scans on the 3rd-generation DSCT were included in this large retrospective study. In a randomized blinded design, two radiologists independently reviewed the scans using a 5-point Likert scale. Radiation dose and objective image quality parameters were calculated.

Results: Mean acquisition time was significantly lower in the 3rd-generation DSCT (2.81 s ± 0.1 in comparison with 9.7 s ± 0.15 [mean ± SD] respectively; p < 0.0001) with the 3rd generation 3.4 times faster. The mean subjective image quality score was 4.33/5 and 4/5 for the 3rd- and 2nd-generation DSCT respectively (p < 0.0001) with strong interobserver reliability agreement. DLP, CTDI, and ED were significantly lower in the 3rd than the 2nd generation (175.6 ± 63.7 mGy cm; 5.3 ± 1.9 mGy and 2.8 ± 1.2 mSv in comparison with 266 ± 255 mGy.cm; 7.8 ± 2.2 mGy and 3.8 ± 4.3 mSv). Noise was significantly lower in the 3rd generation (p < 0.01). Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and figure of merit (FOM), a dose-insensitive index for CNR, were significantly higher in the 3rd-generation DSCT (33.5 ± 23.4; 29.0 ± 21.3 and 543.7 ± 1037 in comparison with 23.4 ± 17.7; 19.4 ± 16.0 and 170.5 ± 284.3).

Conclusion: Objective and subjective image quality are significantly higher on the 3rd-generation DSCT with significantly lower mean acquisition time and radiation dose.

Key Points: • The 3rd-generation DSCT scanner provides an improved image quality, less perceived artifacts, and lower radiation dose in comparison with the 2nd-generation DSCT, when operating in dual-energy (DE) mode. • The 3.4-times-faster 3rd-generation DSCT scanner can be of particular value in patients with chronic lung diseases or breathing difficulties that prevent adequate breathhold.
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http://dx.doi.org/10.1007/s00330-019-06650-6DOI Listing
May 2020

Quick and facile preparation of histone proteins from the green microalga Chlamydomonas reinhardtii and other photosynthetic organisms.

Methods 2020 12 31;184:102-111. Epub 2020 Jan 31.

Department of Biology, Saint Mary's College of California, Moraga, CA 94575, United States. Electronic address:

The development of universal, broadly applicable methods for histone extraction from animal cells and tissues has unlocked the ability to compare these epigenetic-influencing proteins across tissue types, healthy and diseased states, and cancerous versus normal cells. However, for plants and green algae, a quick and easily implemented histone extraction method has yet to be developed. Here, we report an optimized method that provides a unified approach to extract histones for the green microalgal species Chlamydomonas reinhardtii and Scenedesmus dimorphus as well as for maize (corn) leaf tissue. Histone extraction methods include treatment with high salt concentrations and acidification. Preparations of nuclei can be made in ∼3.5 h and histones extracted in ∼3.5 h either immediately or nuclei may be frozen and histone proteins can be later extracted without a change in histone PTM patterns. To examine the efficiency of the new methods provided, we performed both qualitative and quantitative analysis of salt and acid-extracted whole histone proteins (SAEWH) via SDS-PAGE gel electrophoresis and intact protein mass spectrometry. SDS-PAGE analysis indicated that histone yields decrease when using walled Chlamydomonas strains relative to cell-wall-less mutants. Using top-down mass spectrometry (TDMS) for intact protein analysis, we confirmed the presence of H4K79me1 in multiple algal species; however, this unique modification was not identified in corn leaf tissue and has not been reported elsewhere. TDMS measurements of SAEWH extracts also revealed that oxidation which occurs during the histone extraction process does not increase with exposure of harvested algal cells, their nuclei and the extracted histone samples to light.
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http://dx.doi.org/10.1016/j.ymeth.2020.01.019DOI Listing
December 2020

Chondrosarcoma Metastasis to the Choroid.

Ocul Oncol Pathol 2019 Jun 17;5(4):234-237. Epub 2019 Jan 17.

Department of Ophthalmology and Visual Science, Yale New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA.

We report a rare case of chondrosarcoma metastatic to the choroid. A 64-year-old male with a history of chondrosarcoma metastatic to the lungs and to the spine presented with blurred vision. A choroidal tumor was found. Fine-needle biopsy confirmed the histologic identity of the tumor as chondrosarcoma. Metastatic spread of chondrosarcoma to the eye is extremely rare. When present, lesions may grow rapidly, and systemic prognosis is poor. Co-management with medical oncology is of utmost importance. This is the third case of chondrosarcoma metastatic to the choroid in the literature and the first with bilateral involvement.
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http://dx.doi.org/10.1159/000494979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615329PMC
June 2019

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells.

Sci Rep 2019 07 9;9(1):9892. Epub 2019 Jul 9.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Airway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin α7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin α7 expression would revert ASM cells back to a proliferative phenotype to cause an increase in ASM cell mass. This would be detrimental to asthmatic patients who already exhibit increased ASM mass in their airways. Using immunohistochemical analysis of the Melbourne Epidemiological Study of Childhood Asthma (MESCA) cohort, we show for the first time that integrin α7 expression in patients with severe asthma is increased, supporting a clinically relevant role for this protein in asthma pathophysiology. Moreover, inhibition of the laminin-integrin α7 signaling axis results in a reduction in smooth muscle-alpha actin abundance and does not revert ASM cells back to a proliferative phenotype. We determined that integrin α7-induced Kras isoform of p21 Ras acts as a point of convergence between contractile and proliferative ASM phenotypic states. Our study provides further support for targeting integrin α7 for the development of novel anti-asthma therapies.
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http://dx.doi.org/10.1038/s41598-019-46260-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616330PMC
July 2019

Epithelial-Myoepithelial Carcinoma Presenting as a Pseudo Veno-Lymphatic Malformation.

Ophthalmic Plast Reconstr Surg 2018 Sep/Oct;34(5):e157-e160

Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

A 41-year-old woman presented with several days of right eye pain and blurred vision. Examination and radiologic workup were consistent with a veno-lymphatic malformation, including demonstration of cystic fluid-fluid levels on imaging. Histopathology supported the presence of cystic spaces but revealed the final diagnosis of lacrimal epithelial-myoepithelial carcinoma, a rare neoplasm typically associated with the salivary gland. This represents the first reported case of lacrimal epithelial-myoepithelial carcinoma presenting with pain and evidence of intralesional cysts on radiographic and histopathologic evaluation. Better characterization will enable recognition, complete surgical excision, and potential adjuvant radiation therapy.
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http://dx.doi.org/10.1097/IOP.0000000000001179DOI Listing
September 2018

Renitence vacuoles facilitate protection against phagolysosomal damage in activated macrophages.

Mol Biol Cell 2018 03 27;29(5):657-668. Epub 2017 Dec 27.

Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109

As professional phagocytes, macrophages are susceptible to endolysosomal membrane damage inflicted by the pathogens and noxious particles they ingest. Whether macrophages have mechanisms for limiting such damage is not well understood. Previously, we reported a phenomenon, termed "inducible renitence," in which lipopolysaccharide (LPS) activation of macrophages protected their endolysosomes against damage initiated by the phagocytosis of silica beads. To gain mechanistic insight into the process, we analyzed the kinetics of renitence and morphological features of LPS-activated versus resting macrophages following silica bead-mediated injury. We discovered novel vacuolar structures that form in LPS-activated but not resting macrophages following silica bead phagocytosis. Because of their correlation with renitence and damage-resistant nature, we termed these structures "renitence vacuoles" (RVs). RVs formed coincident with silica bead uptake in a process associated with membrane ruffling and macropinocytosis. However, unlike normal macropinosomes (MPs), which shrink within 20 min of formation, RVs persisted around bead-containing phagosomes. RVs fused with lysosomes, whereas associated phagosomes typically did not. These findings are consistent with a model in which RVs, as persistent MPs, prevent fusion between damaged phagosomes and intact lysosomes and thereby preserve endolysosomal integrity.
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http://dx.doi.org/10.1091/mbc.E17-07-0486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004576PMC
March 2018

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer.

Clin Cancer Res 2017 Nov 31;23(21):6487-6497. Epub 2017 Jul 31.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer. We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease. The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to , or , and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of (20% of patients) and activating hotspot mutations in A (20%), with the latter mutually exclusive to truncating mutations in A novel gene fusion was identified in consecutive samples from one patient. Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1140DOI Listing
November 2017

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer.

Clin Cancer Res 2017 Nov 31;23(21):6487-6497. Epub 2017 Jul 31.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer. We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease. The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to , or , and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of (20% of patients) and activating hotspot mutations in A (20%), with the latter mutually exclusive to truncating mutations in A novel gene fusion was identified in consecutive samples from one patient. Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1140DOI Listing
November 2017

Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.

Eur Urol 2017 07 1;72(1):34-42. Epub 2017 Mar 1.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada. Electronic address:

Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy.

Objective: To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA).

Design, Setting, And Participants: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis.

Results And Limitations: Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but, after starting ADT, progressed to mCRPC with a median time of 11.8 mo (95% confidence interval [CI] 5.1-18.4). The median time to prostate-specific antigen progression on first-line AR-targeted therapy in the mCRPC setting was 3.3 mo (95% CI 2.7-3.9). Ten out of 11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. A limitation of this study is absence of a formal control cohort for comparison of clinical outcomes.

Conclusions: Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

Patient Summary: Patients with metastatic prostate cancer and germline DNA repair defects exhibit a poor response to standard hormonal therapies, but may be prioritized for potentially more effective therapies using a blood test.
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http://dx.doi.org/10.1016/j.eururo.2017.02.023DOI Listing
July 2017

Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.

Eur Urol 2017 07 1;72(1):34-42. Epub 2017 Mar 1.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada. Electronic address:

Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy.

Objective: To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA).

Design, Setting, And Participants: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis.

Results And Limitations: Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but, after starting ADT, progressed to mCRPC with a median time of 11.8 mo (95% confidence interval [CI] 5.1-18.4). The median time to prostate-specific antigen progression on first-line AR-targeted therapy in the mCRPC setting was 3.3 mo (95% CI 2.7-3.9). Ten out of 11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. A limitation of this study is absence of a formal control cohort for comparison of clinical outcomes.

Conclusions: Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

Patient Summary: Patients with metastatic prostate cancer and germline DNA repair defects exhibit a poor response to standard hormonal therapies, but may be prioritized for potentially more effective therapies using a blood test.
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http://dx.doi.org/10.1016/j.eururo.2017.02.023DOI Listing
July 2017

The Role of the Immune Response in the Pathogenesis of Thyroid Eye Disease: A Reassessment.

PLoS One 2015 15;10(9):e0137654. Epub 2015 Sep 15.

Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Devers Eye Institute, Legacy Health Systems, Portland, Oregon, United States of America.

Background: Although thyroid eye disease is a common complication of Graves' disease, the pathogenesis of the orbital disease is poorly understood. Most authorities implicate the immune response as an important causal factor. We sought to clarify pathogenesis by using gene expression microarray.

Methods: An international consortium of ocular pathologists and orbital surgeons contributed formalin fixed orbital biopsies. RNA was extracted from orbital tissue from 20 healthy controls, 25 patients with thyroid eye disease (TED), 25 patients with nonspecific orbital inflammation (NSOI), 7 patients with sarcoidosis and 6 patients with granulomatosis with polyangiitis (GPA). Tissue was divided into a discovery set and a validation set. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays which include 54,000 probe sets.

Results: Principal component analysis showed that gene expression from tissue from patients with TED more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, NSOI, or granulomatosis with polyangiitis. Unsupervised cluster dendrograms further indicated the similarity between TED and healthy controls. Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or GPA much more frequently than with TED.

Conclusion: This is the first study to compare gene expression in TED to gene expression associated with other causes of exophthalmos. The juxtaposition shows that inflammatory markers are far less characteristic of TED relative to other orbital inflammatory diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570801PMC
May 2016

IgG4 immunostaining and its implications in orbital inflammatory disease.

PLoS One 2014 10;9(10):e109847. Epub 2014 Oct 10.

Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Devers Eye Institute, Legacy Health Systems, Portland, Oregon, United States of America.

Objective: IgG4-related disease is an emerging clinical entity which frequently involves tissue within the orbit. In order to appreciate the implications of IgG4 immunostaining, we analyzed gene expression and the prevalence of IgG4- immunostaining among subjects with orbital inflammatory diseases.

Methods: We organized an international consortium to collect orbital biopsies from 108 subjects including 22 with no known orbital disease, 42 with nonspecific orbital inflammatory disease (NSOI), 26 with thyroid eye disease (TED), 12 with sarcoidosis, and 6 with granulomatosis with polyangiitis (GPA). Lacrimal gland and orbital adipose tissue biopsies were immunostained for IgG4 or IgG secreting plasma cells. RNA transcripts were quantified by Affymetrix arrays.

Results: None of the healthy controls or subjects with TED had substantial IgG4 staining. Among the 63 others, the prevalence of significant IgG4-immunostaining ranged from 11 to 39% depending on the definition for significant. IgG4 staining was detectable in the majority of tissues from subjects with GPA and less commonly in tissue from subjects with sarcoidosis or NSOI. The detection of IgG4+ cells correlated with inflammation in the lacrimal gland based on histology. IgG4 staining tissue expressed an increase in transcripts associated with inflammation, especially B cell-related genes. Functional annotation analysis confirmed this.

Conclusion: IgG4+ plasma cells are common in orbital tissue from patients with sarcoidosis, GPA, or NSOI. Even using the low threshold of 10 IgG4+ cells/high powered field, IgG4 staining correlates with increased inflammation in the lacrimal gland based on histology and gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109847PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193851PMC
June 2015

Evaluation of pre-analytical variables in a commercial thrombin generation assay.

Thromb Res 2014 Jul 22;134(1):160-4. Epub 2014 Apr 22.

Haematology Division, IMVS, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.

Background: There is minimal data on the influence of pre-analytical variables on the use of calibrated automated thrombography (CAT), to measure thrombin generation.

Objectives: To evaluate the impact of centrifugation methods, time after collection, and contact activation inhibition on the CAT assay performed using two commercial reagents.

Methods And Results: Six different methods of plasma separation were examined. Thrombin generation triggered by a 5 pM tissue factor reagent was not greatly affected by plasma separation method, with similar results obtained with all methods apart from single centrifugation and membrane filtration. Membrane filtration increased APTT and is not recommended. Extended double centrifugation at higher speed was required to minimise the impact of residual phospholipid with 1 pM tissue factor trigger, particularly with inhibition of contact activation. The effect of a delay of up to 24 hours in preparing plasma was assessed. No significant difference in results was observed among samples processed between 0.5 and 6 hours after blood collection into plastic Vacuette® tubes. The presence or absence of corn trypsin inhibitor had a significant impact on all parameters with 1 pM tissue factor trigger, with minor differences seen on Peak and ttPeak results using 5 pM tissue factor.

Conclusions: The impact of pre-analytical variables on thrombin generation results is dependent on the concentration of tissue factor in the trigger reagent used. Results with 1 pM tissue factor are particularly sensitive to centrifugation method and contact activation, and standardisation is required to allow large collaborative studies to be performed.
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http://dx.doi.org/10.1016/j.thromres.2014.04.010DOI Listing
July 2014

Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections.

Ophthalmology 2012 Aug 4;119(8):1609-14. Epub 2012 Apr 4.

Department of Ophthalmology and Vision Sciences, University Health Network/Toronto Western Hospital, Toronto, Canada.

Purpose: To report the incidence of endophthalmitis in association with different antibiotic prophylaxis strategies after intravitreal injections of anti-vascular endothelial growth factors and triamcinolone acetonide.

Design: Retrospective, comparative case series.

Participants: Fifteen thousand eight hundred ninety-five intravitreal injections (9453 ranibizumab, 5386 bevacizumab, 935 triamcinolone acetonide, 121 pegaptanib sodium) were reviewed for 2465 patients between January 5, 2005, and August 31, 2010. The number of injections was determined from billing code and patient records.

Methods: The indications for injection included age-related macular degeneration, diabetic macular edema, central and branch retinal vein occlusion, and miscellaneous causes. Three strategies of topical antibiotic prophylaxis were used by the respective surgeons: (1) antibiotics given for 5 days after each injection, (2) antibiotics given immediately after each injection, and (3) no antibiotics given.

Main Outcome Measures: The primary outcome measures were the incidence of culture-positive endophthalmitis and culture-negative cases of suspected endophthalmitis.

Results: Nine eyes of 9 patients with suspected endophthalmitis after injection were identified. Three of the 9 cases had culture-positive results. The overall incidence of endophthalmitis was 9 in 15 895. The incidence of culture-negative cases of suspected endophthalmitis and culture-proven endophthalmitis after injection was 6 in 15 895 and 3 in 15 895, respectively. Taking into account both culture-positive endophthalmitis and culture-negative cases of suspected endophthalmitis, the incidence per injection was 5 in 8259 for patients who were given antibiotics for 5 days after injection, 2 in 2370 for those who received antibiotics immediately after each injection, and 2 in 5266 who received no antibiotics. However, if considering culture-proven endophthalmitis alone, the use of topical antibiotics, given immediately or for 5 days after injection, showed lower rates of endophthalmitis compared with those without postinjection antibiotics. The risk of endophthalmitis after intravitreal injection varied among agents that were used. Among the 9 cases of clinically suspected endophthalmitis, regardless of prophylactic strategies used, the incidence of endophthalmitis per injection was 2 in 935 for triamcinolone acetonide, 3 in 9453 for ranibizumab, and 4 in 5386 for bevacizumab.

Conclusions: The overall rate of intravitreal injection-related endophthalmitis is greater with the use of topical antibiotics, given immediately or for 5 days after the injection, compared with no antibiotics.
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http://dx.doi.org/10.1016/j.ophtha.2012.02.014DOI Listing
August 2012

Adverse events in medication treatment-naïve children with attention-deficit/hyperactivity disorder: results from a small, controlled trial of lisdexamfetamine dimesylate.

J Child Adolesc Psychopharmacol 2012 Apr 28;22(2):149-56. Epub 2012 Feb 28.

Child Development Center, Department of Pediatrics, University of California, Irvine, Irvine, California 92612, USA.

Objective: To evaluate the type, frequency, duration, and severity of treatment emergent adverse events (TEAEs) of the prodrug lisdexamfetamine dimesylate (LDX) in children with and without previous exposure to stimulant medication in the treatment of attention-deficit/hyperactivity disorder (ADHD).

Methods: This single-blind, modified laboratory school study used open-label, dose optimization of children aged 6-12 years. LDX, initiated at 30 mg, was dose titrated in 20 mg increments to a possible 70 mg over 4-5 weeks. Safety was assessed using adverse effects and LDX levels.

Results: Twenty-eight subjects enrolled in the study, with 27 safety protocol completers (n=14 previous stimulant exposure; n=13 stimulant naïve). The stimulant-naïve group reported more trouble sleeping, stomach pain, and hyperfocus, but only previous-exposure subjects experienced dizziness. Previous-exposure subjects showed trends of more decreased appetite, less talkativeness, and less lip sucking. There were no differences in the mean duration of TEAEs. The epidemiological method of percent person-weeks applied to ADHD treatment offers a novel approach to interpreting the pattern of TEAEs.

Conclusion: LDX reduced the core symptoms of ADHD with more severe adverse events in stimulant-naïve than previous-exposure subjects. Future controlled studies with larger samples should address the impact of previous stimulant exposure on other ADHD treatments.
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http://dx.doi.org/10.1089/cap.2010.0095DOI Listing
April 2012
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