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Minamimoto R.,Stanford University | Fayad L.,University of Houston | Advani R.,00 Pasteur Dr | Vose J.,University of Nebraska Medical Center | And 6 more authors.
Radiology | Year: 2016

Purpose: To compare the performance characteristics of interim fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (after two cycles of chemotherapy) by using the most prominent standardized interpretive criteria (including International Harmonization Project [IHP] criteria, European Organization for Research and Treatment of Cancer [EORTC] criteria, and PET Response Criteria in Solid Tumors (PERCIST) versus those of interim 18F fluorothymidine (FLT) PET/CT and simple visual interpretation. Materials and Methods: This HIPAA-compliant prospective study was approved by the institutional review boards, and written informed consent was obtained. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) underwent both FLT and FDG PET/CT 18-24 days after two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. For FDG PET/CT interpretation, IHP criteria, EORTC criteria, PERCIST, Deauville criteria, standardized uptake value, total lesion glycolysis, and metabolic tumor volume were used. FLT PET/CT images were interpreted with visual assessment by two reviewers in consensus. The interim (after cycle 2) FDG and FLT PET/CT studies were then compared with the end-of-treatment FDG PET/CT studies to determine which interim examination and/or criteria best predicted the result after six cycles of chemotherapy. Results: From November 2011 to May 2014, there were 60 potential patients for inclusion, of whom 46 patients (24 men [mean age, 60.9 years 6 13.7; range, 28-78 years] and 22 women [mean age, 57.2 years 6 13.4; range, 25-76 years]) fulfilled the criteria. Thirty-four patients had complete response, and 12 had residual disease at the end of treatment. FLT PET/CT had a significantly higher positive predictive value (PPV) (91%) in predicting residual disease than did any FDG PET/CT interpretation method (42%-46%). No difference in negative predictive value (NPV) was found between FLT PET/CT (94%) and FDG PET/CT (82%-95%), regardless of the interpretive criteria used. FLT PET/CT showed statistically higher (P < .001-.008) or similar NPVs than did FDG PET/CT. Conclusion: Early interim FLT PET/CT had a significantly higher PPV than standardized FDG PET/CT-based interpretation for therapeutic response assessment in DLBCL. © RSNA, 2016. Source

Mell M.W.,00 Pasteur Dr | Baker L.C.,Stanford University | Baker L.C.,National Bureau of Economic Research | Dalman R.L.,00 Pasteur Dr | Hlatky M.A.,Stanford University
Journal of Vascular Surgery | Year: 2014

Objective Screening and surveillance are recommended in the management of small abdominal aortic aneurysms (AAAs). Gaps in surveillance after early diagnosis may lead to unrecognized AAA growth, rupture, and death. This study investigates the frequency and predictors of rupture of previously diagnosed AAAs. Methods Data were extracted from Medicare claims for patients who underwent AAA repair between 2006 and 2009. Relevant preoperative abdominal imaging exams were tabulated up to 5 years prior to AAA repair. Repair for ruptured AAAs was compared with repair for intact AAAs for those with an early diagnosis of an AAA, defined as having received imaging at least 6 months prior to surgery. Gaps in surveillance were defined as no image within 1 year of surgery or no imaging for more than a 2-year time span after the initial image. Logistic regression was used to examine independent predictors of rupture despite early diagnosis. Results A total of 9298 patients had repair after early diagnosis, with rupture occurring in 441 (4.7%). Those with ruptured AAAs were older (80.2 ± 6.9 vs 77.6 ± 6.2 years; P <.001), received fewer images prior to repair (5.7 ± 4.1 vs 6.5 ± 3.5; P =.001), were less likely to be treated in a high-volume hospital (45.4% vs 59.5%; P <.001), and were more likely to have had gaps in surveillance (47.4% vs 11.8%; P <.001) compared with those receiving repair for intact AAAs. After adjusting for medical comorbidities, gaps in surveillance remained the largest predictor of rupture in a multivariate analysis (odds ratio, 5.82; 95% confidence interval, 4.64-7.31; P <.001). Conclusions Despite previous diagnosis of AAA, many patients experience rupture prior to repair. Improved mechanisms for surveillance are needed to prevent rupture and ensure timely repair for patients with AAAs. © 2014 by the Society for Vascular Surgery. Source

Nishimura T.,00 Pasteur Dr | Hu Y.,00 Pasteur Dr | Wu M.,00 Pasteur Dr | Pham E.,Stanford University | And 15 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source

Keeney M.,00 Pasteur Dr | Jiang X.Y.,00 Pasteur Dr | Yamane M.,Stanford University | Lee M.,Stanford University | And 3 more authors.
Journal of Materials Chemistry B | Year: 2015

Since its introduction in the early 1990s, layer-by-layer (LbL) self-assembly of films has been widely used in the fields of nanoelectronics, optics, sensors, surface coatings, and controlled drug delivery. The growth of this industry is propelled by the ease of film manufacture, low cost, mild assembly conditions, precise control of coating thickness, and versatility of coating materials. Despite the wealth of research on LbL for biomolecule delivery, clinical translation has been limited and slow. This review provides an overview of methods and mechanisms of loading biomolecules within LbL films and achieving controlled release. In particular, this review highlights recent advances in the development of LbL coatings for the delivery of different types of biomolecules including proteins, polypeptides, DNA, particles and viruses. To address the need for co-delivery of multiple types of biomolecules at different timing, we also review recent advances in incorporating compartmentalization into LbL assembly. Existing obstacles to clinical translation of LbL technologies and enabling technologies for future directions are also discussed. © 2015 The Royal Society of Chemistry. Source

Wilson K.D.,00 Pasteur Dr | Wilson K.D.,Stanford Cardiovascular Institute | Shen P.,Stanford University | Fung E.,00 Pasteur Dr | And 14 more authors.
Circulation Research | Year: 2015

Rationale: Thousands of mutations across >50 genes have been implicated in inherited cardiomyopathies. However, options for sequencing this rapidly evolving gene set are limited because many sequencing services and off-the-shelf kits suffer from slow turnaround, inefficient capture of genomic DNA, and high cost. Furthermore, customization of these assays to cover emerging targets that suit individual needs is often expensive and time consuming. Objective: We sought to develop a custom high throughput, clinical-grade next-generation sequencing assay for detecting cardiac disease gene mutations with improved accuracy, flexibility, turnaround, and cost. Methods and Results: We used double-stranded probes (complementary long padlock probes), an inexpensive and customizable capture technology, to efficiently capture and amplify the entire coding region and flanking intronic and regulatory sequences of 88 genes and 40 microRNAs associated with inherited cardiomyopathies, congenital heart disease, and cardiac development. Multiplexing 11 samples per sequencing run resulted in a mean base pair coverage of 420, of which 97% had >20× coverage and >99% were concordant with known heterozygous single nucleotide polymorphisms. The assay correctly detected germline variants in 24 individuals and revealed several polymorphic regions in miR-499. Total run time was 3 days at an approximate cost of $100 per sample. Conclusions: Accurate, high-throughput detection of mutations across numerous cardiac genes is achievable with complementary long padlock probe technology. Moreover, this format allows facile insertion of additional probes as more cardiomyopathy and congenital heart disease genes are discovered, giving researchers a powerful new tool for DNA mutation detection and discovery. © 2015 American Heart Association, Inc. Source

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