Publications by authors named "Robin Elliott"

32 Publications

Computer extracted gland features from H&E predicts prostate cancer recurrence comparably to a genomic companion diagnostic test: a large multi-site study.

NPJ Precis Oncol 2021 May 3;5(1):35. Epub 2021 May 3.

Department of Urology, Case Western Reserve University, Cleveland, OH, USA.

Existing tools for post-radical prostatectomy (RP) prostate cancer biochemical recurrence (BCR) prognosis rely on human pathologist-derived parameters such as tumor grade, with the resulting inter-reviewer variability. Genomic companion diagnostic tests such as Decipher tend to be tissue destructive, expensive, and not routinely available in most centers. We present a tissue non-destructive method for automated BCR prognosis, termed "Histotyping", that employs computational image analysis of morphologic patterns of prostate tissue from a single, routinely acquired hematoxylin and eosin slide. Patients from two institutions (n = 214) were used to train Histotyping for identifying high-risk patients based on six features of glandular morphology extracted from RP specimens. Histotyping was validated for post-RP BCR prognosis on a separate set of n = 675 patients from five institutions and compared against Decipher on n = 167 patients. Histotyping was prognostic of BCR in the validation set (p < 0.001, univariable hazard ratio [HR] = 2.83, 95% confidence interval [CI]: 2.03-3.93, concordance index [c-index] = 0.68, median years-to-BCR: 1.7). Histotyping was also prognostic in clinically stratified subsets, such as patients with Gleason grade group 3 (HR = 4.09) and negative surgical margins (HR = 3.26). Histotyping was prognostic independent of grade group, margin status, pathological stage, and preoperative prostate-specific antigen (PSA) (multivariable p < 0.001, HR = 2.09, 95% CI: 1.40-3.10, n = 648). The combination of Histotyping, grade group, and preoperative PSA outperformed Decipher (c-index = 0.75 vs. 0.70, n = 167). These results suggest that a prognostic classifier for prostate cancer based on digital images could serve as an alternative or complement to molecular-based companion diagnostic tests.
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http://dx.doi.org/10.1038/s41698-021-00174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093226PMC
May 2021

Computationally Derived Cribriform Area Index from Prostate Cancer Hematoxylin and Eosin Images Is Associated with Biochemical Recurrence Following Radical Prostatectomy and Is Most Prognostic in Gleason Grade Group 2.

Eur Urol Focus 2021 Apr 30. Epub 2021 Apr 30.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA. Electronic address:

Background: The presence of invasive cribriform adenocarcinoma (ICC), an expanse of cells containing punched-out lumina uninterrupted by stroma, in radical prostatectomy (RP) specimens has been associated with biochemical recurrence (BCR). However, ICC identification has only moderate inter-reviewer agreement.

Objective: To investigate quantitative machine-based assessment of the extent and prognostic utility of ICC, especially within individual Gleason grade groups.

Design, Setting, And Participants: A machine learning approach was developed for ICC segmentation using 70 RP patients and validated in a cohort of 749 patients from four sites whose median year of surgery was 2007 and with median follow-up of 28 mo. ICC was segmented on one representative hematoxylin and eosin RP slide per patient and the fraction of tumor area composed of ICC, the cribriform area index (CAI), was measured.

Outcome Measurements And Statistical Analysis: The association between CAI and BCR was measured in terms of the concordance index (c index) and hazard ratio (HR).

Results And Limitations: CAI was correlated with BCR (c index 0.62) in the validation set of 411 patients with ICC morphology, especially those with Gleason grade group 2 cancer (n = 192; c index 0.66), and was less prognostic when patients without ICC were included (c index 0.54). A doubling of CAI in the group with ICC morphology was prognostic after controlling for Gleason grade, surgical margin positivity, preoperative prostate-specific antigen level, pathological T stage, and age (HR 1.19, 95% confidence interval 1.03-1.38; p = 0.018).

Conclusions: Automated image analysis and machine learning could provide an objective, quantitative, reproducible, and high-throughput method of quantifying ICC area. The performance of CAI for grade group 2 cancer suggests that for patients with little Gleason 4 pattern, the ICC fraction has a strong prognostic role.

Patient Summary: Machine-based measurement of a specific cell pattern (cribriform; sieve-like, with lots of spaces) in images of prostate specimens could improve risk stratification for patients with prostate cancer. In the future, this could help in expanding the criteria for active surveillance.
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http://dx.doi.org/10.1016/j.euf.2021.04.016DOI Listing
April 2021

Benign Metastasizing Leiomyoma in the Heart of a 45-Year-Old Woman.

Tex Heart Inst J 2021 01;48(1)

Harrington Heart & Vascular Institute, Cardiovascular Medicine Department, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.

We report a rare case of benign metastasizing leiomyoma in the heart of a 45-year-old woman 2 years after a uterine leiomyoma had been discovered during hysterectomy. Computed tomograms at presentation showed a large mixed cystic mass in the pelvis and bilateral lung nodules suggestive of metastatic disease. A large cardiac mass, attached to the chordae of the tricuspid valve and later shown to be histopathologically consistent with uterine leiomyoma, was successfully resected through a right atriotomy. This case suggests that benign metastasizing leiomyoma should be considered in the differential diagnosis of right-sided cardiac tumors.
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http://dx.doi.org/10.14503/THIJ-19-7066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108713PMC
January 2021

Molecular Profiling of Pediatric and Adult Glioblastoma.

Am J Clin Pathol 2021 03;155(4):606-614

Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH.

Objectives: Although glioblastoma (GBM) is rare in the pediatric population, it is the most common cause of death among children with central nervous system neoplasms. Recent molecular profiling of these neoplasms has demonstrated distinct differences in comparison to their adult counterparts. Moreover, many pediatric GBMs occur within the context of cancer predisposition syndromes, such as constitutional mismatch repair deficiency syndrome (CMMRD). Children with CMMRD who develop GBM exhibit a high tumor mutational burden and may benefit from treatment with immune checkpoint inhibitors.

Methods: We performed next-generation sequencing and immunohistochemistry for mismatch repair proteins in our cohort of pediatric and adult GBMs to further characterize the molecular profiles of these groups.

Results: We examined a total of 11 pediatric and 11 adult GBMs. Pediatric patients had a higher number of alterations compared to their adult counterparts. They also had a higher frequency of alterations in the mismatch repair genes, which can be detected by immunohistochemistry (IHC). We also identified one pediatric patient with CMMRD syndrome.

Conclusions: Our study highlighted the distinct molecular differences between pediatric and adult GBM. We also demonstrated that pediatric patients have a higher frequency of alterations in the mismatch repair genes, which may render them susceptible to treatment with immune checkpoint inhibitors. These alterations can be detected using routine IHC and should be performed on all pediatric GBM.
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http://dx.doi.org/10.1093/ajcp/aqaa172DOI Listing
March 2021

Hyaline fibromatosis syndrome: A rare case of multifocal intra-articular involvement.

Clin Imaging 2021 Feb 12;70:51-55. Epub 2020 Oct 12.

Department of Radiology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, United States of America. Electronic address:

Hyaline fibromatosis syndrome (HFS) is a rare, progressive, autosomal recessive disorder that presents with connective tissue deposition of amorphous hyaline material within the musculocutaneous tissue and/or visceral organs. HFS presents clinically in infancy or early childhood and can result in severe disability and life threatening complications. Given the rarity of the disorder, the imaging characteristics of HFS are seldom described in the literature. We describe a case of a 25-year-old patient presenting with bilateral knee pain, limited range of motion in her extremities, and lower extremity weakness with detailed MR imaging demonstrating the first case of multifocal intra-articular deposition of hyaline material within several joints.
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http://dx.doi.org/10.1016/j.clinimag.2020.10.015DOI Listing
February 2021

Multidisciplinary approach for repeat musculoskeletal lesion biopsy after nondiagnostic initial sampling: A 10-year single-center experience.

J Surg Oncol 2021 Jan 13;123(1):342-351. Epub 2020 Oct 13.

Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

Background And Objectives: Success rates for initial image-guided biopsy of musculoskeletal (MSK) lesions have been well documented; evidence regarding success rates for repeat biopsy following initially nondiagnostic (ND) image-guided biopsy of MSK lesions is more limited. This study evaluates the outcomes of repeat computerized tomography-guided MSK biopsies following ND biopsies using a multidisciplinary approach.

Materials And Methods: Electronic medical record search covering a 10-year period identified patients that received two or more biopsies for an MSK tumor or tumor-like process. The decision for initial and repeat image-guided biopsy of each lesion was made following multidisciplinary MSK tumor board review. Lesion location, histopathology results, size of biopsy needle when available, and change in technique between biopsy attempts was documented.

Results: Repeat biopsy rate was 1.6%. 23 patients with repeat MSK biopsy were identified. A total of 17 of 23 (74%) repeat biopsy attempts were diagnostic. A total of 22 of 23 (96%) repeat biopsy attempts were clinically useful. Diagnostic repeat biopsies were described as employing one or more of five technical differences compared to the first biopsy attempt, the most common being improved targeting of the lesion itself.

Conclusions: A multidisciplinary approach may yield improved repeat-biopsy rates and clinical utility of repeat MSK biopsies compared to prior reports.
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http://dx.doi.org/10.1002/jso.26255DOI Listing
January 2021

Computer Extracted Features from Initial H&E Tissue Biopsies Predict Disease Progression for Prostate Cancer Patients on Active Surveillance.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.

In this work, we assessed the ability of computerized features of nuclear morphology from diagnostic biopsy images to predict prostate cancer (CaP) progression in active surveillance (AS) patients. Improved risk characterization of AS patients could reduce over-testing of low-risk patients while directing high-risk patients to therapy. A total of 191 (125 progressors, 66 non-progressors) AS patients from a single site were identified using The Johns Hopkins University's (JHU) AS-eligibility criteria. Progression was determined by pathologists at JHU. 30 progressors and 30 non-progressors were randomly selected to create the training cohort D ( = 60). The remaining patients comprised the validation cohort D ( = 131). Digitized Hematoxylin & Eosin (H&E) biopsies were annotated by a pathologist for CaP regions. Nuclei within the cancer regions were segmented using a watershed method and 216 nuclear features describing position, shape, orientation, and clustering were extracted. Six features associated with disease progression were identified using D and then used to train a machine learning classifier. The classifier was validated on D. The classifier was further compared on a subset of D ( = 47) against pro-PSA, an isoform of prostate specific antigen (PSA) more linked with CaP, in predicting progression. Performance was evaluated with area under the curve (AUC). A combination of nuclear spatial arrangement, shape, and disorder features were associated with progression. The classifier using these features yielded an AUC of 0.75 in D. On the 47 patient subset with pro-PSA measurements, the classifier yielded an AUC of 0.79 compared to an AUC of 0.42 for pro-PSA. Nuclear morphometric features from digitized H&E biopsies predicted progression in AS patients. This may be useful for identifying AS-eligible patients who could benefit from immediate curative therapy. However, additional multi-site validation is needed.
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http://dx.doi.org/10.3390/cancers12092708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563653PMC
September 2020

T1 and T2 MR fingerprinting measurements of prostate cancer and prostatitis correlate with deep learning-derived estimates of epithelium, lumen, and stromal composition on corresponding whole mount histopathology.

Eur Radiol 2021 Mar 2;31(3):1336-1346. Epub 2020 Sep 2.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.

Objectives: To explore the associations between T1 and T2 magnetic resonance fingerprinting (MRF) measurements and corresponding tissue compartment ratios (TCRs) on whole mount histopathology of prostate cancer (PCa) and prostatitis.

Materials And Methods: A retrospective, IRB-approved, HIPAA-compliant cohort consisting of 14 PCa patients who underwent 3 T multiparametric MRI along with T1 and T2 MRF maps prior to radical prostatectomy was used. Correspondences between whole mount specimens and MRI and MRF were manually established. Prostatitis, PCa, and normal peripheral zone (PZ) regions of interest (ROIs) on pathology were segmented for TCRs of epithelium, lumen, and stroma using two U-net deep learning models. Corresponding ROIs were mapped to T2-weighted MRI (T2w), apparent diffusion coefficient (ADC), and T1 and T2 MRF maps. Their correlations with TCRs were computed using Pearson's correlation coefficient (R). Statistically significant differences in means were assessed using one-way ANOVA.

Results: Statistically significant differences (p < 0.01) in means of TCRs and T1 and T2 MRF were observed between PCa, prostatitis, and normal PZ. A negative correlation was observed between T1 and T2 MRF and epithelium (R = - 0.38, - 0.44, p < 0.05) of PCa. T1 MRF was correlated in opposite directions with stroma of PCa and prostatitis (R = 0.35, - 0.44, p < 0.05). T2 MRF was positively correlated with lumen of PCa and prostatitis (R = 0.57, 0.46, p < 0.01). Mean T2 MRF showed significant differences (p < 0.01) between PCa and prostatitis across both transition zone (TZ) and PZ, while mean T1 MRF was significant (p = 0.02) in TZ.

Conclusion: Significant associations between MRF (T1 in the TZ and T2 in the PZ) and tissue compartments on corresponding histopathology were observed.

Key Points: • Mean T2 MRF measurements and ADC within cancerous regions of interest dropped with increasing ISUP prognostic groups (IPG). • Mean T1 and T2 MRF measurements were significantly different (p < 0.001) across IPGs, prostatitis, and normal peripheral zone (NPZ). • T2 MRF showed stronger correlations in the peripheral zone, while T1 MRF showed stronger correlations in the transition zone with histopathology for prostate cancer.
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http://dx.doi.org/10.1007/s00330-020-07214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882016PMC
March 2021

Extraprostatic extension in prostate cancer: primer for radiologists.

Abdom Radiol (NY) 2020 12;45(12):4040-4051

Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

The presence of extraprostatic extension (EPE) on multiparametric MRI (mpMRI) is an important factor in determining the management of prostate cancer. EPE is an established risk factor for biochemical recurrence of prostate cancer after radical prostatectomy (RP) and patients with EPE may be considered for wider resection margins, non-nerve-sparing surgery, adjuvant radiation therapy (RT), or androgen deprivation therapy (ADT). Several statistical nomograms and scoring systems have been developed to predict pathological stage at time of RP but with varying accuracies. Using the current PI-RADS v2 mpMRI staging guidelines results in high specificity but lacks in sensitivity. These findings reveal the need for more standardization and further refinement of existing MRI protocols and prostate cancer prediction tools. Current studies have looked into indirect additional imaging criteria such as index tumor volume, length of capsular contact, and apparent diffusion coefficient. Measuring for these features can improve the robustness of mpMRI in staging prostate cancer, as they have been shown to be independent predictors of EPE. MRI/ultrasound fusion-guided targeted biopsy can detect EPE not found on standard biopsy. Collectively, these measurements and imaging techniques can augment the detection of EPE and subsequent risk stratification.
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http://dx.doi.org/10.1007/s00261-020-02555-xDOI Listing
December 2020

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo.

Oncogene 2020 06 10;39(23):4581-4591. Epub 2020 May 10.

Department of Orthopaedics, Case Western Reserve University, Cleveland, OH, USA.

Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. Jun activation domain-binding protein 1 (JAB1) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1-knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1-knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability, and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers.
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http://dx.doi.org/10.1038/s41388-020-1320-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274902PMC
June 2020

Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients.

Clin Cancer Res 2020 04 5;26(8):1915-1923. Epub 2020 Mar 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Purpose: Between 30%-40% of patients with prostate cancer experience disease recurrence following radical prostatectomy. Existing clinical models for recurrence risk prediction do not account for population-based variation in the tumor phenotype, despite recent evidence suggesting the presence of a unique, more aggressive prostate cancer phenotype in African American (AA) patients. We investigated the capacity of digitally measured, population-specific phenotypes of the intratumoral stroma to create improved models for prediction of recurrence following radical prostatectomy.

Experimental Design: This study included 334 radical prostatectomy patients subdivided into training (V, = 127), validation 1 (V, = 62), and validation 2 (V, = 145). Hematoxylin and eosin-stained slides from resected prostates were digitized, and 242 quantitative descriptors of the intratumoral stroma were calculated using a computational algorithm. Machine learning and elastic net Cox regression models were constructed using V to predict biochemical recurrence-free survival based on these features. Performance of these models was assessed using V and V, both overall and in population-specific cohorts.

Results: An AA-specific, automated stromal signature, AAstro, was prognostic of recurrence risk in both independent validation datasets [V: AUC = 0.87, HR = 4.71 (95% confidence interval (CI), 1.65-13.4), = 0.003; V: AUC = 0.77, HR = 5.7 (95% CI, 1.48-21.90), = 0.01]. AAstro outperformed clinical standard Kattan and CAPRA-S nomograms, and the underlying stromal descriptors were strongly associated with IHC measurements of specific tumor biomarker expression levels.

Conclusions: Our results suggest that considering population-specific information and stromal morphology has the potential to substantially improve accuracy of prognosis and risk stratification in AA patients with prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165025PMC
April 2020

Primary cardiac epithelioid angiosarcoma with frond-like features: a rare and ominous radiological mimicker of benign cardiac tumors.

Cardiovasc Pathol 2019 Jul - Aug;41:18-20. Epub 2019 Apr 8.

Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address:

Most primary cardiac tumors are benign neoplasms, which generally can be differentiated from malignant neoplasms via certain radiological features. We present briefly a case of a 26-year-old man undergoing resection of a right atrial mass that based on preceding radiologic findings represent a myxoma. After pathologic examination, the lesion was determined to be an epithelioid angiosarcoma with unique frond-like architecture and multiple pedicular attachments to the atrial wall.
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http://dx.doi.org/10.1016/j.carpath.2019.04.001DOI Listing
July 2019

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways.

Front Pharmacol 2019 14;10:51. Epub 2019 Feb 14.

Institut für Physiologie, Universität Regensburg, Regensburg, Germany.

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca-activated Cl channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.
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http://dx.doi.org/10.3389/fphar.2019.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382696PMC
February 2019

Teaching Genomic Pathology: Translating Team-Based Learning to a Virtual Environment Using Computer-Based Simulation.

Arch Pathol Lab Med 2019 04 30;143(4):513-517. Epub 2018 Nov 30.

From the Departments of Pathology (Dr Haspel) and Medicine (Dr Huang), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the American Society for Clinical Pathology, Chicago, Illinois (Dr Ali and Mr Smith); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Atkinson); the Department of Pathology, TriCore Reference Laboratories and the University of New Mexico, Albuquerque (Dr Chabot-Richards); the Department of Pathology, UH Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr Elliott); the Department of Pathology, NorthShore University HealthSystem and the University of Chicago Pritzker School of Medicine, Evanston, Illinois (Dr Kaul); the Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas (Dr Powell); Baylor Scott and White Central Region Pathology and Texas A&M Medical School, Temple (Dr Rao); the Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut (Dr Rinder); the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Vanderbilt); and the Department of Pathology and Laboratory Medicine, Larner College of Medicine and University of Vermont Medical Center, Burlington (Dr Wilcox). Dr Ali is now with AA Associates, Oak Park, Illinois. Mr Smith is now with Intracon Spain, Barcelona, Spain.

Context.—: Developing skills related to use of computer-based tools is critical for practicing genomic pathology. However, given the relative novelty of genomics education, residency programs may lack faculty members with adequate expertise and/or time to implement training. A virtual team-based learning (TBL) environment would make genomic pathology education available to more trainees.

Objective.—: To translate an extensively implemented in-person TBL genomic pathology workshop into a virtual environment and to evaluate both knowledge and skill acquisition.

Design.—: Using a novel interactive simulation approach, online modules were developed translating aspects of the TBL experience into the virtual environment with a goal of acquisition of necessary computer-related skills. The modules were evaluated at 10 postgraduate pathology training programs using a pre-post test design with participants deidentified. A postmodule anonymous survey obtained participant feedback on module quality and efficacy.

Results.—: There were 147 trainees who received an email request to voluntarily participate in the study. Of these, 43 trainees completed the pretest and 15 (35%) subsequently completed the posttest. Mean overall scores were 45% on the pretest compared with 70% on the posttest ( P < .001; effect size = 1.4). Posttest improvement of results was similar for questions testing acquisition of knowledge versus skills. Regarding the 19 participants who took the survey, 18 (95%) would recommend the modules to others and believed they met the stated objectives.

Conclusions.—: A simulation-based approach allows motivated pathology trainees to acquire computer-related skills for practicing genomic pathology. Future work can explore efficacy in a nonvoluntary setting and adaptation to different specialties, learners, and computer tools.
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http://dx.doi.org/10.5858/arpa.2018-0153-OADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467077PMC
April 2019

Stable and discriminating features are predictive of cancer presence and Gleason grade in radical prostatectomy specimens: a multi-site study.

Sci Rep 2018 10 8;8(1):14918. Epub 2018 Oct 8.

Case Western Reserve University, Dept. of Biomedical Engineering, Cleveland, OH, 44106, United States.

Site variation in fixation, staining, and scanning can confound automated tissue based image classifiers for disease characterization. In this study we incorporated stability into four feature selection methods for identifying the most robust and discriminating features for two prostate histopathology classification tasks. We evaluated 242 morphology features from N = 212 prostatectomy specimens from four sites for automated cancer detection and grading. We quantified instability as the rate of significant cross-site feature differences. We mapped feature stability and discriminability using 188 non-cancerous and 210 cancerous regions via 3-fold cross validation, then held one site out, creating independent training and testing sets. In training, one feature set was selected only for discriminability, another for discriminability and stability. We trained a classifier with each feature set, testing on the hold out site. Experiments were repeated with 117 Gleason grade 3 and 112 grade 4 regions. Stability was calculated across non-cancerous regions. Gland shape features yielded the best stability and area under the receiver operating curve (AUC) trade-off while co-occurrence texture features were generally unstable. Our stability-informed method produced a cancer detection AUC of 0.98 ± 0.05 and increased average Gleason grading AUC by 4.38%. Color normalization of the images tended to exacerbate feature instability.
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http://dx.doi.org/10.1038/s41598-018-33026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175913PMC
October 2018

Identifying the morphologic basis for radiomic features in distinguishing different Gleason grades of prostate cancer on MRI: Preliminary findings.

PLoS One 2018 31;13(8):e0200730. Epub 2018 Aug 31.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States of America.

Translation of radiomics into the clinic may require a more comprehensive understanding of the underlying morphologic tissue characteristics they reflect. In the context of prostate cancer (PCa), some studies have correlated gross histological measurements of gland lumen, epithelium, and nuclei with disease appearance on MRI. Quantitative histomorphometry (QH), like radiomics for radiologic images, is the computer based extraction of features for describing tumor morphology on digitized tissue images. In this work, we attempt to establish the histomorphometric basis for radiomic features for prostate cancer by (1) identifying the radiomic features from T2w MRI most discriminating of low vs. intermediate/high Gleason score, (2) identifying QH features correlated with the most discriminating radiomic features previously identified, and (3) evaluating the discriminative ability of QH features found to be correlated with spatially co-localized radiomic features. On a cohort of 36 patients (23 for training, 13 for validation), Gabor texture features were identified as being most predictive of Gleason grade on MRI (AUC of 0.69) and gland lumen shape features were identified as the most predictive QH features (AUC = 0.75). Our results suggest that the PCa grade discriminability of Gabor features is a consequence of variations in gland shape and morphology at the tissue level.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118356PMC
January 2019

Subtypes of Barrett's oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis.

Gut 2019 03 8;68(3):389-399. Epub 2018 Jun 8.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Objective: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE).

Design: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.

Results: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.

Conclusions: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.
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http://dx.doi.org/10.1136/gutjnl-2017-314544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565505PMC
March 2019

Evaluating stability of histomorphometric features across scanner and staining variations: prostate cancer diagnosis from whole slide images.

J Med Imaging (Bellingham) 2016 Oct 24;3(4):047502. Epub 2016 Oct 24.

Case Western Reserve University , Department of Biomedical Engineering, 2071 Martin Luther King Jr. Drive, Cleveland, Ohio 44106, United States.

Quantitative histomorphometry (QH) is the process of computerized feature extraction from digitized tissue slide images to predict disease presence, behavior, and outcome. Feature stability between sites may be compromised by laboratory-specific variables including dye batch, slice thickness, and the whole slide scanner used. We present two new measures, preparation-induced instability score and latent instability score, to quantify feature instability across and within datasets. In a use case involving prostate cancer, we examined QH features which may detect cancer on whole slide images. Using our method, we found that five feature families (graph, shape, co-occurring gland tensor, sub-graph, and texture) were different between datasets in 19.7% to 48.6% of comparisons while the values expected without site variation were 4.2% to 4.6%. Color normalizing all images to a template did not reduce instability. Scanning the same 34 slides on three scanners demonstrated that Haralick features were most substantively affected by scanner variation, being unstable in 62% of comparisons. We found that unstable feature families performed significantly worse in inter- than intrasite classification. Our results appear to suggest QH features should be evaluated across sites to assess robustness, and class discriminability alone should not represent the benchmark for digital pathology feature selection.
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http://dx.doi.org/10.1117/1.JMI.3.4.047502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076015PMC
October 2016

Early Clinical Predictors of Treatment-Resistant and Functional Outcomes in Parkinson's Disease.

Mov Disord Clin Pract 2016 Jan-Feb;3(1):53-58. Epub 2015 Dec 14.

Georgetown University Washington District of Columbia USA.

Background: The aim of this work was to identify early clinical predictors of important outcomes in Parkinson's disease (PD). In PD, treatment-resistant (e.g., dementia, falling) and other important functional outcomes (e.g., declines in quality of life [QOL] and activities of daily living [ADL]) emerge and become increasingly disabling.

Methods: We analyzed longitudinal data from 491 early, untreated PD subjects who enrolled in the PreCEPT trial, had baseline SPECT dopamine transporter deficit, and have continued in the PostCEPT observational cohort. After PreCEPT, antiparkinsonian medications were added if needed. Baseline clinical precursors were examined as potential predictors of selected outcomes. Separate and multivariate logistic regressions, adjusted for certain baseline factors, were performed for dichotomized outcomes evaluated at the last PostCEPT visit.

Results: On enrollment, subjects had average disease duration of 0.8 years and were followed for an average of 5.5 years. Some baseline precursors were found to be predictive: disease stage, cognitive, and ADL scores for dementia; disease stage, ADL, and motor and freezing scores for hallucinations; disease stage, depression, ADL, and freezing and walking scores for falling; and ADL, depression, and motor and walking scores and disease stage for QOL decline. No baseline clinical feature predicted decline in ADL. Being on levodopa was not a significant predictor of any outcome, but subjects on a dopamine agonist were significantly impaired with respect to falling, abnormal Mini-Mental State Examination, and QOL.

Conclusions: Although there are limitations, results support the value of longitudinal follow-up of clinical trial populations to identify early clinical precursors of important outcomes and thereby identify high-risk patients early on.
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http://dx.doi.org/10.1002/mdc3.12273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178710PMC
December 2015

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.

J Med Chem 2015 Sep 31;58(17):6784-802. Epub 2015 Aug 31.

Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.

To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00495DOI Listing
September 2015

Computer-extracted Features Can Distinguish Noncancerous Confounding Disease from Prostatic Adenocarcinoma at Multiparametric MR Imaging.

Radiology 2016 Jan 17;278(1):135-45. Epub 2015 Jul 17.

From the Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, the Netherlands (G.J.S.L., T.K., C.H.v.d.K., J.O.B., H.J.H.); Departments of Pathology (R.E.) and Biomedical Engineering (A.M.), Case Western University Hospitals, Cleveland, Ohio; and Department of Pathology, University of Pennsylvania, Philadelphia, Pa (N.N.C.S., M.D.F.).

Purpose: To determine the best features to discriminate prostate cancer from benign disease and its relationship to benign disease class and cancer grade.

Materials And Methods: The institutional review board approved this study and waived the need for informed consent. A retrospective cohort of 70 patients (age range, 48-70 years; median, 62 years), all of whom were scheduled to undergo radical prostatectomy and underwent preoperative 3-T multiparametric magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging, were included. The digitized prostatectomy slides were annotated for cancer and noncancerous disease and coregistered to MR imaging with an interactive deformable coregistration scheme. Computer-identified features for each of the noncancerous disease categories (eg, benign prostatic hyperplasia [BPH], prostatic intraepithelial neoplasia [PIN], inflammation, and atrophy) and prostate cancer were extracted. Feature selection was performed to identify the features with the highest discriminatory power. The performance of these five features was evaluated by using the area under the receiver operating characteristic curve (AUC).

Results: High-b-value diffusion-weighted images were more discriminative in distinguishing BPH from prostate cancer than apparent diffusion coefficient, which was most suitable for distinguishing PIN from prostate cancer. The focal appearance of lesions on dynamic contrast-enhanced images may help discriminate atrophy and inflammation from cancer. Which imaging features are discriminative for different benign lesions is influenced by cancer grade. The apparent diffusion coefficient appeared to be the most discriminative feature in identifying high-grade cancer. Classification results showed increased performance by taking into account specific benign types (AUC = 0.70) compared with grouping all noncancerous findings together (AUC = 0.62).

Conclusion: The best features with which to discriminate prostate cancer from noncancerous benign disease depend on the type of benign disease and cancer grade. Use of the best features may result in better diagnostic performance.
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http://dx.doi.org/10.1148/radiol.2015142856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699495PMC
January 2016

Quantitative identification of magnetic resonance imaging features of prostate cancer response following laser ablation and radical prostatectomy.

J Med Imaging (Bellingham) 2014 Oct 27;1(3):035001. Epub 2014 Oct 27.

Case Western Reserve University , Department of Biomedical Engineering, Cleveland, Ohio 44106, United States.

Laser interstitial thermotherapy (LITT) is a relatively new focal therapy technique for the ablation of localized prostate cancer. In this study, for the first time, we are integrating ex vivo pathology and magnetic resonance imaging (MRI) to assess the imaging characteristics of prostate cancer and treatment changes following LITT. Via a unique clinical trial, which gave us the availability of ex vivo histology and pre- and post-LITT MRIs, (1) we investigated the imaging characteristics of treatment effects and residual disease, and (2) evaluated treatment-induced feature changes in the ablated area relative to the residual disease. First, a pathologist annotated the ablated area and the residual disease on the ex vivo histology. Subsequently, we transferred the annotations to the post-LITT MRI using a semi-automatic elastic registration. The pre- and post-LITT MRIs were registered and features were extracted. A scoring metric based on the change in median pre- and post-LITT feature values was introduced, which allowed us to identify the most treatment responsive features. Our results show that (1) image characteristics for treatment effects and residual disease are different, and (2) the change of feature values between pre- and post-LITT MRIs can be a quantitative biomarker for treatment response. Finally, using feature change improved discrimination between the residual disease and treatment effects.
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http://dx.doi.org/10.1117/1.JMI.1.3.035001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478957PMC
October 2014

In Reply.

Arch Pathol Lab Med 2015 Jul;139(7):845-6

Department of Pathology, University Hospitals, Case Medical Center and Case Western Reserve University, Cleveland, OH 44106.

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http://dx.doi.org/10.5858/arpa.2014-0530-LEDOI Listing
July 2015

Testicular Adnexal Smooth Muscle Hyperplasia: A Mimic of Malignancy.

J Urol 2015 Jul 11;194(1):207-8. Epub 2015 Apr 11.

University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.

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http://dx.doi.org/10.1016/j.juro.2015.04.020DOI Listing
July 2015

Touch preparations for the intraoperative evaluation of sentinel lymph nodes after neoadjuvant therapy have high false-negative rates in patients with breast cancer.

Arch Pathol Lab Med 2014 Jun;138(6):814-8

From the Departments of Pathology (Drs Elliott and Gilmore) Surgery (Dr Shenk), and Family Medicine (Dr Thompson), University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, Ohio.

Context: The use of a touch preparation for intraoperative sentinel lymph node diagnosis has become a preferred method of many pathologists because of its reported high sensitivity and rapid turnaround time. However, after neoadjuvant chemotherapy many lymph nodes have significant treatment-related changes that may affect the diagnostic accuracy of the intraoperative evaluation.

Objective: To determine the accuracy of touch preparation for the intraoperative diagnosis of metastatic breast carcinoma in the neoadjuvant setting.

Design: We reviewed retrospectively the results of intraoperative evaluations for 148 different sentinel lymph nodes from 63 patients who had undergone neoadjuvant chemotherapy for invasive breast cancer at our institution. The intraoperative touch preparation results were compared with the final pathology reports in conjunction with relevant clinical data.

Results: Use of touch preparation for the evaluation of sentinel lymph nodes intraoperatively after neoadjuvant therapy was associated with a low sensitivity of 38.6% (95% confidence interval [CI], 24.4-54.5) but high specificity of 100% (95% CI, 96.5-100). There was no difference in sensitivity rates between cytopathologists and noncytopathologists in this cohort (P = .40). Patients with invasive lobular carcinoma and those who had a clinically positive axilla before the initiation of neoadjuvant therapy were the most likely to have a false-negative result at surgery.

Conclusions: Intraoperative touch preparations should not be used alone for the evaluation of sentinel lymph nodes in the setting of neoadjuvant therapy for breast cancer because of low overall sensitivity.
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http://dx.doi.org/10.5858/arpa.2013-0281-OADOI Listing
June 2014

A practical approach to remote longitudinal follow-up of Parkinson's disease: the FOUND study.

Mov Disord 2014 May 11;29(6):743-9. Epub 2014 Feb 11.

Clinical Research, The Parkinson's Institute, Sunnyvale, California, USA; Department of Health Research and Policy, Stanford University, Palo Alto, California, USA.

The objective of this study was to examine a remote method for maintaining long-term contact with Parkinson's disease (PD) patients participating in clinical studies. Long-term follow-up of PD patients is needed to fill critical information gaps on progression, biomarkers, and treatment. Prospective in-person assessment can be costly and may be impossible for some patients. Remote assessment using mail and telephone contact may be a practical follow-up method. Patients enrolled in the multi-center Longitudinal and Biomarker Study in Parkinson's Disease (LABS-PD) in-person follow-up study in 2006 were invited to enroll in Follow-up of Persons With Neurologic Diseases (FOUND), which is overseen by a single center under a separate, central institutional review board protocol. FOUND uses mailed questionnaires and telephone interviews to assess PD status. FOUND follow-up continued when LABS-PD in-person visits ended in 2011. Retention and agreement between remote and in-person assessments were determined. In total, 422 of 499 (84.5%) of eligible patients volunteered, AND 96% of participants were retained. Of 60 patients who withdrew consent from LABS-PD, 51 were retained in FOUND. Of 341 patients who were active in LABS-PD, 340 were retained in FOUND (99.7%) when the in-person visits ceased. Exact agreement between remote and in-person assessments was ≥ 80% for diagnosis, disease features (eg, dyskinesias), and PD medication. Correlation between expert-rated and self-reported Unified Parkinson's Disease Rating Scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale, which were examined at times separated by several months, was moderate or substantial for most items. Retention was excellent using remote follow-up of research participants with PD, providing a safety net when combined with in-person visits, and also is effective as a stand-alone assessment method, providing a useful alternative when in-person evaluation is not feasible.
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http://dx.doi.org/10.1002/mds.25814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656448PMC
May 2014

Generation and characterization of fully human monoclonal antibodies against human Orai1 for autoimmune disease.

J Pharmacol Exp Ther 2013 May 8;345(2):225-38. Epub 2013 Mar 8.

Protein Technologies, Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Mail Stop: 14-2-A, Thousand Oaks, CA 91320, USA.

Calcium entry into T cells following antigen stimulation is crucial for nuclear factor of activated T cells (NFAT)-mediated T cell activation. The movement of calcium is mediated by calcium release-activated calcium (CRAC) channels. There are two key components of this channel: Orai1 is the pore-forming subunit located in the plasma membrane, and stromal interaction molecule 1 (STIM1) functions as a Ca(2+) sensor in the endoplasmic reticulum. A subset of human patients carry mutations in either STIM1 or Orai1 that affect protein function or expression, resulting in defective store-operated Ca(2+) influx and CRAC channel function, and impaired T cell activation. These patients suffer from a hereditary form of severe combined immune deficiency syndrome, highlighting the importance of the CRAC channel for T lymphocyte function in humans. Since autoreactive T cells play an important role in the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and organ transplantation, Orai1 becomes an attractive therapeutic target for ameliorating autoimmune disease. We developed a novel approach to inhibiting CRAC function by generating high-affinity fully human monoclonal antibodies to human Orai1. These antibodies inhibited ICRAC current, store-operated Ca(2+) influx, NFAT transcription, and cytokine release. These fully human antibodies to human Orai1 may represent a novel therapeutic approach for the treatment of autoimmunity.
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http://dx.doi.org/10.1124/jpet.112.202788DOI Listing
May 2013

Maternal immune activation increases neonatal mouse cortex thickness and cell density.

J Neuroimmune Pharmacol 2012 Sep 9;7(3):529-32. Epub 2012 May 9.

Departments of Neurology and Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Center for Life Sciences, 330 Brookline Ave, E/CLS-717, Boston, MA 02215, USA.

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http://dx.doi.org/10.1007/s11481-012-9372-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672058PMC
September 2012