Publications by authors named "Laura Spruill"

38 Publications

Mass Spectrometry Imaging of Fibroblasts: Promise and Challenge.

Expert Rev Proteomics 2021 Jul 24:1-14. Epub 2021 Jul 24.

Bruker-MUSC Center of Excellence, Clinical Glycomics, Medical University of South Carolina, Charleston, SC, USA.

Introduction: Fibroblasts maintain tissue and organ homeostasis through output of extracellular matrix that affects nearby cell signaling within the stroma. Altered fibroblast signaling contributes to many disease states and extracellular matrix secreted by fibroblasts has been used to stratify patient by outcome, recurrence, and therapeutic resistance. Recent advances in imaging mass spectrometry allow access to single cell fibroblasts and their ECM niche within clinically relevant tissue samples.

Areas Covered: We review biological and technical challenges as well as new solutions to proteomic access of fibroblast expression within the complex tissue microenvironment. Review topics cover conventional proteomic methods for single fibroblast analysis and current approaches to accessing single fibroblast proteomes by imaging mass spectrometry approaches. Strategies to target and evaluate the single cell stroma proteome on the basis of cell signaling are presented.

Expert Opinion: The promise of defining proteomic signatures from fibroblasts and their extracellular matrix niches is the discovery of new disease markers and the ability to refine therapeutic treatments. Several imaging mass spectrometry approaches exist to define the fibroblast in the setting of pathological changes from clinically acquired samples. Continued technology advances are needed to access and understand the stromal proteome and apply testing to the clinic.
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http://dx.doi.org/10.1080/14789450.2021.1941893DOI Listing
July 2021

A case report of inverted Meckel's diverticulum.

Radiol Case Rep 2021 May 4;16(5):1118-1122. Epub 2021 Mar 4.

Department of Radiology, Medical University of South Carolina University Medical Center, 25 Courtenay St., Charleston, SC, 29412 USA.

Inverted Meckel's diverticulum is an entity often discovered incidentally or through a clinical evaluation for gastrointestinal bleeding. While rare, inverted Meckel's diverticulum should be considered in the evaluation of a patient presenting with gastrointestinal bleeding, intestinal obstruction, or intussusception. In this case, a 67-year-old female with a remote history of surgically treated breast cancer presents to an urgent care facility with weakness and fatigue. She was found to be anemic with hemoglobin of 4. Imaging revealed a blind-ending pouch in the mid to distal ileum consistent with an inverted Meckel's diverticulum. Inverted Meckel's diverticulum is identified on computerized tomography as an intraluminal, blind-ending structure in the mid to distal ileum. The possibility of a lead point should be investigated and surgical resection is indicated to prevent intestinal obstruction.
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http://dx.doi.org/10.1016/j.radcr.2021.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937938PMC
May 2021

Zonal regulation of collagen-type proteins and posttranslational modifications in prostatic benign and cancer tissues by imaging mass spectrometry.

Prostate 2020 09 20;80(13):1071-1086. Epub 2020 Jul 20.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Proteomics Center, Medical University of South Carolina, Charleston, South Carolina.

Background: The emergence of reactive stroma is a hallmark of prostate cancer (PCa) progression and a potential source for prognostic and diagnostic markers of PCa. Collagen is a main component of reactive stroma and changes systematically and quantitatively to reflect the course of PCa, yet has remained undefined due to a lack of tools that can define collagen protein structure. Here we use a novel collagen-targeting proteomics approach to investigate zonal regulation of collagen-type proteins in PCa prostatectomies.

Methods: Prostatectomies from nine patients were divided into zones containing 0%, 5%, 20%, 70% to 80% glandular tissue and 0%, 5%, 25%, 70% by mass of PCa tumor following the McNeal model. Tissue sections from zones were graded by a pathologist for Gleason score, percent tumor present, percent prostatic intraepithelial neoplasia and/or inflammation (INF). High-resolution accurate mass collagen targeting proteomics was done on a select subset of tissue sections from patient-matched tumor or nontumor zones. Imaging mass spectrometry was used to investigate collagen-type regulation corresponding to pathologist-defined regions.

Results: Complex collagen proteomes were detected from all zones. COL17A and COL27A increased in zones of INF compared with zones with tumor present. COL3A1, COL4A5, and COL8A2 consistently increased in zones with tumor content, independent of tumor size. Collagen hydroxylation of proline (HYP) was altered in tumor zones compared with zones with INF and no tumor. COL3A1 and COL5A1 showed significant changes in HYP peptide ratios within tumor compared with zones of INF (2.59 ± 0.29, P value: .015; 3.75 ± 0.96 P value .036, respectively). By imaging mass spectrometry COL3A1 showed defined localization and regulation to tumor pathology. COL1A1 and COL1A2 showed gradient regulation corresponding to PCa pathology across zones. Pathologist-defined tumor regions showed significant increases in COL1A1 HYP modifications compared with COL1A2 HYP modifications. Certain COL1A1 and COL1A2 peptides could discriminate between pathologist-defined tumor and inflammatory regions.

Conclusions: Site-specific posttranslational regulation of collagen structure by proline hydroxylation may be involved in reactive stroma associated with PCa progression. Translational and posttranslational regulation of collagen protein structure has potential for new markers to understand PCa progression and outcomes.
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http://dx.doi.org/10.1002/pros.24031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857723PMC
September 2020

Peyronie disease: a clinicopathologic study of 71 cases with emphasis on histopathologic patterns and prevalent metaplastic ossification.

Hum Pathol 2020 10 15;104:9-17. Epub 2020 Jul 15.

Department of Pathology, VCU School of Medicine, Richmond, VA, 23298, USA; Division of Urology, Department of Surgery, VCU School of Medicine, Richmond, VA, 23298, USA.

Peyronie disease (PD) is a benign, superficial fibromatosis involving the fascial structures of the penis, causing deformity, pain, and loss of function, for which there are few contemporary studies of the histopathology. We performed a multi-institutional review of 74 routine and consultation specimens submitted with clinical concern for PD. Of these, three non-PD lesions were identified and excluded (a myointimoma, a mammary-type myofibroblastoma, and fibrocalcific atherosclerosis). Of the 71 confirmed to be PD, the majority of patients were white (83%), with a median age of 55 years (range: 26-88). The dorsal aspect of the penis was the most common site involved (78%), followed by lateral (12%) and ventral (10%) aspects. The median degree of curvature was 70° (range: 20-360°). On review, three overall histologic patterns characterized the lesions resected: dense fibrotic plaque (61%), dense fibrotic plaque with focal or patchy metaplastic ossification (35%), and plaque composed predominantly of metaplastic ossification (4%). The fibrotic component was predominantly nodular (18%), hyalinized/lamellar (46%), or mixed (32%), excepting two cases consisting entirely of metaplastic bone. Chronic inflammation, when present, was most often focal and perivascular in distribution. In one case, an excision after collagenase treatment showed myxoid change and increased stromal cellularity. Overall, these findings define the range of PD histology, particularly emphasizing that the calcification noted clinically nearly always represents bona fide metaplastic ossification. Such context will be of value in evaluating specimens prospectively, in light of changing practices and the use of new technologies for treatment.
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http://dx.doi.org/10.1016/j.humpath.2020.07.013DOI Listing
October 2020

#EBUSTwitter: Novel Use of Social Media for Conception, Coordination, and Completion of an International, Multicenter Pathology Study.

Arch Pathol Lab Med 2020 07;144(7):878-882

From the Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia (Dr Lepe); the Department of Pathology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey (Dr Oltulu); the Department of Pathology, Rhode Island Hospital, Providence (Dr Canepa); the Department of Clinical Pathology & Laboratory Medicine, University of Pennsylvania Health System, Philadelphia (Dr Wu); the Department of Pathology, Summa Health Systems, Akron, Ohio (Drs Deeken and Jelinek); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Drs Alex and Sauter); Patologia, Vall d'Hebron Hospital, Barcelona, Spain (Drs Dinares and Sansano); the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Drs Doxtader and Mukhopadhyay); the Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark (Dr Fitzhugh); Centre de Biologie, University of Lille, Lille, France (Dr Gibier); the Department of Pathology, All India Institute of Medical Sciences, New Delhi, India (Dr Jain); the Department of Pathology, Case Western Reserve University, Cleveland, Ohio (Drs Janaki and Michael); Patologia, Complejo Hospitalario de Navarra, Navarra, Spain (Drs Labiano and Panizo); the Department of Pathology, University of Milano Biocca, Monza, Italy (Dr L'Imperio and Pagni); Patologia, Hospital del Mar, Barcelona, Spain (Drs Pijuan and Sanchez-Font); the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Quintana); the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Roy-Chowdhuri); the Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston (Drs Skipper and Spruill); the Department of Pathology, Massachusetts General Hospital, Boston (Dr Torous); the Department of Pathology, Dermatopathology, Bone & Soft Tissue, University of Arkansas for Medical Sciences, Little Rock (Dr Gardner); and the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Jiang).

Context.—: Social media sites are increasingly used for education, networking, and rapid dissemination of medical information, but their utility for facilitating research has remained largely untapped.

Objective.—: To describe in detail our experience using a social media platform (Twitter) for the successful initiation, coordination, and completion of an international, multi-institution pathology research study.

Design.—: Following a tweet describing a hitherto-unreported biopsy-related histologic finding in a mediastinal lymph node following endobronchial ultrasound-guided transbronchial needle aspiration, a tweet was posted to invite pathologists to participate in a validation study. Twitter's direct messaging feature was used to create a group to facilitate communication among participating pathologists. Contributing pathologists reviewed consecutive cases of mediastinal lymph node resection following endobronchial ultrasound-guided transbronchial needle aspiration and examined them specifically for biopsy site changes. Data spreadsheets containing deidentified data and digital photomicrographs of suspected biopsy site changes were submitted via an online file hosting service for central review by 5 pathologists from different institutions.

Results.—: A total of 24 pathologists from 14 institutions in 5 countries participated in the study within 143 days of study conception, and a total of 297 cases were collected and analyzed. The time interval between study conception and acceptance of the manuscript for publication was 346 days.

Conclusions.—: To our knowledge, this is the first time that a social media platform has been used to generate a research idea based on a tweet, recruit coinvestigators publicly, communicate with collaborating pathologists, and successfully complete a pathology study.
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http://dx.doi.org/10.5858/arpa.2019-0297-OADOI Listing
July 2020

Pilomatrixoma, a Rare Mimicker of Male Breast Cancer.

J Clin Imaging Sci 2019 6;9:46. Epub 2019 Nov 6.

Departments of Radiology, Medical University of South Carolina, Charleston, South Carolina, USA.

Pilomatrixoma or calcifying epithelioma of Malherbe is a benign skin tumor arising from the hair follicle; breast occurrence is considered a rarity. Clinically presenting as a palpable abnormality and with both benign and malignant mammographic and sonographic features, it can be easily misdiagnosed as a breast neoplasm. We report a very rare case of pilomatrixoma of the male breast in a 36-year-old male presenting with a firm, superficial nodule in the upper outer quadrant. Though the sonographic trifecta of imaging features (shape- margins-orientation/oval, circumscribed mass, parallel to the skin) is consistent with a benign lesion, a histologic diagnosis was warranted based on its most suspicious feature of internal pleomorphic calcifications. Pathologic diagnosis revealed the uncommon benign entity of pilomatrixoma in the male breast. Our patient was recommended for surgical excision based on current literature recommendations for management in most reports of pilomatrixoma. One alternative recommendation presented in a single report of pilomatrixoma in the breast supported follow-up imaging based on benign imaging characteristics.
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http://dx.doi.org/10.25259/JCIS_64_2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884983PMC
November 2019

Development of a Novel Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein-2 That Inhibits Triple-Negative Breast Cancer and Angiosarcoma Growth In Vivo.

Ann Surg Oncol 2019 Dec 12;26(13):4782-4790. Epub 2019 Sep 12.

Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.

Background: We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth.

Methods: The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4 mg/kg intravenously every 3 days for 3 weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40 days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis.

Results: Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy.

Conclusion: We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.
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http://dx.doi.org/10.1245/s10434-019-07800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261905PMC
December 2019

Specific N-Linked Glycosylation Patterns in Areas of Necrosis in Tumor Tissues.

Int J Mass Spectrom 2019 Mar 9;437:69-76. Epub 2018 Jan 9.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics and MUSC Proteomics Center, Medical University of South Carolina, Charleston, South Carolina.

Tissue necrosis is a form of cell death common in advanced and aggressive solid tumors, and is associated with areas of intratumoral chronic ischemia. The histopathology of necrotic regions appear as a scaffold of cellular membrane remnants, reflective of the hypoxia and cell degradation events associated with this cellular death pathway. Changes in the glycosylation of cell surface proteins is another common feature of cancer progression. Using a recently developed mass spectrometry imaging approach to evaluate N-linked glycan distributions in human formalin-fixed clinical cancer tissues, differences in the glycan structures of regions of tumor, stroma and necrosis were evaluated. While the structural glycan classes detected in the tumor and stromal regions are typically classified as high mannose or branched glycans, the glycans found in necrotic regions displayed limited branching, contained sialic acid modifications and lack fucose modifications. While this phenomenon was initially classified in breast cancer tissues, it has been also seen in cervical, thyroid and liver cancer samples. These changes in glycosylation within the necrotic regions could provide further mechanistic insight to necrotic changes in cancer tissue and provide new research directions for identifying prognostic markers of necrosis.
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http://dx.doi.org/10.1016/j.ijms.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483403PMC
March 2019

Increases in Tumor N-Glycan Polylactosamines Associated with Advanced HER2-Positive and Triple-Negative Breast Cancer Tissues.

Proteomics Clin Appl 2019 01;13(1):e1800014

Department of Cell and Molecular Pharmacology and Experimental Therapeutics and MUSC Proteomics Center, Medical University of South Carolina, Charleston, 29425, SC, USA.

Purpose: Using a recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) method, human breast cancer formalin-fixed paraffin-embedded (FFPE) tissue sections and tissue microarrays (TMA) are evaluated for N-linked glycan distribution in the tumor microenvironment.

Experimental Design: Tissue sections representing multiple human epidermal growth factor receptor 2 (HER2) receptor-positive and triple-negative breast cancers (TNBC) in both TMA and FFPE slide format are processed for high resolution N-glycan MALDI-IMS. An additional FFPE tissue cohort of primary and metastatic breast tumors from the same donors are also evaluated.

Results: The cumulative N-glycan MALDI-IMS analysis of breast cancer FFPE tissues and TMAs indicate the distribution of specific glycan structural classes to stromal, necrotic, and tumor regions. A series of high-mannose, branched and fucosylated glycans are detected predominantly within tumor regions. Additionally, a series of polylactosamine glycans are detected in advanced HER2+, TNBC, and metastatic breast cancer tissues. Comparison of tumor N-glycan species detected in paired primary and metastatic tissues indicate minimal changes between the two conditions.

Conclusions And Clinical Relevance: The prevalence of tumor-associated polylactosamine glycans in primary and metastatic breast cancer tissues indicates new mechanistic insights into the development and progression of breast cancers. The presence of these glycans could be targeted for therapeutic strategies and further evaluation as potential prognostic biomarkers.
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http://dx.doi.org/10.1002/prca.201800014DOI Listing
January 2019

Displaced Cartilage Within Lymph Node Parenchyma Is a Novel Biopsy Site Change in Resected Mediastinal Lymph Nodes Following EBUS-TBNA.

Am J Surg Pathol 2019 04;43(4):497-503

Department of Pathology, Cleveland Clinic.

Biopsy site changes in mediastinal lymph nodes (LNs) attributable to prior endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been studied in a systematic manner. Twenty-four contributors from 14 institutions in 5 countries collaborated via social media (Twitter) to retrospectively review consecutive cases of resected mediastinal LNs from patients with prior EBUS-TBNA. Resected LNs were reexamined by submitting pathologists for changes attributable to EBUS-TBNA. Patients who received neoadjuvant therapy were excluded. Cases with suspected biopsy site changes underwent central review by 5 pathologists. A total of 297 mediastinal LN resection specimens from 297 patients (183 male/114 female, mean age: 65 y, range: 23 to 87) were reviewed. Biopsy site changes were most common in station 7 (10 cases) followed by 11R, 4R, and 10R, and were found in 34/297 (11.4%) cases, including displacement of tiny cartilage fragments into LN parenchyma in 26, intranodal or perinodal scars in 7, and hemosiderin in 1. Cartilage fragments ranged from 0.26 to 1.03 mm in length and 0.18 to 0.62 mm in width. The mean interval between EBUS-TBNA and LN resection was 38 days (range: 10 to 112) in cases with biopsy site changes. A control group of 40 cases without prior EBUS-TBNA, including 193 mediastinal LN stations, showed no evidence of biopsy site changes. Biopsy site changes are identified in a subset of resected mediastinal LNs previously sampled by EBUS-TBNA. The location of the abnormalities, temporal association with prior EBUS-TBNA, and the absence of such findings in cases without prior EBUS-TBNA support the contention that they are caused by EBUS-TBNA.
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http://dx.doi.org/10.1097/PAS.0000000000001197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558851PMC
April 2019

Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.

Breast Cancer Res Treat 2019 Feb 27;173(3):559-571. Epub 2018 Oct 27.

Department of Pathology & Laboratory Medicine, Medical University of South Carolina (MUSC), Charleston, SC, USA.

Purpose: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer.

Methods: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors.

Results: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors.

Conclusions: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.
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http://dx.doi.org/10.1007/s10549-018-4992-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394600PMC
February 2019

The Value of a Second Opinion for Breast Cancer Patients Referred to a National Cancer Institute (NCI)-Designated Cancer Center with a Multidisciplinary Breast Tumor Board.

Ann Surg Oncol 2018 Oct 3;25(10):2953-2957. Epub 2018 Jul 3.

Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.

Background: This study aimed to investigate the changes in diagnosis after a second opinion for breast cancer patients from a multi-disciplinary tumor board (MTB) review at an National Cancer Institute (NCI)-designated cancer center.

Methods: A retrospective study analyzed patients with a breast cancer diagnosed at an outside institution who presented for a second opinion from August 2015 to March 2016 at the Medical University of South Carolina (MUSC). Radiology, pathology, and genetic testing reports from outside institutions were compared with reports generated after an MTB review and subsequent workup at MUSC. The second-opinion cases were categorized based on whether diagnostic variations were present or not.

Results: The review included 70 patients seeking second opinions, and 33 (47.1%) of these patients had additional radiologic images. A total of 30 additional biopsies were performed for 25 patients, with new cancers identified in 16 patients. Overall, 16 (22.8%) of the 70 of patients had additional cancers diagnosed. For 14 (20%) of the 70 patients, a second opinion led to a change in pathology interpretation. Genetic testing was performed for 11 patients (15.7%) who met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, but none showed a mutation other than a variant of unknown significance. After a complete workup, 30 (42.8%) of the 70 patients had a change in diagnosis as a result of the MTB review.

Conclusion: A review by an MTB at an NCI-designated cancer center changed the diagnosis for 43% of the patients who presented for a second opinion for breast cancer. The study findings support the conclusion that referral for a second opinion is beneficial and has a diagnostic impact for many patients.
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http://dx.doi.org/10.1245/s10434-018-6599-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132422PMC
October 2018

Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3.

Breast Cancer Res Treat 2017 Jul 8;164(2):349-358. Epub 2017 May 8.

Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, 68 President St, Charleston, SC, 29425, USA.

Purpose: NSD3 has been implicated as a candidate driver oncogene from the 8p11-p12 locus, and we have previously published evidence for its amplification and overexpression in human breast cancer. This aim of this study was to further characterize the transforming function of NSD3 in vivo.

Methods: We generated a transgenic mouse model in which NSD3 gene expression was driven by the MMTV promoter and expressed in mammary epithelium of FVB mice. Mammary glands were fixed and whole mounts were stained with carmine to visualize gland structure. Mammary tumors were formalin-fixed, and paraffin embedded (FFPE) tumors were stained with hematoxylin and eosin.

Results: Pups born to transgenic females were significantly underdeveloped compared to pups born to WT females due to a lactation defect in transgenic female mice. Whole mount analysis of the mammary glands of transgenic female mice revealed a profound defect in functional differentiation of mammary gland alveoli that resulted in the lactation defect. We followed parous and virgin NSD3 transgenic and control mice to 50 weeks of age and observed that several NSD3 parous females developed mammary tumors. Whole mount analysis of the mammary glands of tumor-bearing mice revealed numerous areas of mammary hyperplasia and ductal dysplasia. Histological analysis showed that mammary tumors were high-grade ductal carcinomas, and lesions present in other mammary glands exhibited features of alveolar hyperplasia, ductal dysplasia, and carcinoma in situ.

Conclusions: Our results are consistent with our previous studies and demonstrate that NSD3 is a transforming breast cancer oncogene.
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http://dx.doi.org/10.1007/s10549-017-4258-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928774PMC
July 2017

CD8, FoxP3, and CD45RO+ Lymphocytic Infiltrates in Type I and Type II Endometrial Cancers in African American and European American Females.

Int J Gynecol Pathol 2017 Nov;36(6):540-549

College of Medicine (T.R.) Departments of Obstetrics and Gynecology (J.L.Y.-P., W.G., S.N.) Public Health Sciences (E.G.-M.) Pathology and Laboratory Medicine (L.S.S.), Medical University of South Carolina, Charleston, SC.

African American (AA) females with endometrial carcinoma have a significantly worse prognosis with regard to disease-free survival and overall survival than their European American (EA) counterparts and this finding is true across all stages and grades. The presence of tumor-infiltrating lymphocytes (TILs) has been demonstrated to be of prognostic significance in a variety of malignancies, including endometrial cancers. This study aims to determine whether clinically significant differences in levels of CD8+ cytotoxic T lymphocytes, FoxP3+ regulatory T lymphocytes, and CD45RO+ memory T lymphocytes exist between races and to document the clinical impact of TILs. One hundred ten patients with endometrial adenocarcinoma, treated with hysterectomy from 2003 to 2011 were studied. Patients were selected to provide equal representation across type and grade for both EAs and AAs. Immunohistochemical stains were used to highlight CD8-positive, FoxP3-positive, and CD45RO-positive TILs at the endometrial-myometrial interface on slides from paraffin-embedded tissue. Patients with "high" or "low" levels of TILs were compared with respect to the race, tumor type, and survival. High levels of CD45RO+ TILs were associated with improved overall survival in EA women (hazard ratio, 0.32; 95% confidence interval, 0.11-0.92; P=0.034). Comparatively, AA women with high levels of CD45RO+ TILs received no survival benefit (hazard ratio, 0.96; 95% confidence interval, 0.35-2.64; P=0.94). High levels of CD8-positive or FoxP3-positive TILs, alone, had no impact on survival. EA patients with TILs containing high levels of CD45RO cells but low levels of CD8+ cells lost the survival benefit; however, limited numbers preclude significant conclusions from this observation. Neither tumor type nor race were predictive of the levels of TILs of any type. Further study with a larger sample size is required to determine the impact of TIL subtype combinations on survival.
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http://dx.doi.org/10.1097/PGP.0000000000000359DOI Listing
November 2017

Peritoneal Deciduoid Mesothelioma: An Unusual Presentation Complicating an Already Challenging Diagnosis.

Int J Surg Pathol 2017 Jun 23;25(4):352-356. Epub 2017 Jan 23.

1 Medical University of South Carolina, Charleston, SC, USA.

This report highlights a diagnostically challenging case of diffuse deciduoid mesothelioma occurring in the peritoneum of a 25-year-old woman, 8 months postpartum. Optimally debulked tumor consisted of sheets of polygonal cells arranged in solid, trabecular, and pseudopapillary configurations, with vesicular, occasionally grooved nuclei and small nucleoli. A barrage of immunohistochemical stains revealed an unusual staining pattern characterized by diffusely positive keratin, WT-1, and mesothelin staining, but lack of calretinin positivity. Electron microscopy demonstrated only rare thin, long, branching cellular projections. Cytogenetics revealed balanced translocations of 12p and 1q and 16p. Based on compiled ancillary studies, a diagnosis of deciduoid mesolthelioma was made and supported by consultations from experts at 3 outside facilities. Twenty-seven months after diagnosis, the patient is alive and undergoing treatment with progression of disease. This case is presented in detail, and a discussion of the diagnostic criteria and current application of those criteria is provided.
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http://dx.doi.org/10.1177/1066896916688084DOI Listing
June 2017

Right Atrial Angiosarcoma Diagnosed by Cardiac Magnetic Resonance Imaging.

Am J Med Sci 2016 Oct 11;352(4):435-437. Epub 2016 Jun 11.

Department of Radiology, Radiological Science and Medicine, Medical University of South Carolina, Charleston, SC.

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http://dx.doi.org/10.1016/j.amjms.2016.06.004DOI Listing
October 2016

Radiologic-pathologic Correlation-An Advanced Fourth-year Elective: How We Do It.

Acad Radiol 2016 07 1;23(7):889-93. Epub 2016 Apr 1.

Medical University of South Carolina, Charleston, South Carolina.

Traditionally, the radiology elective has been designed to teach medical students the fundamentals of radiologic interpretation. When questioned, many students state that they want to take a radiology elective so they can "interpret images." For the students on radiology, rotation/elective education was often passive, consisting of didactic conferences and observational shadowing of radiologists as they interpreted images. Students had only a superficial appreciation of how radiologists interacted with clinical services, multidisciplinary teams, and pathology. There was very little emphasis on imaging appropriateness or the most efficient and effective imaging for various clinical problems. With the expansion of numerous imaging modalities and the emphasis on patient-centered care, including imaging safety and dose reduction, it is important to change the focus of radiology education from interpretation to the optimal integration of imaging into clinical medicine. Radiology-pathology (rad path) electives were created at Allegheny General Hospital and the Medical University of South Carolina as a new option to provide a high-quality advanced elective for fourth-year medical students. These electives enable students to correlate radiologic images with gross and microscopic pathology specimens, thus increasing their knowledge and understanding of both. The rad path elective combines aspects of surgery, radiology, and pathology and requires students to be active learners. The implementation of this elective is an exciting work in progress that has been evolving over the past 2 and 4 years at Medical University of South Carolina and Allegheny General Hospital, respectively. We will discuss the historical basis for the elective, the advantages and challenges of having such an integrated course, and some different strategies for creating a rad path elective.
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http://dx.doi.org/10.1016/j.acra.2016.01.019DOI Listing
July 2016

A three dimensional nerve map of human bladder trigone.

Neurourol Urodyn 2017 04 6;36(4):1015-1019. Epub 2016 Jun 6.

Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina.

Aim: Central efferent and afferent neural pathways to and from the human urinary bladder are well-characterized, but the location and arborization of these nerves as they traverse the serosa, muscularis, and urothelial layers are not clearly defined. The purpose of this study was to create a three dimensional map of the innervation of the human bladder trigone from the extrinsic perivesical adventitial nerve trunks to the urothelium.

Methods: A male and a female human bladder were harvested from fresh frozen cadavers and fixed in formalin. The bladder neck and trigone region were serially sectioned (5 μm) and every 20th slide was stained (S100), scanned and aligned to create 3D maps.

Results: Nerve penetration into the detrusor muscle occurs with the highest frequency at the bladder neck and interureteric ridge. Nerves traveling parallel to the bladder lumen do so in the adventitia, beyond the outer border of detrusor. In females, the depth of these nerve bands is uniform at 0.7-1.7 cm below the luminal surface, the outer limits of which include the anterior vaginal wall. In the male, depth is more variable owing to detrusor hypertrophy with the minimum depth of nerves approximately 0.5 cm near the interureteric ridge and over 1 cm near the bladder neck.

Conclusions: Myelinated neural pathways traversing in the human bladder in the region of the trigone have a discreet regional density. This 3D map of trigonal innervation may provide guidance to more precisely direct therapies for urinary incontinence or pelvic pain. Neurourol. Urodynam. 36:1015-1019, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/nau.23049DOI Listing
April 2017

Assessing the Relationship of Mammographic Breast Density and Proliferative Breast Disease.

Breast J 2016 Sep 4;22(5):541-6. Epub 2016 Jun 4.

Department of Radiology, Medical University of South Carolina, Charleston, South Carolina.

Increased breast density and a history of benign breast biopsy are both considered risk factors for developing breast cancer. Understanding the specifics of these risk factors and their relationship to each other can lead to a better understanding of a patient's propensity for breast cancer development and improved surveillance strategies. We included 245 women who underwent a benign breast biopsy without atypia between October 2011 and June 2013. Biopsies were performed for suspicious calcifications as well as masses and architectural distortion. Lesions biopsied were divided into two groups: calcified and noncalcified lesions. The patient's breast density was assessed on most recent mammogram and was classified using the American College of Radiology BI-RADS density categories. Based on histologic diagnosis, each case was classified as proliferative or nonproliferative breast disease. The median age of the cohort (n = 245) was 55 years (range, 40-84 years). There were 162 (66%) postmenopausal women in the study. A core biopsy was performed for calcifications in 33.5% cases and for noncalcified lesions in 58% cases. In patients with dense breast tissue, an underlying proliferative histology was found significantly more frequently with calcifications (66.7%) as opposed to noncalcified lesions (35.9%) (RR = 2.3 (1.3-4.0); χ(2) = 8.7; p = 0.003). In nondense breast patients, there was no significant difference (RR = 1.1 (0.7-1.8); χ(2) = 0.1; p = 0.738). In the postmenopausal group, women with dense breasts had proliferative histology significantly more frequently than women with nondense breasts (55.3% versus 38.3%; p < 0.05), regardless of the underlying lesion type. Postmenopausal women with dense breasts who underwent a breast biopsy with benign histology had a significantly higher likelihood of having proliferative breast disease, regardless of underlying lesion type. Women with dense breasts also showed proliferative histology significantly more often for calcifications as opposed to noncalcified lesions.
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http://dx.doi.org/10.1111/tbj.12620DOI Listing
September 2016

Rapidly Growing Lateral Neck Mass.

JAMA Otolaryngol Head Neck Surg 2016 Feb;142(2):185-6

Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston.

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http://dx.doi.org/10.1001/jamaoto.2015.2928DOI Listing
February 2016

Benign mimickers of malignant breast lesions.

Authors:
Laura Spruill

Semin Diagn Pathol 2016 Jan 5;33(1):2-12. Epub 2015 Sep 5.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Ave, MSC 908, Charleston, South Carolina 29425-9080. Electronic address:

Breast pathology is filled with pitfalls, including underdiagnosis of bland-appearing lesions, both invasive and non-invasive, misdiagnosis of malignant lesions as belonging to the wrong subgroup, for example, calling LCIS as DCIS or missing the metaplastic component of an invasive lesion, and overdiagnosis of benign lesions as malignancy. While each is a sin of varying severity, the overdiagnosis of benign lesions can be the most scarring, especially in this age where Angelina Jolie׳s prophylactic mastectomy is the headline news and patients are pushing for aggressive preventive treatment. In this review, we will consider some of the more common benign lesions and the malignant counterpart that they mimic, with the goal of identifying characteristic features that will lead to the correct diagnosis. Much of the discussions will center around the assessment of core biopsies, as smaller tissue volume is most often contributory to overcalling benign lesions.
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http://dx.doi.org/10.1053/j.semdp.2015.09.002DOI Listing
January 2016

A Rare Case of Intrapulmonary Ewing Sarcoma Presenting with Left Atrial Tumor Thrombus.

J Thorac Oncol 2015 Jul;10(7):1120-2

*Department of Radiology and Radiological Science, Heart and Vascular Center, Medical University of South Carolina, Charleston, South Carolina; and †Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.

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http://dx.doi.org/10.1097/JTO.0000000000000428DOI Listing
July 2015

A novel urodynamic model for lower urinary tract assessment in awake rats.

BJU Int 2015 Apr;115 Suppl 6:8-15

Brain Research Institute, Balgrist University Hospital, University of Zürich, Zürich, Switzerland; Neuro-Urology, Spinal Cord Injury Center and Research, Balgrist University Hospital, University of Zürich, Zürich, Switzerland; Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.

Objectives: To develop a urodynamic model incorporating external urethral sphincter (EUS) electromyography (EMG) in awake rats.

Materials And Methods: Bladder catheters and EUS EMG electrodes were implanted in female Sprague Dawley rats. Assessments were performed in awake, lightly restrained rats on postoperative day 12-14. Measurements were repeated in the same rat on day 16 under urethane anaesthesia. Urodynamics and EUS EMG were performed simultaneously. In addition, serum creatinine and bladder histology was assessed.

Results: No significant differences in urodynamic parameters were found between bladder catheter only vs bladder catheter and EUS EMG electrode groups. Urethane anaesthesia evoked prominent changes in both urodynamic parameters and EUS EMG. Serum creatinine was within the normal limits in all rats. Bladder weight and bladder wall thickness were significantly increased in both the bladder catheter only and the bladder catheter and EUS EMG group compared with controls.

Conclusions: Our novel urodynamic model allows repetitive measurements of both bladder and EUS function at different time points in the same rat under fully awake conditions and opens promising avenues to investigate lower urinary tract dysfunction in a translational approach.
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http://dx.doi.org/10.1111/bju.13039DOI Listing
April 2015

Correlation of cardiac magnetic resonance imaging and histopathology in eosinophilic endomyocarditis.

Circ Cardiovasc Imaging 2015 Jan 31;8(1). Epub 2014 Dec 31.

From the Department of Radiology and Radiological Science, Heart and Vascular Center (S.B., C.N.D.C., U.J.S., W.B.W., P.S., A.V.-S.) and Department of Pathology and Laboratory Medicine (L.S.S.), Medical University of South Carolina, SC; First Department of Medicine, Faculty of Medicine Mannheim, University Medical Center Mannheim (UMM), University of Heidelberg, Mannheim, Germany (S.B.); and Department of Radiological Sciences, Oncology and Pathology, University of Rome Sapienza-Polo Pontino, Latina, Italy (C.N.D.C.).

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http://dx.doi.org/10.1161/CIRCIMAGING.114.002501DOI Listing
January 2015

AGE metabolites: a biomarker linked to cancer disparity?

Cancer Epidemiol Biomarkers Prev 2014 Oct 22;23(10):2186-91. Epub 2014 Jul 22.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina. Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.

Socioeconomic and environmental influences are established factors promoting cancer disparity, but the contribution of biologic factors is not clear. We report a mechanistic link between carbohydrate-derived metabolites and cancer that may provide a biologic consequence of established factors of cancer disparity. Glycation is the nonenzymatic glycosylation of carbohydrates to macromolecules, which produces reactive metabolites called advanced glycation end products (AGE). A sedentary lifestyle and poor diet all promote disease and the AGE accumulation pool in our bodies and also increase cancer risk. We examined AGE metabolites in clinical specimens of African American and European American patients with prostate cancer and found a higher AGE concentration in these specimens among African American patients when compared with European American patients. Elevated AGE levels corresponded with expression of the receptor for AGE (RAGE or AGER). We show that AGE-mediated increases in cancer-associated processes are dependent upon RAGE. Aberrant AGE accumulation may represent a metabolic susceptibility difference that contributes to cancer disparity.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-0564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184970PMC
October 2014

Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.

Am J Physiol Renal Physiol 2014 Feb 27;306(3):F299-308. Epub 2013 Nov 27.

Jr., Dept. of Urology, CSB644, Medical Univ. of South Carolina, 96 Jonathan Lucas St., Charleston, SC 29425.

Bladder inflammation (cystitis) underlies numerous bladder pathologies and is elicited by a plethora of agents such as urinary tract infections, bladder outlet obstruction, chemotherapies, and catheters. Pattern recognition receptors [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] that recognize pathogen- and/or damage-associated molecular patterns (PAMPs and/or DAMPs, respectively) are key components of the innate immune system that coordinates the production (TLRs) and maturation (NLRs) of proinflammatory IL-1β. Despite multiple studies of TLRs in the bladder, none have investigated NLRs beyond one small survey. We now demonstrate that NLRP3 and NLRC4, and their binding partners apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain (ASC) and NLR family apoptosis inhibitory protein (NAIP), are expressed in the bladder and localized predominantly to the urothelia. Activated NLRs form inflammasomes that activate caspase-1. Placement of a NLRP3- or NLRC4-activating PAMP or NLRP3-activating DAMPs into the lumen of the bladder stimulated caspase-1 activity. To investigate inflammasomes in vivo, we induced cystitis with cyclophosphamide (CP, 150 mg/kg ip) in the presence or absence of the inflammasome inhibitor glyburide. Glyburide completely blocked CP-induced activation of caspase-1 and the production of IL-1β at 4 h. At 24 h, glyburide reduced two markers of inflammation by 30-50% and reversed much of the inflammatory morphology. Furthermore, glyburide reversed changes in bladder physiology (cystometry) induced by CP. In conclusion, NLRs/inflammasomes are present in the bladder urothelia and respond to DAMPs and PAMPs, whereas NLRP3 inhibition blocks bladder dysfunction in the CP model. The coordinated response of NLRs and TLRs in the urothelia represents a first-line innate defense that may provide an important target for pharmacological intervention.
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http://dx.doi.org/10.1152/ajprenal.00297.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073918PMC
February 2014

Liposarcoma of the head and neck: analysis of 318 cases with comparison to non-head and neck sites.

Head Neck 2014 Mar 1;36(3):393-400. Epub 2013 Jun 1.

Mercer University School of Medicine, Savannah, Georgia.

Background: Liposarcomas are rare in the head and neck. We analyzed a large series of head and neck liposarcomas to determine features unique to the head and neck.

Methods: Three hundred eighteen liposarcomas of the head and neck were contrasted with 9485 liposarcomas of other regions using the Surveillance, Epidemiology, and End Results (SEER) database.

Results: Head and neck liposarcomas were most commonly subcutaneous (81.%), low grade (70.1%; p < .001), and early stage (p < .001). They were more likely to be treated with surgery alone, whereas conventional liposarcomas were more likely to receive adjuvant radiation (p < .001). Treatment that included surgery had better survival than radiation therapy alone (p = .008). Overall, liposarcomas of the head and neck had significantly higher disease-specific survival (DSS) and overall survival (OS) than conventional liposarcomas (p < .001).

Conclusion: Liposarcomas of the head and neck are usually early stage, low grade, and with fewer nodal metastases than conventional liposarcomas. DSS and OS were significantly greater for liposarcomas of the head and neck.
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http://dx.doi.org/10.1002/hed.23311DOI Listing
March 2014

Severe hypercalcemia associated with uterine leiomyoma in pregnancy.

Obstet Gynecol 2011 Feb;117(2 Pt 2):473-476

From the Departments of Obstetrics and Gynecology and Pathology, Medical University of South Carolina, Charleston, South Carolina.

Background: Uterine leiomyomas are the most common pelvic tumor, and a frequent indication of the need for gynecologic surgery. Although usually asymptomatic, life-threatening cases can occur. We present a case of critical hypercalcemia associated with a leiomyoma during pregnancy with the intention of highlighting the endocrinology of leiomyomas, features shared with malignant neoplasms, and the potential for effects on obstetric outcomes.

Case: A 32-year-old gravid woman with a large leiomyoma presented at 33 5/7 weeks of gestation with critical hypercalcemia requiring intensive care. Postpartum myomectomy cured her hypercalcemia, which was driven by parathyroid hormone-related protein (PTHrP) produced by the tumor.

Conclusion: Obstetricians should be aware of the existence of humoral hypercalcemia related to leiomyomas and the potential effects on pregnancy.
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http://dx.doi.org/10.1097/AOG.0b013e3181fd29aeDOI Listing
February 2011
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