Department of Pathology and Laboratory Medicine
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Item [(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease(e-Century Publishing Corporation, 2016) Deters, Kacie D.; Risacher, Shannon L.; Yoder, Karmen K.; Oblak, Adrian L.; Unverzagt, Frederick W.; Murrell, Jill R.; Epperson, Francine; Tallman, Eileen F.; Quaid, Kimberly A.; Farlow, Martin R.; Saykin, Andrew J.; Ghetti, Bernardino; Department of Pathology & Laboratory Medicine, IU School of MedicineGerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.Item A 2-year-old boy with hemolytic uremic syndrome and pneumocephalus(Wiley, 2012-01) Martin, Sarah E.; Allen, Steven D.; Faught, Phillip; Hawley, Dean A.; Bonnin, Jose M.; Hattab, Eyas M.; Pathology and Laboratory Medicine, School of MedicineClostridium septicum infection following hemolytic uremic syndrome is rare and carries a poor prognosis, especially when the brain is involved. We report a case of a previously healthy 2-year-old boy who presented with two days of anuria and bloody diarrhea. He was admitted to the local children's hospital with a diagnosis of hemolytic uremic syndrome, presumably secondary to E. coli O157. He soon required intubation and was noted to have fixed and dilated pupils. Head CT revealed left frontal subcortical white matter vasogenic edema and scattered pockets of pneumocephalus. The patient expired 14 hours after admission. Antemortem blood cultures grew C. septicum. Gross pathologic examination of the brain revealed a large intraparenchymal cerebral hemorrhage in the left frontal and parietal lobes. There was extensive cystic changes as well. Microscopic examination revealed vacuolization and diffuse colonization with rod-shaped bacteria, but without the expected tissue response. There have been only six previously reported cases of C. septicum infection following hemolytic uremic syndrome, four of which had brain involvement. Mortality rate is high, with the only known survivor among those with brain involvement having a brain abscess rather than diffuse pneumocephalus.Item 322. Evaluation of the BioFire® Bone and Joint Infection (BJI) Panel for the Detection of Microorganisms and Antimicrobial Resistance Genes in Synovial Fluid Specimens(Oxford University Press, 2020-12) Graue, Corrin; Schmitt, Bryan H.; Waggoner, Amy; Laurent, Frederic; Abad, Lelia; Bauer, Thomas; Mazariegos, Irving; Balada-Llasat, Joan-Miquel; Horn, Jarid; Wolk, Donna; Jefferis, Alexa; Hermans, Mirjam; Verhoofstad, Irma; Butler-Wu, Susan; Umali-Wilcox, Minette; Murphy, Caitlin N.; Cabrera, Barbara J.; Esteban, Jaime; Macias-Valcayo, Alicia; Craft, David; von Bredow, Benjamin; Leber, Amy; Everhart, Kathy; Dien Bard, Jennifer; Mestas, Jvier; Daly, Judy; Barr, Rebecca; Kensinger, Bart; Pons, Benedicte; Jay, Corinne; Pathology and Laboratory Medicine, School of MedicineBackground Bone and Joint Infections (BJIs) present with non-specific symptoms that may include pain, swelling, and fever and are associated with high morbidity and significant risk of mortality. BJIs can be caused by a variety of bacteria and fungi, including anaerobes and microorganisms that can be challenging to culture or identify by traditional microbiological methods. Clinicians primarily rely on culture to identify the pathogen(s) responsible for infection. The BioFire® Bone and Joint Infection (BJI) Panel (BioFire Diagnostics, Salt Lake City, UT) is designed to detect 15 gram-positive bacteria (including seven anaerobes), 14 gram-negative bacteria (including one anaerobe), two yeast, and eight antimicrobial resistance (AMR) genes from synovial fluid specimens in about an hour. The objective of this study was to evaluate the performance of an Investigational Use Only (IUO) version of the BioFire BJI Panel compared to various reference methods. Methods Remnant synovial fluid specimens, which were collected for routine clinical care at 13 study sites in the US and Europe, underwent testing using an IUO version of the BioFire BJI Panel. Performance of this test was determined by comparison to Standard of Care (SoC) consisting of bacterial culture performed at each study site according to their routine procedures. Results A total of 1544 synovial fluid specimens were collected and tested with the BioFire BJI Panel. The majority of specimens were from knee joints (77.9%) and arthrocentesis (79.4%) was the most common collection method. Compared to SoC culture, overall sensitivity was 90.2% and specificity was 99.8%. The BioFire BJI Panel yielded a total of 268 Detected results, whereas SoC yielded a total of 215 positive results for on-panel analytes. Conclusion The BioFire BJI Panel is a sensitive, specific, and robust test for rapid detection of a wide range of analytes in synovial fluid specimens. The number of microorganisms and resistance genes included in the BioFire BJI Panel, together with a reduced time-to-result and increased diagnostic yield compared to culture, is expected to aid in the timely diagnosis and appropriate management of BJIs.Item A 41-year-old woman with von Hippel-Lindau and a cerebellar lesion(Wiley, 2010-03) Martin, Sarah E.; Al-Khatib, Sohaib M.; Turner, Michael S.; Douglas-Akinwande, Annette C.; Hattab, Eyas M.; Pathology and Laboratory Medicine, School of MedicineA 41-year-old woman with a 12-year history of von Hippel-Lindau disease presented with progressive quadriparesis and difficulty swallowing. MRI revealed a well-circumscribed, partially cystic cerebellar neoplasm, consistent with hemangioblastoma. The tumor was resected and the diagnosis of hemangioblastoma confirmed. Embedded within the hemangioblastoma was a small focus of metastatic renal cell carcinoma (RCC). RCC metastatic to a CNS hemangioblastoma is the second most common type of tumor-to-tumor metastasis, which may be due to a number of factors. Proper immunostaining panels are required to clearly identify these cases since both tumor may have similar histology.Item A 61-year-old woman with osteomalacia and a thoracic spine lesion(Wiley, 2010-03) Marshall, Ann E.; Martin, Sarah E.; Agaram, Narasimhan P.; Chen, Jey-Hsin; Horn, Eric M.; Douglas-Akinwande, Annette C.; Hattab, Eyas M.; Pathology and Laboratory Medicine, School of MedicinePhosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) is a rare, largely benign, mesenchymal neoplasm almost invariably associated with oncogenic osteomalacia. It is generally found in the soft tissue and bone of the extremities. We report a case of a 61-year-old female with long-standing osteomalacia who was found to have PMT-MCT of the thoracic spine. There have been very few previously reported cases of PMT involving the spinal vertebrae and neuropathologists should be aware of this lesion. Recognition of PMT-MCT is critical for optimal patient care since complete surgical resection without additional therapy is curative.Item 754. Performance Characterization of a Real Time PCR Assay for Pneumocystis jirovecii in Bronchoalveolar Lavage Fluid and Sputum(Oxford University Press, 2020-10) Bell, Drew T.; Koehlinger, Jeremy; Schmitt, Bryan H.; Pathology and Laboratory Medicine, School of MedicineBackground Pneumocystis jirovecii pneumonia (PJP) affects immunocompromised patients and contributes significantly to mortality. Outcomes depend on early treatment, making timely and accurate diagnosis critical. Typically, PJP diagnosis is through identification of trophozoite or cyst forms in bronchoalveolar lavage (BAL) fluid or sputum, a labor-intensive and insensitive process. Options for more accessible and sensitive molecular detection are limited. It is known that patients may be colonized, which can cast doubt on the clinical significance of low levels of DNA amplification in qualitative result reporting. In this study, we describe a real time (rt) PCR assay utilizing analyte specific reagent primers targeting the mtLSU gene of P. jirovecii and correlate amplification with morphological PJP identification. Methods IUHPL Clinical Microbiology assessed sputum or BAL fluid from 109 patients with clinical concern for PJP microscopically via fungal stains (GMS, calcofluor white). Comparative rtPCR was conducted as follows. First, 2µL of residual specimen or control were mixed with an 8µL combination of rtPCR mastermix, control DNA, and primer pairs (Simplexa). No nucleic acid extraction was performed. Real time PCR was executed and analyzed on the LIAISON MDX (DiaSorin) platform. Qualitative amplification results and cycle threshold (CT) values were correlated with microscopic methods to establish performance. Chart review was performed to assess the clinical impact of this assay. Results P. jirovecii was microscopically detected in 26% (29/109) of samples, while 31.1% (34/109) exhibited amplification by rtPCR. Agreement between the two methods was 95.4%; rtPCR demonstrated 100% sensitivity and 93.8% specificity in comparison. Conclusion Our results indicate that this assay has exceptional negative predictive value (100%), and therefore may be valuable as a screening test. Considering this data alone, the positive predictive value is lower (85.3%). Further examination of the data, however, revealed that 80% (4/5) of discrepant results demonstrated CT values of >34, while the highest CT for a microscopically positive sample was 31.2. Further clinical correlation may establish a CT cutoff that will reduce false positive and potentially clinically insignificant cases.Item A deep learning framework for automated classification of histopathological kidney whole-slide images(Elsevier, 2022-04-18) Abdeltawab, Hisham A.; Khalifa, Fahmi A.; Ghazal, Mohammed A.; Cheng, Liang; El-Baz, Ayman S.; Gondim, Dibson D.; Pathology and Laboratory Medicine, School of MedicineBackground: Renal cell carcinoma is the most common type of malignant kidney tumor and is responsible for 14,830 deaths per year in the United States. Among the four most common subtypes of renal cell carcinoma, clear cell renal cell carcinoma has the worst prognosis and clear cell papillary renal cell carcinoma appears to have no malignant potential. Distinction between these two subtypes can be difficult due to morphologic overlap on examination of histopathological preparation stained with hematoxylin and eosin. Ancillary techniques, such as immunohistochemistry, can be helpful, but they are not universally available. We propose and evaluate a new deep learning framework for tumor classification tasks to distinguish clear cell renal cell carcinoma from papillary renal cell carcinoma. Methods: Our deep learning framework is composed of three convolutional neural networks. We divided whole-slide kidney images into patches with three different sizes where each network processes a specific patch size. Our framework provides patchwise and pixelwise classification. The histopathological kidney data is composed of 64 image slides that belong to 4 categories: fat, parenchyma, clear cell renal cell carcinoma, and clear cell papillary renal cell carcinoma. The final output of our framework is an image map where each pixel is classified into one class. To maintain consistency, we processed the map with Gauss-Markov random field smoothing. Results: Our framework succeeded in classifying the four classes and showed superior performance compared to well-established state-of-the-art methods (pixel accuracy: 0.89 ResNet18, 0.92 proposed). Conclusions: Deep learning techniques have a significant potential for cancer diagnosis.Item A Large Open Access Dataset of Brain Metastasis 3D Segmentations with Clinical and Imaging Feature Information(Springer Nature, 2024-02-29) Ramakrishnan, Divya; Jekel, Leon; Chadha, Saahil; Janas, Anastasia; Moy, Harrison; Maleki, Nazanin; Sala, Matthew; Kaur, Manpreet; Cassinelli Petersen, Gabriel; Merkaj, Sara; von Reppert, Marc; Baid, Ujjwal; Bakas, Spyridon; Kirsch, Claudia; Davis, Melissa; Bousabarah, Khaled; Holler, Wolfgang; Lin, MingDe; Westerhoff, Malte; Aneja, Sanjay; Memon, Fatima; Aboian, Mariam S.; Pathology and Laboratory Medicine, School of MedicineResection and whole brain radiotherapy (WBRT) are standard treatments for brain metastases (BM) but are associated with cognitive side effects. Stereotactic radiosurgery (SRS) uses a targeted approach with less side effects than WBRT. SRS requires precise identification and delineation of BM. While artificial intelligence (AI) algorithms have been developed for this, their clinical adoption is limited due to poor model performance in the clinical setting. The limitations of algorithms are often due to the quality of datasets used for training the AI network. The purpose of this study was to create a large, heterogenous, annotated BM dataset for training and validation of AI models. We present a BM dataset of 200 patients with pretreatment T1, T1 post-contrast, T2, and FLAIR MR images. The dataset includes contrast-enhancing and necrotic 3D segmentations on T1 post-contrast and peritumoral edema 3D segmentations on FLAIR. Our dataset contains 975 contrast-enhancing lesions, many of which are sub centimeter, along with clinical and imaging information. We used a streamlined approach to database-building through a PACS-integrated segmentation workflow.Item Aberrant ERG expression associates with downregulation of miR‐4638‐5p and selected genomic alterations in a subset of diffuse large B‐cell lymphoma(Wiley, 2019-10) Zhang, Shanxiang; Wang, Lin; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineERG (avian v‐ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B‐cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome‐wide microRNA (miRNA) expression profiling, real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell‐of‐origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty‐three miRNAs showed significant differential expression between ERG+ and ERG− DLBCLs. Downregulation of miR‐4638‐5p was confirmed by real‐time RT‐PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR‐4638‐5p. In comparison with ERG‐negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B‐cell receptor‐mediated signaling and degradation of β‐catenin. Further clinicopathological correlation and functional studies of ERG‐related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.Item Aberrant Expression Profiles of lncRNAs and Their Associated Nearby Coding Genes in the Hippocampus of the SAMP8 Mouse Model with AD(Cell Press, 2020-06-05) Hong, Honghai; Mo, Yousheng; Li, Dongli; Xu, Zhiheng; Liao, Yanfang; Yin, Ping; Liu, Xinning; Xia, Yong; Fang, Jiansong; Wang, Qi; Fang, Shuhuan; Pathology and Laboratory Medicine, School of MedicineThe senescence-accelerated mouse prone 8 (SAMP8) mouse model is a useful model for investigating the fundamental mechanisms involved in the age-related learning and memory deficits of Alzheimer's disease (AD), while the SAM/resistant 1 (SAMR1) mouse model shows normal features. Recent evidence has shown that long non-coding RNAs (lncRNAs) may play an important role in AD pathogenesis. However, a comprehensive and systematic understanding of the function of AD-related lncRNAs and their associated nearby coding genes in AD is still lacking. In this study, we collected the hippocampus, the main area of AD pathological processes, of SAMP8 and SAMR1 animals and performed microarray analysis to identify aberrantly expressed lncRNAs and their associated nearby coding genes, which may contribute to AD pathogenesis. We identified 3,112 differentially expressed lncRNAs and 3,191 differentially expressed mRNAs in SAMP8 mice compared to SAMR1 mice. More than 70% of the deregulated lncRNAs were intergenic and exon sense-overlapping lncRNAs. Gene Ontology (GO) and pathway analyses of the AD-related transcripts were also performed and are described in detail, which imply that metabolic process reprograming was likely related to AD. Furthermore, six lncRNAs and six mRNAs were selected for further validation of the microarray results using quantitative PCR, and the results were consistent with the findings from the microarray. Moreover, we analyzed 780 lincRNAs (also called long "intergenic" non-coding RNAs) and their associated nearby coding genes. Among these lincRNAs, AK158400 had the most genes nearby (n = 13), all of which belonged to the histone cluster 1 family, suggesting regulation of the nucleosome structure of the chromosomal fiber by affecting nearby genes during AD progression. In addition, we also identified 97 aberrant antisense lncRNAs and their associated coding genes. It is likely that these dysregulated lncRNAs and their associated nearby coding genes play a role in the development and/or progression of AD.