Toby Charles Cornish

• MD, PhD
• Professor and Director of Informatics at Medical College of Wisconsin

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered...

Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence suggests that pancreatic intraepithelial neoplasia (PanIN), a microscopic precursor lesion that gives rise to pancreatic cancer, is larger and more prevalent than previously believed. Better understanding of the growth-law dynamics of PanINs may improve our ability to und...

Pancreatic ductal adenocarcinoma (PDAC) develops from 2 known precursor lesions: a majority (∼85%) develops from pancreatic intraepithelial neoplasia (PanIN), and a minority develops from intraductal papillary mucinous neoplasms (IPMNs). Clinical classification of PanIN and IPMN relies on a combination of low-resolution, 3-dimensional (D) imaging (...

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study¹. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we prov...

Immunotherapies are generally ineffective in pancreatic ductal adenocarcinoma (PDAC). Paradoxically, inflammation is believed to play a key role in PDAC development and invasion: patients suffering from chronic pancreatitis have a 13-fold increase in risk of developing PDAC. PDAC cells are surrounded by a dense network of fibrotic tissue containing...

Methods for partially resolved cellular profiling has enabled in-depth quantitative tissue mapping via thinly cut sections to study inter-patient and intra-patient differences in normal human anatomy and disease onset and progression. These methods often profile extremely limited spatial regions, which may impact the evaluation of heterogeneity due...

Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence reveals that pancreatic intraepithelial neoplasms (PanINs), the microscopic precursor lesions in the pancreatic ducts that can give rise to invasive pancreatic cancer, are significantly larger and more prevalent than previously believed. Better understanding of the growth...

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learni...

Background: Network-connected medical devices have rapidly proliferated in the wake of recent global catalysts, leaving clinical laboratories and healthcare organizations vulnerable to malicious actors seeking to ransom sensitive healthcare information. As organizations become increasingly dependent on integrated systems and data-driven patient ca...

A central challenge in biology is obtaining high-content, high-resolution information while analyzing tissue samples at volumes relevant to disease progression. We address this here with CODA, a method to reconstruct exceptionally large (up to multicentimeter cubed) tissues at subcellular resolution using serially sectioned hematoxylin and eosin-st...

Due to domain shifts, deep cell/nucleus detection models trained on one microscopy image dataset might not be applicable to other datasets acquired with different imaging modalities. Unsupervised domain adaptation (UDA) based on generative adversarial networks (GANs) has recently been exploited to close domain gaps and has achieved excellent nucleu...

Despite technological advances in the analysis of digital images for medical consultations, many health information systems lack the ability to correlate textual descriptions of image findings linked to the actual images. Images and reports often reside in separate silos in the medical record throughout the process of image viewing, report authorin...

Background Eponyms are ubiquitous in dermatology; however, their usage trends have not been studied. Objective To characterize the usage of eponyms in dermatology from 1880 to 2020. Methods Candidate eponyms were collected from a textbook and an online resource. A subset of these eponyms was deemed to be dermatology-focused by a panel of experien...

Whole slide imaging (WSI) is a versatile technology with many applications in teaching, research, quality assurance, and clinical diagnostics. As a “store and forward” digital imaging technology, WSI is naturally suited to distribution over high-speed communication networks, which enables long-distance viewing of whole slide images originating at r...

Whole slide imaging is the process of digitizing a glass slide into a single file, high magnification virtual image object, or whole slide image (WSI). This process requires the use of slide scanners and specialized WSI devices that automate the image capture process. While slide scanners trace their roots to automated robotic microscopes developed...

Diagnostic and evidential static image, video clip, and sound multimedia are captured during routine clinical care in cardiology, dermatology, ophthalmology, pathology, physiatry, radiation oncology, radiology, endoscopic procedural specialties, and other medical disciplines. Providers typically describe the multimedia findings in contemporaneous e...

Artificial intelligence has been applied to histopathology for decades, but the recent increase in interest is attributable to well-publicized successes in the application of deep-learning techniques, such as convolutional neural networks, for image analysis. Recently, generative adversarial networks (GANs) have provided a method for performing ima...

Eponyms are common in medicine; however, their usage has varied between specialties and over time. A search of specific eponyms will reveal the frequency of usage within a medical specialty. While usage of eponyms can be studied by searching PubMed, but manual searching can be time-consuming. As an alternative, we modified an existing Biopython met...

Advances in artificial intelligence (AI), especially in deep learning, improve pathological image analysis in basic, translational, and clinical research and in routine clinical practice. Deep learning is currently the dominant technique among the best solutions for many tasks in digital pathology. This chapter provides a general overview of differ...

Background Eponyms are commonly used in medicine, but there are no specific studies of the use of eponyms in clinical chemistry. Methods Clinical chemistry eponyms were manually collected from books, review articles and journal articles from 1847 through 2020. Eponym usage was examined by searching titles and abstracts in PubMed. Custom Python scr...

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Accumulating evidence indicates the tumor microenvironment is highly associated with tumorigenesis through regulation of cellular physiology, signaling systems, and gene expression profiles of cancer cells. Yet the mechanisms by which the microenvironment evolves from...

Cell or nucleus detection is a fundamental task in microscopy image analysis and has recently achieved state-of-the-art performance by using deep neural networks. However, training supervised deep models such as convolutional neural networks (CNNs) usually requires sufficient annotated image data, which is prohibitively expensive or unavailable in...

PURPOSE We focus on the problem of scarcity of annotated training data for nucleus recognition in Ki-67 immunohistochemistry (IHC)–stained pancreatic neuroendocrine tumor (NET) images. We hypothesize that deep learning–based domain adaptation is helpful for nucleus recognition when image annotations are unavailable in target data sets. METHODS We...

Quantitative biomarkers are key prognostic and predictive factors in the diagnosis and treatment of cancer. In the clinical laboratory, the majority of biomarker quantitation is still performed manually, but digital image analysis (DIA) methods have been steadily growing and account for around 25% of all quantitative immunohistochemistry (IHC) test...

Objectives: Histologic findings after endoscopic resection using submucosal lifting agents Eleview and ORISE gel are described. Methods: Four cases were identified based on the histologic presence of ORISE gel. Cases were selected to illustrate the histologic appearance of the lifting agent immediately after injection (day 0) and after an interv...

Objective: Nucleus recognition is a critical yet challenging step in histopathology image analysis, for example in Ki67 immunohistochemistry stained images. Although many automated methods have been proposed, most use a multi-stage processing pipeline to categorize nuclei, leading to cumbersome, low-throughput and error-prone assessments. To addre...

April 12, 2017, marked a significant day in the evolution of digital pathology in the United States, when the US Food and Drug Administration announced its approval of the Philips IntelliSite Pathology Solution for primary diagnosis in surgical pathology. Although this event is expected to facilitate more widespread adoption of whole slide imaging...

Objectives: Recent commercialization of methods for in situ hybridization using Z-pair probe/branched DNA amplification has led to increasing adoption of this technology for interrogating RNA expression in formalin-fixed, paraffin-embedded (FFPE) tissues. Current practice for FFPE block storage is to maintain them at room temperature, often for ma...

Purpose: PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications. Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thi...

Importance: The programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway play an important immunosuppressive role in cancer and chronic viral infection, and have been effectively targeted in cancer therapy. Anal squamous cell carcinoma (SCC) is associated with both human papillomavirus and HIV infection. To date, patien...

Background: Mast cells are of interest in prostate cancer because they possess both pro- and anti-tumorigenic properties and are present in the tumor microenvironment. We studied the association of mast cell count and densities with prostate cancer recurrence using tissue microarrays (TMAs) for 462 men who recurred (cases) and 462 controls that we...

Background The National Cancer Institute-60 (NCI-60) cell lines are among the most widely used models of human cancer. They provide a platform to integrate DNA sequence information, epigenetic data, RNA and protein expression, and pharmacologic susceptibilities in studies of cancer cell biology. Genome-wide studies of the complete panel have includ...

Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of panc...

Supplementary Figures 1-9, Supplementary Tables 1-3

Purpose: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intraarterial therapy (HAIAT) with evofosfamide in a rabbit model. Experimental design: VX2-tumor-bearing rabbits were assigned to 4 intraarterial therapy (IAT) groups (n=7/group): 1) saline (control); 2) evofosfamide (Evo); 3) doxorubicin-Lipiodol emul...

Background Long INterspersed Element-1 (LINE-1 or L1) is the only autonomously active, transposable element in the human genome. L1 sequences comprise approximately 17 % of the human genome, but only the evolutionarily recent, human-specific subfamily is retrotransposition competent. The L1 promoter has a bidirectional orientation containing a sens...

Semiquantitative immunohistochemistry (IHC) is commonly used in combination with fluorescence in situ hybridization (FISH) to detect HER2 amplification in gastroesophageal adenocarcinomas. Most laboratories apply these tests in a sequential algorithm, using IHC as a frontline test and reserving FISH for IHC-equivocal cases. To gain a better underst...

Prostate cancer afflicts African American men to a greater degree than European American men, with a 60% greater incidence and 2-3 times greater mortality. In addition, studies have shown that the incidence rate of distant metastasis is 4 times greater in African American men than in European American men, consistent with the notion that prostate c...

Cytomegalovirus (CMV) causes significant morbidity and mortality in congenitally-infected children and immunocompromised hosts. Among healthy individuals, CMV is generally thought to cause mild, self-limited illness. CMV enterocolitis, in particular, is rarely considered among immunocompetent children presenting with diarrhea. We describe two cases...

Objective: Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. D...

Small RNA RNA-seq for microRNAs (miRNAs) is a rapidly developing field where opportunities still exist to create better bioinformatics tools to process these large datasets and generate new, useful analyses. We built miRge to be a fast, smart small RNA-seq solution to process samples in a highly multiplexed fashion. miRge employs a Bayesian alignme...

Programmed death ligand 1 (PD-L1) expression by tumor-infiltrating lymphocytes (TILs) and tumor cells in breast cancer has been reported, but the relationships between PD-L1 expression by TIL, carcinoma cells, and other immunologic features of the breast tumor microenvironment remain unclear. We therefore evaluated the interrelationships between tu...

Background Immunohistochemical detection of PD-L1 may be used in the future as a biomarker to help select an immunotherapeutic regimen for patients with advanced melanoma. For example, patients whose tumors are PD-L1+ may receive anti-PD-1 monotherapy, and those whose tumors are PD-L1(-) may receive combination anti-PD-1 and anti-CTLA-4. The evalua...

s: Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; November 9-12, 2014; San Antonio, TX The goal of the current study is to establish the mechanism by which mast cells may serve as a prognostic factor in and possibly explain the racial disparity associated with prostate cancer...

Background: Prostate cancers composed exclusively of Gleason pattern 3 have an excellent prognosis,while those containing Gleason pattern 4 or higher are more aggressive. Gleason pattern 4 is composed of either fused glands, poorly formed glands or cribriform structures with cribriform structures being most readily recognized and shown to be of ind...

Purpose: Tumor hypoxia is considered a challenge of anticancer therapy. The use of hypoxia-activated prodrugs (HAPs) in the setting of transarterial chemoembolization (TACE) is particularly appealing by allowing the locoregional delivery of high-doses of chemotherapy which has the potential to reach distal hypoxic tumor regions. Moreover, the embol...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Evidence suggests that there is a strong association between chronic inflammation and prostate cancer development and/or progression. While chronic inflammation is known to serve as an “enabling characteristic” in many cancers, the mechanism whereby it contributes to...

The human protein atlas (HPA) is a powerful proteomic tool for visualizing the distribution of protein expression across most human tissues and many common malignancies. The HPA includes immunohistochemically-stained images from tissue microarrays (TMAs) that cover 48 tissue types and 20 common malignancies. The TMA data are used to provide express...

We previously demonstrated the ability to detect metastatic prostate cancer using (18)F-DCFBC (DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant h...

Background: In adaptive resistance, tumors use PDL1 induction as a protective mechanism against an antitumor immune response implying underlying immuno-surveillance. By upregulating the expression of ligands for inhibitory receptors on tumor specific lymphocytes in the tumor microenvironment a growing malignancy can avoid immune elimination. Here w...

Background: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. Methods: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-program...

We examined Ki-67 heterogeneity within single and between synchronous liver metastases of small intestine neuroendocrine tumors. There were 27 patients (10 men and 17 women) with two or more liver metastases. The Ki-67 index was used to classify the tumors into World Health Organization grade 1, 2, or 3. The association between Ki-67 heterogeneity...

Telepathology is lauded for its potential to overcome geographic barriers and bring expert diagnostic opinions to underserved regions. However, the legal and regulatory aspects governing its use in the United States and abroad are disparate and incomplete. In addition, there is essentially no case law that specifically addressed telepathology. Impo...

Purpose: To evaluate the diagnostic performance of three-dimensional ( 3D three-dimensional ) quantitative enhancement-based and diffusion-weighted volumetric magnetic resonance (MR) imaging assessment of hepatocellular carcinoma ( HCC hepatocellular carcinoma ) lesions in determining the extent of pathologic tumor necrosis after transarterial che...

The long-term use of proton pump inhibitors has been linked to an increased risk for the development of gastric polyps, hip fractures, pneumonia, and Clostridium difficile colitis. There is evidence that chronic acid suppression from long-term use of proton pump inhibitors poses some risk for the development of C difficile-associated diarrhea by de...

miR-143 and miR-145 are co-expressed microRNAs (miRNAs) that have been extensively studied as potential tumor suppressors. These miRNAs are highly expressed in the colon and are consistently reported as being downregulated in colorectal and other cancers. Through regulation of multiple targets, they elicit potent effects on cancer cell growth and t...

Background Cytologic screening for urothelial carcinoma is fraught with low sensitivity, a high indeterminate rate, and until recently, poor standardization of terminology. The Johns Hopkins Hospital John K. Frost Cytopathology Laboratory has recently developed and published a template for reporting urine cytopathology; herein we evaluate its inter...

Purpose To evaluate the predictive value of a three-dimensional (3D) HCC tumor necrosis assessment using quantitative EASL (qEASL) and quantitative Apparent Diffusion Coefficient (qADC), we compare radiologic and pathologic findings in patients with HCC, who underwent tumor resection (TR) or liver transplantation (LT) after TACE. Materials and Me...

MicroRNAs (miRNAs) are small (∼22-nt), stable RNAs that critically modulate post-transcriptional gene regulation. MicroRNAs can be found in the blood as components of serum, plasma and peripheral blood mononuclear cells (PBMCs). Many microRNAs have been reported to be specific biomarkers in a variety of non-neoplastic diseases. To date, no one has...

PURPOSE To evaluate the precision of a three-dimensional (3D) HCC tumor necrosis assessment using quantitative EASL (qEASL) and volumetric RECIST (vRECIST), we correlate radiologic and pathologic findings in patients with HCC, who underwent tumor resection (TR) or liver transplantation (LT) after TACE. METHOD AND MATERIALS This retrospective study...

Hematolymphoid neoplasms frequently harbor recurrent genetic abnormalities. Some of the most well recognized lesions are chromosomal translocations, and many of these are known to play pivotal roles in pathogenesis. In lymphoid malignancies, some translocations result from erroneous V(D)J-type events. However, other translocation junctions appear r...

The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but s...

Objectives: To examine the accuracy of software-assisted measurement of the Ki-67 proliferation index (PI) and its correlation with the grade and clinical progression of follicular lymphoma (FL). Methods: High-power field equivalents were extracted from H&E- and Ki-67-immunostained slides of FL, and a nuclear quantitation algorithm was used to c...

Genomic instability represented by genetic and epigenetic changes is a hallmark of oncogenesis and tumor progression. The study of genomic instability using conventional methods has necessarily been restricted to regions of unique DNA and excludes repetitive DNA sequences. Repeat elements derived from mobile DNAs comprise a large portion of the hum...

Objective: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. Background: The natural history and prognosis of PanN...

Background. The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated. Methods. A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and...

Objectives: To determine how high-resolution transrectal ultrasound (HiTRUS) compares with conventional TRUS (LoTRUS) for the visualization of prostate cancer. Methods and materials: Twenty-five men with known prostate cancer scheduled for radical prostatectomy were preoperatively imaged with both LoTRUS (5MHz) and HiTRUS (21MHz). Dynamic cine l...

Background: The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated. Methods: A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, a...

Unlabelled: Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver...

Digital pathology systems offer pathologists an alternate, emerging mechanism to manage and interpret information. They offer increasingly fast and scalable hardware platforms for slide scanning and software that facilitates remote viewing, slide conferencing, archiving, and image analysis. Deployed initially and validated largely within the resear...

Distinguishing between solid-pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) may pose a diagnostic dilemma. Both can demonstrate solid growth patterns, and both can be immunoreactive with neuroendocrine markers such as synaptophysin and CD56. One well-established feature of SPNs is the presence of hyaline globules, w...

Plant-derived polyphenols such as curcumin hold promise as a therapeutic agent in the treatment of chronic liver diseases. However, its development is plagued by poor aqueous solubility resulting in poor bioavailability. To circumvent the suboptimal bioavailability of free curcumin, we have developed a polymeric nanoparticle formulation of curcumin...

Pancreatic intraepithelial neoplasias (PanINs) are microscopic lesions of the pancreas. Traditionally viewed as a benign metaplasia of small ducts, evidence suggests that PanINs are neoplastic and that some PanINs progress to invasive ductal adenocarcinoma. The primary diagnostic challenge is distinguishing PanINs from other lesions, including inva...

Male circumcision reduces human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2) acquisition, and HSV-2 infection is associated with an increased risk of HIV acquisition. To assess the cellular basis for these associations, we estimated immunologic cellular densities in foreskin tissue. Immunostained CD1a(+) dendritic cell and C...

Autoimmune metaplastic atrophic gastritis (AMAG) is an early manifestation of pernicious anemia that precedes the hematologic changes by years to decades. It is associated with metaplastic changes and neoplasms, including pyloric gland adenomas (PGAs). We investigated the frequency of PGAs and other lesions in all nonconsultation gastric biopsies a...

Tissue microarrays (TMAs) are composite tissue blocks capable of accommodating over 1,000 unique tissue cores on a single glass slide. TMAs have become widely adopted in pathology and biomarker research. This chapter briefly discusses the design and construction of TMAs, the state of TMA imaging, and current methods for the analysis and management...

Clear cell change is seen in <1% of colonic tubular adenomas (TAs) and remains incompletely characterized. Associated adenocarcinomas can also demonstrate a clear cell phenotype. Eleven TAs with at least focal clear cell change with or without associated invasive adenocarcinoma, from 10 patients were studied. The lesions were stained with periodic...

The morphology of gastric hamartomatous polyps from patients with juvenile polyposis syndrome (JuvPS) and Peutz-Jeghers' Syndrome (PJS) is poorly characterized. We investigated the histologic features of gastric polyps in patients with established JuvPS or PJS to develop improved histologic criteria to distinguish these from gastric hyperplastic (H...

To analyze tissue microarrays (TMAs) using color deconvolution, a method for separating component dyes in digital images, and compare the results to observer scoring. TMAs were constructed from tissues from 100 adult autopsies and immunohistochemically stained for connective tissue growth factor. A region of interest (ROI) was created for each core...