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Context.—The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility.Objective.—To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology.Design.—The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review.Results.—The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, −0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities.Conclusions.—WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis.We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed.Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity θ logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree θ logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model.While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome.

Background: Artificial intelligence (AI) is fast becoming the tool of choice for scalable and reliable analysis of medical images. However, constraints in sharing medical data outside the institutional or geographical space, as well as difficulties in getting AI models and modeling platforms to work across different environments, have led to a “reproducibility crisis” in digital medicine. Methods: This study details the implementation of a web platform that can be used to mitigate these challenges by orchestrating a digital pathology AI pipeline, from raw data to model inference, entirely on the local machine. We discuss how this federated platform provides governed access to data by consuming the Application Program Interfaces exposed by cloud storage services, allows the addition of user-defined annotations, facilitates active learning for training models iteratively, and provides model inference computed directly in the web browser at practically zero cost. The latter is of particular relevance to clinical workflows because the code, including the AI model, travels to the user's data, which stays private to the governance domain where it was acquired. Results: We demonstrate that the web browser can be a means of democratizing AI and advancing data socialization in medical imaging backed by consumer-facing cloud infrastructure such as Box.com. As a case study, we test the accompanying platform end-to-end on a large dataset of digital breast cancer tissue microarray core images. We also showcase how it can be applied in contexts separate from digital pathology by applying it to a radiology dataset containing COVID-19 computed tomography images. Conclusions: The platform described in this report resolves the challenges to the findable, accessible, interoperable, reusable stewardship of data and AI models by integrating with cloud storage to maintain user-centric governance over the data. It also enables distributed, federated computation for AI inference over those data and proves the viability of client-side AI in medical imaging. Availability: The open-source application is publicly available at https://episphere.github.io/path , with a short video demonstration at https://youtu.be/z59jToy2TxE .

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.

Background & Aims Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6–60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy). Methods Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC. Results Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58–11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs. Conclusion In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway.

The Job or hyper-immunoglobulinemia E syndrome is a primary immunodeficiency that is usually inherited in an autosomal dominant fashion. With the discovery of mutations in the STAT3 gene in the majority of autosomal dominant cases, it is now possible to make a molecular diagnosis of hyper-IgE syndrome. Both primary and secondary immunodeficiencies, including hyper-IgE syndrome, may predispose for malignancies, especially lymphomas, mainly mature B cell lymphomas, and classical Hodgkin lymphoma. Here, we report of a 48-year-old male with hyper-IgE syndrome who developed a primary parotid gland diffuse large B cell lymphoma. Analysis for STAT3 mutations demonstrated that the causal mutation of hyper-IgE syndrome, R382Q, arose de novo in the patient and it was transmitted to three of his five children, all three of whom are clinically affected. We review the literature regarding lymphoma in hyper-IgE syndrome and the possible etiologic relationship with STAT3 mutations.

The primary tumors that typically cause carcinomatous meningitis include lung cancer, breast cancer, leukemia, lymphoma and melanoma. A variety of neurological signs and symptoms can be seen depending on the extent and location of the meningeal metastasis. Once the diagnosis of carcinomatous meningitis is confirmed, the search for the primary tumor can be a challenge and at times may require extensive radiographic or even surgical evaluation to obtain specimen for pathological confirmation. Here we report a patient who presented with bilateral cranial nerve VIII and cerebellar symptoms, and was diagnosed with carcinomatous meningitis. Only after an exploratory laporatomy did it become clear that the initial symptoms were related to a metastatic gallbladder carcinoma.

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL. Prognostic biomarkers are needed for better risk-stratification and therapy selection. Microarray-based genome-wide profiling studies in pediatric patients have revealed recurrent abnormalities in B-cell development and cell cycle regulation. IKZF1 alterations convey a negative prognostic impact in pediatric B-ALL, but their significance is not well characterized in adult B-ALL. CDKN2A alterations have also been associated with a poorer prognosis in adult Ph+ ALL, possibly by mediating resistance to targeted therapy. The copy number landscape of adult B-ALL has not been fully assessed, and given its inferior prognosis, may be distinct from its pediatric counterpart. We identified 70 adult B-ALL patients (median age 45 years, range 18-83) from 1998-2013 at three institutions. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) diagnostic bone marrow clots and assessed with the OncoScan FFPE Express genome-wide single nucleotide polymorphism (SNP) assay (Affymetrix). Copy number alteration (CNA) analysis was performed using Nexus Software V7 (Biodiscovery) and in-house coding. The most frequent CNAs called by the software were manually verified for probe evidence. Clinical data available on this cohort included age, gender, hematologic laboratory values at presentation, CSF involvement, receipt of allogeneic transplant, cytogenetic profile, presence of t(9;22), event-free survival (EFS), and overall survival (OS). Estimated median survival time of the entire adult B-ALL patient cohort was 29 months. Recurrent deletions in the diagnostic samples were noted at several loci, including CDKN2A (47%), IKZF1 (40%), PAX5 (24%), BTG1 (17%), and BTLA (14%). Recurrent gains were identified at the following loci: ERG (30%), ETS2 (21%), MYB (20%), UBASH3B (20%), PRKCH (19%), CDK6 (17%), and ETV6 (16%). No individual CNA heralded a significant prognostic impact in the entire cohort or in subgroup analyses stratified by presence of t(9;22) for either EFS or OS, though this could be due to our relatively smaller sample size in contrast to pediatric studies that have observed a prognostic impact at some of these loci. However, the combination of both CDK2NA and IKZF1 deletions (26%) correlated with a significantly worse overall survival than having only one or neither of these deletions (both vs CDKN2A only: p = 0.028, both vs IKZF1 only: p = 0.027, both vs neither deleted: p = 0.048). Age was the only other covariate significant in univariate analyses for OS, yet IKZF1/CDKN2A co-deletion remained significant in multivariate analysis adjusting for age. Adult B-ALL demonstrates frequent CDKN2A deletions, IKZF1 deletions, and CDKN2A/IKZF1 co-deletions. To our knowledge, the negative prognostic impact of the CDKN2A/IKZF1 co-deletion is a novel finding in adult B-ALL and requires further validation in larger cohorts. Citation Format: Shiven Patel, Clinton C. Mason, Martha J. Glenn, Christian N. Paxton, Sara T. South, Melissa H. Cessna, Julie Asch, Erin F. Cobain, Dale L. Bixby, Lauren B. Smith, Joshua D. Schiffman, Rodney R. Miles. IKZF1/CDKN2A co-deletion predicts shorter survival in adult B-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1723. doi:10.1158/1538-7445.AM2015-1723