In clinical trials for ulcerative colitis (UC), pathologists assess disease severity through standardized histological indices, including the Geboes Score, Robarts Histopathology Index (RHI), and Nancy Histologic Index (NHI). Despite strong associations with clinical outcomes, histologic scoring suffers from inter- and intra-reader variability, and consensus criteria for histologic remission remain uncertain. Through a consortium approach, we developed an artificial intelligence-based measurement (AIM) tool for scoring histology in UC mucosal biopsies (AIM-HI UC). This model, trained on a large dataset of UC biopsies (N=10,230), utilizes additive multiple instance learning models leveraging PLUTO, a pathology foundation model, that predict each of the Geboes subgrades, from which the Geboes grade-level score, RHI, and NHI can be calculated. Evaluation of this model on a standalone verification set including clinical trial specimens established algorithm non-inferiority and/or superiority relative to standard qualified pathologists through comparison of algorithm-consensus and pathologist-consensus agreement metrics (non-inferior if difference >-0.1, superior if difference >0, inclusive of confidence intervals). AIM-HI UC was determined to be non-inferior to pathologists (N=3) for the prediction of all seven Geboes subgrades, grade-level Geboes, RHI, NHI, histologic improvement (GS≤3.1), 2A histologic remission (GS<2A.0), and 2B histologic remission (GS<2B.0). AIM-HI UC was superior to pathologists for several Geboes subgrades (GS 0, GS 1, GS 2B, and GS 5), as well as grade-level Geboes, RHI, and positive percent agreement of 2A histologic remission. The model was shown to be greater than 99% repeatable for all histologic scoring metrics examined. Model-derived scores were shown to strongly correlate with canonical histologic features of inflammation, including the proportion of total epithelium that is inflamed (Spearman r=0.83; p<0.01), the proportion of neutrophils localized within crypt epithelium (Spearman r=0.83, p<0.01), and the amount of mucosal area classified as erosion or ulceration (Spearman r=0.80, p<0.01). Overall, these results suggest that AIM-HI UC has the potential to improve consistency of UC histology interpretation, providing a path toward standardization of UC histology scoring in clinical trials.

In clinical trials for ulcerative colitis (UC), pathologists assess disease severity through standardized histological indices, including the Geboes Score, Robarts Histopathology Index (RHI), and Nancy Histologic Index (NHI). Despite strong associations with clinical outcomes, histologic scoring suffers from inter- and intra-reader variability, and consensus criteria for histologic remission remain uncertain. Through a consortium approach, we developed an artificial intelligence-based measurement (AIM) tool for scoring histology in UC mucosal biopsies (AIM-HI UC). This model, trained on a large dataset of UC biopsies (N=10,230), utilizes additive multiple instance learning models leveraging PLUTO, a pathology foundation model, that predict each of the Geboes subgrades, from which the Geboes grade-level score, RHI, and NHI can be calculated. Evaluation of this model on a standalone verification set including clinical trial specimens established algorithm non-inferiority and/or superiority relative to standard qualified pathologists through comparison of algorithm-consensus and pathologist-consensus agreement metrics (non-inferior if difference >-0.1, superior if difference >0, inclusive of confidence intervals). AIM-HI UC was determined to be non-inferior to pathologists (N=3) for the prediction of all seven Geboes subgrades, grade-level Geboes, RHI, NHI, histologic improvement (GS<3.1), 2A histologic remission (GS<2A.0), and 2B histologic remission (GS<2B.0). AIM-HI UC was superior to pathologists for several Geboes subgrades (GS 0, GS 1, GS 2B, and GS 5), as well as grade-level Geboes, RHI, and positive percent agreement of 2A histologic remission. The model was shown to be greater than 99% repeatable for all histologic scoring metrics examined. Model-derived scores were shown to strongly correlate with canonical histologic features of inflammation, including the proportion of total epithelium that is inflamed (Spearman r=0.83; p<0.01), the proportion of neutrophils localized within crypt epithelium (Spearman r=0.83, p<0.01), and the amount of mucosal area classified as erosion or ulceration (Spearman r=0.80, p<0.01). Overall, these results suggest that AIM-HI UC has the potential to improve consistency of UC histology interpretation, providing a path toward standardization of UC histology scoring in clinical trials. ### Competing Interest Statement WT, JS, JT, LKC, MG, CS, GS, DF, KS, JAB-C, and CJ are current or former employees of PathAI and receive salary and stock options from PathAI. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Anonymized digitized whole slide images of H&E-stained intestinal biopsies were obtained from adult patients with UC that had participated in the following complete clinical trials of UC therapeutics: [NCT02958865][1] [28], [NCT02840721][2] [29], [NCT02407236][3] [30], and NCT002209456 [31]. Approval by central institutional review boards was previously described, and all patients had provided informed consent for future research and tissue histology. Additional biopsy WSIs were obtained from Mt. Sinai Hospital (New York, New York; IRB# 21-00714) and PathAI Diagnostics (Memphis, Tennessee; IRB# 20214284). The final sets of WSIs used herein were generously provided by Cleveland Clinic Foundation (CCF; Cleveland, Ohio) under a data licensing arrangement approved by the CCF Institutional Review Board, or were obtained from South Bend Medical Foundation (South Bend, Indiana), and Discovery Life Sciences (Huntsville, Alabama). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to feature tables, cell- and tissue- heatmaps will be considered on a case by case basis at the discretion of trial sponsors. Access requests can be made to publications{at}pathai.com. Model parameters for AIM-HI UC and IBDExplore model training, inference, and feature extractions are not disclosed. Access requests for such a code will not be considered to safeguard PathAI intellectual property. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02958865&atom=%2Fmedrxiv%2Fearly%2F2026%2F06%2F11%2F2026.06.09.26355212.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02840721&atom=%2Fmedrxiv%2Fearly%2F2026%2F06%2F11%2F2026.06.09.26355212.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02407236&atom=%2Fmedrxiv%2Fearly%2F2026%2F06%2F11%2F2026.06.09.26355212.atom

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a serious public health concern. At times, MRSA is isolated from the blood along with other pathogens, the significance and consequences of which are not well described. This study aims to outline the clinical characteristics and outcomes of those with polymicrobial MRSA BSI compared with those with monomicrobial MRSA BSI. We conducted a retrospective case-control study of those with and without polymicrobial MRSA BSI from 2014 to 2022 at a single quaternary care center in New York City. Risk factors and outcomes for polymicrobial MRSA BSI were assessed using logistic regression analyses. Of 559 patients with MRSA BSI during the study period, 49 (9%) had polymicrobial MRSA BSI. Gram-positive Enterococcus (23%) was the most common co-pathogen. The presence of urinary (P = 0.02) and gastrointestinal (P < 0.01) devices was significantly associated with polymicrobial MRSA BSI. Polymicrobial MRSA BSI was associated with intensive care unit (ICU) admission after BSI (P = 0.01). Mortality did not differ. While polymicrobial MRSA BSI is relatively uncommon, it complicates an already complex clinical scenario of MRSA BSI. IMPORTANCE Staphylococcus aureus is a common human pathogen associated with severe disease and high mortality rates. Although clinically observed, little is known about the impact of polymicrobial staphylococcal bloodstream infection. This study evaluates polymicrobial methicillin-resistant S. aureus bloodstream infection (BSI), highlighting the increased risk of intensive care unit admission and impact on morbidity. Identifying risk factors for polymicrobial BSI, such as the presence of specific devices, can aid in early recognition and targeted interventions. Clarifying the risks and outcomes of polymicrobial infections can lead to strategies to minimize and manage these infections and explore the potential interactions between pathogens.

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a serious public health concern. At times, MRSA is isolated from the blood along with other pathogens, the significance and the consequences of which are not well described. This study aims to outline the clinical characteristics and outcomes of those with polymicrobial MRSA BSI compared with those with monomicrobial MRSA BSI. Methods We conducted a retrospective case-control study of those with and without polymicrobial MRSA BSI from 2014 to 2022 at a single quaternary care center in New York. Risk factors and outcomes for polymicrobial MRSA BSI were assessed using logistic regression analyses in SAS. Results Of 646 patients with MRSA BSI during the study period, 48 (7.4%) had polymicrobial MRSA BSI. In the univariate analysis, the presence of urinary device (p = 0.0174), and gastrointestinal device (p = 0.0287) were significantly associated with polymicrobial BSI. Polymicrobial BSI was associated with ICU admission after BSI (p = 0.0184). Mortality did not differ. Gram-positive Enterococcus sp. (22%) was the most common co-pathogen of MRSA in polymicrobial BSI. Conclusion While polymicrobial BSI remains relatively infrequent, risk factors for development may include devices in the genitourinary and gastrointestinal systems. Those who develop polymicrobial MRSA BSI may be at higher risk of being admitted to the ICU, signifying increased morbidity during hospital stay. Further studies are needed to evaluate the impact of polymicrobial MRSA BSI to elucidate the interplay between pathogens and the impact on infected hosts. Disclosures All Authors: No reported disclosures

Introduction: COVID-19 vaccination substantially reduces morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe illness. However, despite effective COVID-19 vaccines many questions remain about the efficacy of vaccines and the durability and robustness of immune responses, especially in immunocompromised persons. The NCI-funded Serological Sciences Network (SeroNet) is a coordinated effort including 11 sites to advance research on the immune response to SARS-CoV-2 infection and COVID-19 vaccination among diverse and vulnerable populations. The goals of the Pooling Project are: (1) to conduct real-world data (RWD) analyses using electronic medical records (EMR) data from four health care systems (Kaiser Permanente Northern California, Northwell Health, Veterans Affairs-Case Western, and Cedars-Sinai) to determine vaccine effectiveness in (a) cancer patients; (b) autoimmune diseases and (c) solid organ transplant recipients (SOTR); (2) to conduct meta-analyses of prospective cohort studies from eight SeroNet institutions (Cedars-Sinai, Johns Hopkins, Northwell Health, Emory University, University of Minnesota, Mount Sinai, Yale University) to determine post-vaccine immune responses in (a) lung cancer patients; (b) hematologic cancers/hematopoietic stem cell transplant (HSCT) recipients; (c) SOTR; (d) lupus. Methods: For our RWD analyses, data is extracted from EMR using standardized algorithms using ICD-10 codes to identify immunocompromised persons (hematologic and solid organ malignancy; SOTR; autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and SLE). We use common case definitions to extract data on demographic, laboratory values, clinical co-morbidity, COVID-19 vaccination, SARS-CoV-2 infection and severe COVID-19, and disease-specific variables. In addition, we pool individual-level data from prospective cohorts enrolling patients with cancer and other immunosuppressed conditions from across network. Surveys and biospecimens from serology and immune profiling are collected at pre-specified timepoints across longitudinal cohorts. Results: Currently, we have EMR data extracted from 4 health systems including >715,000 cancer patients, >9,500 SOTR and >180,000 with autoimmune conditions. Prospective cohorts across the network have longitudinal data on >450 patients with lung cancer, >1,200 patients with hematologic malignancies, >400 SOTR and >400 patients with lupus. We will report results examining vaccine effectiveness for prevention of SARS-CoV-2 infection, severe COVID-19 and post-acute sequelae of COVID-19 (PAS-C or long COVID) in cancer patients compared to other immunocompromised conditions. Conclusion: Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations. Citation Format: Elham Kazemain, Jane Figueiredo, Jacek Skarbinski, Russell McBride, Viviana Simon, Amy B. Karger, F. Eun-Hyung Lee, Fred R. Hirsch, Andrea Cox, Sabra Klein, Rong Fan, Stephanie Halene, David A. Zidar, James M. Crawford, Bharat Thyagarajan, Charles Gleason, Alex Mathson, Komal Srivastava, Puleng Moshele, Toby Amoss, Martin Runnstrom, Susanne Linderman, Ananda M. Rodilla, Philip C. Mack, Yu Shyr, Anna Yin, Patrick Shea, Jennifer VanOudenhove, Hinnah Siddiqui, Brigid M. Wilson, Eric P. Elkin, Crystal A. Hsiao, Yonah Ziemba, Cheryl B. Schleicher, Sharon Fox, Lawrence H. Kushi, Karen Reckamp, Akil Merchant, Noah Merin. SeroNet Pooling Project of immunocompromised populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 798.

Background Histological response to treatment is an important outcome in patients with ulcerative colitis (UC). The accuracy of biopsy-based measurements of inflammation may be limited by error imposed by natural microscopic heterogeneity on the scale of individual biopsies. We determined the magnitude of this error, its histological correlates, and the density of biopsy sampling within mucosal regions of interest required to meet specified benchmarks for accuracy. Methods A total of 994 sequential 1-mm digital microscopic images (virtual biopsies) from consecutive colectomies from patients with clinically severe UC were scored by 2 pathologists. Agreement statistics for Geboes subscores and Nancy (NHI) and Robarts Histological Indices (RHI) between random samples from 1 to 10 biopsies and a reference mean score across a 2-cm region of mucosa were calculated using bootstrapping with 2500 iterations. Results The agreement statistics improved across all indices as the biopsy density increased, with the largest proportional gains occurring with addition of the second and third biopsies. One biopsy achieved moderate to good agreement with 95% confidence for NHI and RHI corresponding to scale-specific errors of 0.40 (0.25-0.66) and 3.02 (2.08-5.36), respectively; and 3 biopsies achieved good agreement with 95% confidence corresponding to scale-specific errors of 0.22 (0.14-0.39) and 1.87 (1.19-3.25), respectively. Of the individual histological features, erosions and ulcers had the greatest impact on the agreement statistics. Conclusions In the setting of active colitis, up to 3 biopsy samples per region of interest may be required to overcome microscopic heterogeneity and ensure accurate histological grading.

Background: Pandemics are unpredictable and can rapidly spread. Proper planning and preparation for managing the impact of outbreaks is only achievable through continuous and systematic collection and analysis of health-related data. We describe our experience on how to comply with required reporting and develop a robust platform for surveillance data during an outbreak. Materials and Methods: At Mount Sinai Health System, New York City, we applied Visiun, a laboratory analytics dashboard, to support main response activities. Epic System Inc.’s SlicerDicer application was used to develop clinical and research reports. We followed World Health Organization (WHO); federal and state guidelines; departmental policies; and expert consultation to create the framework. Results: The developed dashboard integrated data from scattered sources are used to seamlessly distribute reports to key stakeholders. The main report categories included federal, state, laboratory, clinical, and research. The first two groups were created to meet government and state reporting requirements. The laboratory group was the most comprehensive category and included operational reports such as performance metrics, technician performance assessment, and analyzer metrics. The close monitoring of testing volumes and lab operational efficiency was essential to manage increasing demands and provide timely and accurate results. The clinical data reports were valuable for proper managing of medical surge requirements, such as healthcare workforce and medical supplies. The reports included in the research category were highly variable and depended on healthcare setting, research priorities, and available funding. We share a few examples of queries that were included in the designed framework for research projects. Conclusion: We reviewed here the key components of a conceptual surveillance framework required for a robust response to COVID-19 pandemics. We demonstrated leveraging a lab analytics dashboard, Visiun, combined with Epic reporting tools to function as a surveillance system. The framework could be used as a generic template for possible future outbreak events.

The oncologic outcomes for atypical meningiomas can be poor. Generally, patients that have had a prior recurrence have a substantially elevated risk of a future recurrence. Additionally, certain tumor genomic profiles have been shown as markers of poor prognosis. We sought to characterize the genomic differences between primary and recurrent tumors as well as assess if those differences had implications on recurrence. We identified primary and recurrent gross totally resected WHO grade II meningiomas with > 30 days of post-surgical follow-up at our institution. For genes with a prevalence of > 5

OBJECTIVE Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication. METHODS Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression. RESULTS In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation. CONCLUSIONS A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.

INTRODUCTION: A subset of grade I and II meningiomas, in contrast to their predicted favorable oncologic course, recur. Recent interest has been paid to the development of predictive measures to identify which tumors may necessitate more aggressive initial management or more frequent post-resection surveillance. METHODS: Using our tissue bank of 255 meningiomas with linked targeted next-generation sequencing, we identified 173 with at >90 days of post-surgical follow-up. We computed progression free survival cox-regression models for each of the 5% most prevalent tumor mutations corrected for tumor grade, recurrence status, and resection status. Grade III tumors were excluded due to issues with the proportional hazards assumption. We then built a multi-gene model by including all individual gene predictors with a p-value of less than 0.20. Starting with that model, we performed automated backwards selection. RESULTS: In the single gene analysis, ATM (HR = 5.22; 95%CI: 1.81 – 15.08), CREBBP (HR = 2.71; 95% CI = 1.15 – 6.38), and POLE (HR = 0.56; (95%CI = 0.32 – 0.97) were significantly associated with alterations in disease progression. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates and the genes ATM, ATR, CREBBP, RNF43, and SETD2. Backwards selection identified recurrence status, resection status, and mutations in ATM (HR = 8.14; 95%CI = 2.65 – 24.99) and POLE (HR = 0.45; 95% CI = 0.25 – 0.78) as predictive of recurrence. CONCLUSIONS: There is an association between ATM, CREBBP and POLE with progression free survival after accounting for tumor grade, resection extent, and recurrence status. In a muiti-gene model, POLE was the only gene found to alter survival. Backwards variable selection identified ATM as deleterious and POLE as protective.

High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT). From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status. Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068–0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88–6.73, p = 0.087). This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship.

Abstract Background Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation’s largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. We sought to determine whether histologic features correlate with disease extension. The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as “Extenders” (n = 21), whereas “Non-extenders” (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r =  − 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.

PURPOSE:Meningiomas occur more frequently in older adults, with the incidence rates increasing from 5.8/100,000 for adults 35-44 years old to 55.2/100,000 for those 85+. Due to the increased risk of surgical management in older adults, there is a need to characterize the risk factors for aggressive disease course to inform management decisions in this population. We therefore sought to determine age-stratified relationships between tumour genomics and recurrence after resection of atypical meningiomas. METHODS:We identified 137 primary and recurrent Grade 2 meningiomas from our existing meningioma genomic sequencing database. We examined the differential distribution of genomic alterations in those older than 65 compared to younger. We then performed an age stratified survival analysis to model recurrence for a mutation identified as differentially present. RESULTS:In our cohort of 137 patients with grade 2 meningiomas, alterations in NF2 were present at a higher rate in older adults compared to younger (37.8% in < 65 vs. 55.3% in > 65; recurrence adjusted p-value =0.04). There was no association between the presence of NF2 and recurrence in the whole cohort. In the age-stratified model for those less than 65 years old, there was again no relationship. For patients in the older age stratum, there is a relationship between NF2 and worsened recurrence outcomes (HR = 3.64 (1.125 - 11.811); p = 0.031). CONCLUSIONS:We found that mutations in NF2 were more common in older adults. Further, the presence of mutant NF2 was associated with an increased risk of recurrence in older adults.

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10 −8 , tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis ( P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk ( P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

The need for reliable and widely available SARS-CoV-2 testing is well recognized, but it will be equally necessary to develop quantitative methods that determine viral load in order to guide patient triage and medical decision making. We are the first to report that SARS-CoV-2 viral load at the time of presentation is an independent predictor of COVID-19 mortality in a large patient cohort (n=1,145). Viral loads should be used to identify higher-risk patients that may require more aggressive care and should be included as a key biomarker in the development of predictive algorithms.

Meningiomas are the most common primary central nervous system tumor with an incidence rate of 8.33 per 100 000.1 The majority of meningiomas (80–90%) are low grade (grade I) and have a 7–20% recurrence risk. While more rare, high-grade meningiomas harbor an increased risk of recurrence and death: grade II occurring 5–15% with a 30–40% recurrence risk and grade III occurring 1–3% with a 50–80% recurrence risk.2,3 A total of 134 high-grade (grade II or grade III) meningiomas were screened for the presence of isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations using next-generation exome sequencing. This study was approved by the human subjects institutional review board and complied with Health Insurance Portability and Accountability Act guidelines. We identified 134 patients with high-grade meningioma (grade II or grade III) who underwent neurosurgical resection at our institution from 1995 to 2017 with available archival formalin-fixed, paraffin-embedded (FFPE) tissue. A board-certified neuropathologist reviewed histopathological diagnosis, grade, and purity of each case according to 2016 World Health Organization (WHO) guidelines. DNA was extracted using Maxwell FFPE Plus DNA Purification Kit (Promega). DNA tissue libraries were generated using Ion AmpliSeq Oncomine Comprehensive research panel versions 2.0 and 3.0 as described previously.4 Sequencing data analysis performed using Torrent Suite (versions 5.6.0., 5.8.0) and Ion Reporter (versions 5.2, 5.6, 5.8). We are the first to report recurrent IDH1/2 mutations in highgrade meningiomas using next-generation exome sequencing. Mutations in IDH1/2 were identified in 2.2% (3/134) of our cohort. Case 1 involved a 53-year-old woman with a preoperative CT that revealed a heterogeneously enhancing, partially calcified extra-axial right frontal mass measuring 4.1 × 3.6 × 4.1 cm (Fig. 1A). Survival after neurosurgical resection is currently 10.1 years. Histopathologic evaluation demonstrated a primary grade II atypical meningioma with focal brain invasion (Fig. 1B) and epithelial membrane antigen (EMA) and progesterone receptor (PR) positivity. Targeted sequencing revealed an IDH1 p.Arg132His alteration (10.5%, 334x). However, IDH1 R132H immunohistochemistry was negative. In order to provide orthogonal validation for the G395A mutation in the IDH1 gene, which results in a missense Arg to His mutation, we designed targeted primers to amplify this region as part of a targeted 250 bp amplicon where the G395A mutation in IDH1 is centered with upand downstream flanks (hg19; chr2:209112972-209113205). Two hundred fifty nanograms of amplified DNA was used as input into library prep for downstream single molecule, real-time sequencing on the RSII platform (Pacific Biosciences). Following raw data collection, highly accurate (>99.9%) circular consensus sequences (CCS) were generated using web-based SMRTLink 7.0 bioinformatics suite in order to call single nucleotide polymorphism variants. A total of 50 497 CCS reads were generated, with 362 (0.7%) distinct molecules validating the G395A variant of interest at QV40. Case 2 is from a 37-year-old woman with a preoperative MRI that revealed a left frontal mass measuring 5.4 × 7.5 × 6.9 cm. Histopathologic evaluation demonstrated a recurrent grade III anaplastic meningioma (papillary) with focal brain invasion and applyparastyle "fig//caption/p[1]" parastyle "FigCapt" applyparastyle "fig" parastyle "Figure"