tbuckley/cabot-search huggingface dataset:
EXTH-66. NEO100 TRANSIENTLY OPENS UP THE BLOOD BRAIN BARRIER VIA TIGHT JUNCTION INHIBITION
Authors: Thomas Chen, Weijun Wang, Nagore Marin Ramos, Axel Schonthal
Journal: Neuro-Oncology (2020)

Abstract The blood brain barrier (BBB) prevents effective entry of nearly all therapeutics to the central nervous system (CNS), preventing effective treatment of brain-related malignancies. Intracarotid mannitol injection has been the main technique to transiently open up the BBB, with its attendant variability and complications. A more direct and better tolerated method is needed to open up the BBB. We present our discovery that intraarterial (IA) injection of NEO100, a cGMP-quality form of perillyl alcohol (POH), transiently opens up the BBB in a safe and reversible manner. We used in-vitro models of MDCK1 and patient derived brain endothelial cell (BEC) + astrocyte barriers to determine that NEO100 increased FITC-antibody diffusion across the in-vitro BBB model and decreased trans-epithelial/endothelial electrical resistance (TEER). NEO100 effects on transcellular and paracellular pathways were studied using western blot, flow cytometry, HPLC, fluorescent probes, microarray analysis, and transmission electron microscopy. In-vivo studies were performed using ultrasound-guided intracardiac administration of NEO100 in mice with subsequent intravenous delivery of non-BBB permeable therapeutic agents. We determined that NEO100 transiently disrupts the transcellular pathway by permeabilizing BEC membranes, and the paracellular pathway via delocalization of tight junction proteins. In vivo IA NEO100 administration caused an effective dose- and time-dependent BBB permeabilization, which was reversible and well tolerated by the mice. This was evidenced by the spreading of Evans blue dye, and of therapeutics with different molecular weights, ie methotrexate, anti-PD-1 antibody, and CAR-T cells in the brain. Our results demonstrate that IA NEO100 is able to open the BBB in a controlled and reversible manner, allowing it to facilitate drug delivery to the CNS.
NCMP-05. DECODING THE IMMUNE SYSTEM RESPONSE TO LEPTOMENINGEAL METASTASIS
Authors: Jan Remsik, Xinran Tong, Ugur Sener, Danille Isakov, Yudan Chi, Christine Iacobuzio-Donahue, Dana Pe’er, Andrea Schietinger, Adrienne Boire
Journal: Neuro-Oncology (2020)

Abstract For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle’ state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient’s own immune system into an active weapon against pathogens and cancer.
QOL-54. HEIGHT, WEIGHT AND CARDIOVASCULAR EFFECTS OF STIMULANTS ON CHILDREN WITH BRAIN TUMOR
Authors: Raja Khan, Maha Bano, Igal Mirman, Fang Wang, Pan Haitao, Jessica Smith, Simmons Andrea, William Greene, Anthony Christensen, Zsila Sadighi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Children with brain tumors may develop inattention, slow processing, and hypersomnia. Stimulant medications improve these problems but their effect on growth, heart rate, and blood pressure are inadequately explored. METHODS We retrospectively studied children with brain tumors treated at our institution that had data available for one-year pre and two year post stimulant treatment. Tumor location, gender, radiation treatment (RT), age at RT, drug type, and hormone therapy were variables of interest. RESULTS We identified 65 children (35 males) that fulfilled eligibility criteria. Focal RT was utilized in 58; 11 additionally received whole brain RT. Thirty were treated for hypersomnia and inattention, 8 for hypersomnia alone, and rest for inattention. Modafinil was the first drug in 18 (27.7%) and methylphenidate in the others. Forty-seven (72.3%), 40 (61.5%) and 49 (75.4%) were on thyroxine, cortisone and growth hormone respectively. There was no difference in pre and post stimulant BMI, heart rate, and blood pressure. There was also no difference between modafinil and methylphenidate groups. Rate of increase in height slowed on stimulants (p=0.0096). Thyroxine treatment correlated with increase in BMI after stimulants (p=0.0434). Younger age (p=0.0003) and higher BMI (p=0.0063) pre stimulants correlated with increased heart rate on stimulants, while higher age at RT (0.0159) correlated with elevated systolic BP on stimulants. No association of studied variables was found with height and diastolic BP. CONCLUSION Stimulants are well tolerated by children with brain tumors that are appropriately managed for endocrine deficiencies but may reduce the trajectory of height attainment.
Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial
Authors: Wendy A. Cooper, Annabelle Mahar, Jeffrey L. Myers, Christopher Grainge, Tamera J. Corte, Jonathan P. Williamson, Michael P. Vallely, Simon Lai, Ellie Mulyadi, Paul J. Torzillo, Martin J. Phillips, Edmund M. T. Lau, Ganesh Raghu, Lauren K. Troy
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).
Abstract 14363: Clustering of Multiple Cardiometabolic Risk Factors by Race/Ethnicity and Age
Authors: Olivia P Kizzee, Joan C Lo
Journal: Circulation (2020)

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among Americans. The burden of cardiometabolic risk factor clustering in ethnic subgroups is not well described for US Asians compared to other race/ethnicities. Methods: This cross-sectional study was conducted using electronic health data for White (N=634,200), Black (N=85,156), Hispanic (N=188,071), Filipino (N=78,000) and Chinese (N=72,545) Kaiser Permanente Northern California health plan members in 2016 who were aged 40-84y and had weight status assessed. We examined the proportions of men and women in each racial/ethnic group with clustered cardiometabolic risks (CCR), defined as having diabetes, hypertension, and obesity. Diabetes mellitus (DM) was based on a clinical DM diagnosis, lab criteria, or receipt of DM pharmacotherapy. Hypertension was defined by clinical diagnosis. Obesity was characterized by WHO standard (BMI ≥30 kg/m 2 ) and Asian-specific (BMI ≥27.5 kg/m 2 ) thresholds. Results: CCR prevalence varied by race/ethnicity, age, and the BMI criteria used for obesity (standard or Asian threshold). Use of the Asian threshold resulted in Filipinos having CCR prevalence that approached Blacks and Hispanics across all age groups (Figure). The Asian criterion nearly doubled the proportion of at-risk Filipinos, particularly older adults aged 65-84y. Filipinos had more than 2x higher CCR prevalence compared to Chinese. Among all ethnic groups except for Blacks, men were more likely than women to have CCR. Conclusion: Using an Asian-specific BMI obesity threshold, Filipino-Americans have a higher prevalence of cardiometabolic risk factor clustering than Chinese-Americans, resembling that of Blacks and Hispanics. Identifying Asian ethnicity in electronic health records could help facilitate earlier metabolic assessment and management to further reduce CVD burden, which may be especially important for men.
A Randomized Clinical Trial Assessing Continuous Glucose Monitoring (CGM) Use With Standardized Education With or Without a Family Behavioral Intervention Compared With Fingerstick Blood Glucose Monitoring in Very Young Children With Type 1 Diabetes
Authors: Lori Laffel, Kara Harrington, Anat Hanono, Nisha Naik, Louise Ambler-Osborn, Alan Schultz, Linda DiMeglio, Stephanie Woerne, Heather Jolivette, Heba Ismail, Megan Tebbe, America Newman, Megan Legge, William Tamborlane, Michelle Van Name, Kate Weyman, Jennifer Finnegan, Amy Steffen, Melinda Zgorski, Daniel DeSalvo, Marisa Hilliard, Kylie DeLaO, Cicilyn Xie, Wendy Levy, R. Paul Wadwa, Greg Forlenza, Shideh Majidi, Guy Alonso, Isabel Weber, Michelle Clay, Emily Simmons, Brandon Nathan, Muna Sunni, Jessica Sweet, Beth Pappenfus, Anne Kogler, Marrissa Ludwig, Brittney Nelson, Anne Street, Darcy Weingartner, Anastasia Albanese-O’Neill, Michael Haller, Janey Adams, Miriam Cintron, Nicole Thomas, Jennifer Kelley, Jill Simmons, George William, Faith Brendle, Robin Goland, Kristen Williams, Rachelle Gandica, Sarah Pollak, Emily Casciano, Elizabeth Robinson, Steven Willi, Pantea Minnock, Diana Olivos, Cathy Carchidi, Brian Grant, Jenise C. Wong, Saleh Adi, Sarah Corathers, Nicole Sheanon, Cathy Fox, Tammy Weis, Sarah MacLeish, Jamie Wood, Terri Casey, Wendy Campbell, Paul McGuigan, Kupper Wintergerst, Sara Watson, Suzanne Kingery, Gwen Pierce, Heather Ruch, Lauren Rayborn, Manuel Rodriguez-Luna, Amy Deuser
Journal: Diabetes Care (2020)

This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to <8 years with type 1 diabetes.This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to <8 years of age with type 1 diabetes. Primary analysis included treatment group comparisons of percent time in range (TIR) (70-180 mg/dL) across follow-up visits.Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI -0.5, 7.0), Standard-CGM vs. BGM 0.5% (-2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (-0.6, 6.1). Mean time with glucose level <70 mg/dL was reduced from baseline to follow-up in the CGM+FBI (from 5.2% to 2.6%) and Standard-CGM (5.8% to 2.5%) groups, compared with 5.4% to 5.8% with BGM (CGM+FBI vs. BGM, P < 0.001, and Standard-CGM vs. BGM, P < 0.001). No severe hypoglycemic events occurred in the CGM+FBI group, one occurred in the Standard-CGM group, and five occurred in the BGM group. CGM+FBI parents reported greater reductions in diabetes burden and fear of hypoglycemia compared with Standard-CGM (P = 0.008 and 0.04) and BGM (P = 0.02 and 0.002).CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.
Prevalence and Prognostic Significance of Mitral Regurgitation in Acute Decompensated Heart Failure
Authors: Sameer Arora, Krishan Sivaraj, Michael Hendrickson, Patricia P Chang, Thelsa Weickert, Arman Qamar, Muthiah Vaduganathan, Melissa C Caughey, Ambarish Pandey, Matthew A Cavender, Wayne Rosamond, John P Vavalle
Journal: JACC Heart Failure (2020)
Calling for pan-European commitment for rapid and sustained reduction in SARS-CoV-2 infections
Authors: Viola Priesemann, Melanie M Brinkmann, Sandra Ciesek, Sarah Cuschieri, Thomas Czypionka, Giulia Giordano, Deepti Gurdasani, Claudia Hanson, Niel Hens, Emil Iftekhar, Michelle Kelly-Irving, Peter Klimek, Mirjam Kretzschmar, Andreas Peichl, Matjaž Perc, Francesco Sannino, Eva Schernhammer, Alexander Schmidt, Anthony Staines, Ewa Szczurek
Journal: The Lancet (2020)
RARE-42. PRIMARY INTRACRANIAL SARCOMA WITH <i>DICER1</i>-MUTATION - TREATMENT RESULTS OF A NEW MOLECULAR ENTITY
Authors: Rosdali Diaz, Martin Mynarek, Sandro Casavilca, Antonio Wachtel Aptomizer, Pamela Mora, Christian Koelsche, Andreas Von Deimling, Ulrich Schüller, Raymundo Sernaque, Gustavo Sarria, Tatiana Negreiros, Luis Ojeda, Pamela Garcia-Corrochano, Danny Campos, Jimena Ponce, Stefan Rutkowski, Juan Garcia
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE An unexpectedly high incidence of sarcomas of the Central Nervous System (SCNS) was recently observed in Peru. We describe clinical and biological characteristics of the disease. METHODS Seventy pediatric patients with primary SCNS diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling and gene panel sequencing was available from 28 and 27 tumors, respectively. RESULTS Median age was 6 years (range 2–17.5), 66/70 patients had supratentorial tumors, 56 patients intratumoral hemorrhage at diagnosis. Three patients fulfilled clinical criteria of NF1; 35 had café-au-lait spots and/or freckling. DNA-methylation profiling classified 28/28 as “intracranial spindle cell sarcoma with rhabdomyosarcoma-like features and DICER1 mutations”. DICER1 mutations were found in 26/27, TP53 mutations in 22/27, and RAS-pathway gene mutations (NF1, KRAS, NRAS) in 19/27 tumors, all of which were somatic (germline control available in n=19 cases). Survival was analyzed in 57 patients with non-metastatic disease who received adjuvant therapy. Two patients had metastatic disease, eleven did not receive or abandoned treatment. Two-year OS was 66.3% (95%-CI: 54–81%), 2-year PFS 51% (38–67%). PFS was highest in patients treated with postoperative ICE chemotherapy followed by radiotherapy and ICE (2y-EFS 79% [59–100%], n=18) and worse after upfront radiotherapy followed by ICE (40% [19–85%]; n=10) or VAC (50% [28–88%], n=12) and radiotherapy only (21% [6–71%], n=11; p=0.008). CONCLUSION Primary SCNS with DICER1 mutation have an aggressive clinical course. A combination of chemotherapy and radiotherapy seems beneficial. A link to a cancer predisposition syndrome could not be established so far.
Abstract 3456: Assessment of Genetic Risk for Hypertriglyceridemia
Authors: Kimihiko Kato, Mitsutoshi Oguri, Tetsuro Yoshida, Takeshi Hibino, Kazuhiro Yajima, Tetsuo Fujimaki, Kiyoshi Yokoi, Hitoshi Matsuo, Shunichiro Warita, Tomonori Segawa, Sachiro Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Yukitoshi Aoyagi, Akitomo Yasunaga, Hyuntae Park, Masashi Tanaka, Yoshinori Nozawa, Sahoko Ichihara, Yoshiji Yamada
Journal: Circulation (2007)

Introduction. Hypertriglyceridemia is an important risk factor for coronary heart disease. The purpose of the present study was to identify gene polymorphisms associated with hypertriglyceridemia (serum triglyceride concentration, ≥1.65 mmol/L) for assessment of the genetic risk for this condition. Methods. A total of 5206 individuals from two independent populations was examined: Subject panel A comprised 3787 individuals who either visited outpatient clinics of or were admitted to the participating hospitals because of various symptoms or for a health checkup; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Given the multiple comparisons of genotypes with hypertriglyceridemia, we adopted the criterion of a false discovery rate (FDR) of &lt;0.05 for significant association in initial screening with the chi-square test. Results. Evaluation of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that seven polymorphisms [−1131T→ C, −3A→G, and 553G→T (Gly185Cys) of APOA5 ; 1100C→T of APOC3 ; 85T→C of APOA1 ; 41A→G (Glu14Gly) of ACAT2 ; C→G (Ser47Stop) of LPL ] were significantly (FDR &lt; 0.05) associated with hypertriglyceridemia in subject panel A. To validate these associations, we examined the same polymorphisms in subject panel B. The six polymorphisms of APOA5 , APOC3 , APOA1 , and LPL , but not that of ACAT2 , were again significantly associated with hypertriglyceridemia. Serum triglyceride concentrations differed significantly ( P&lt; 0.05, ANOVA) among genotypes of each of these six polymorphisms in both subject panels. The three polymorphisms of APOA5 were in linkage disequilibrium. Conclusions. Polymorphisms of APOA5 , APOC3 , APOA1 , and LPL are determinants of hypertriglyceridemia. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for hypertriglyceridemia and may contribute to the personalized prevention of this condition.
RADT-13. EARLY CONCURRENT IMMUNOTHERAPY WITH STEREOTACTIC RADIOSURGERY IS ASSOCIATED WITH PROLONGED SURVIVAL AND DECREASED DISTANT BRAIN FAILURE IN PATIENTS WITH NEWLY DIAGNOSED MELANOMA BRAIN METASTASES (MBM)
Authors: Alexander Augustyn, Roshal Patel, Ethan Ludmir, Lauren Haydu, Nandita Guha-Thakurta, Andrew Bishop, Caroline Chung, Amol Ghia, Mary Frances McAleer, Susan McGovern, Chenyang Wang, Kristina Woodhouse, Debra Yeboa, Sherise Ferguson, Betty Kim, Isabella Glitza, Jing Li
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We evaluated outcomes of patients with newly diagnosed MBM treated with concurrent immune checkpoint inhibition (ICI) and stereotactic radiosurgery (SRS) (concurrentTx), defined as treatment delivery within 30 days of each other. METHODS Screening of 2,617 melanoma patients who received ICI (anti-CTLA4/anti-PD1/both) between 2011-2019 identified 151 pts who received concurrentTx for MBM. Among these, 51 had newly-diagnosed MBM and received no prior ICI or SRS, and were included in the current study. Overall survival (OS) and distant brain failure (DBF) were estimated using the Kaplan-Meier method. Incidence of radiation necrosis (RN) was captured. RESULTS Median follow up from treatment initiation (either ICI or SRS, whichever occurred first) was 37 months. Median OS was 30 months. Median interval between ICI/SRS was 12 days (range: 1-29). Twenty-two patients received ICI first and 29 received SRS first, without differences in OS (p=0.22), DBF (p=0.91), or development of RN (p=0.86). However, the interval between ICI and SRS was significant. Patients who received concurrentTx 1-11 days apart (n=25, “early”) experienced a significant improvement in OS and DBF compared to 12-29 days apart (n=26, “delayed”) (p=0.01, HR 2.8; 95%CI 1.3-6.2 for OS and p=0.02, HR 2.5; 95%CI 1.2-5.6 for DBF). OS and DBF at 36 months were 67% vs. 26% and 60% vs. 27%, respectively, for the early vs. delayed groups. Time to concurrentTx as a continuous variable was significantly associated with DBF (p=0.02), but not OS (p=0.06). Although not significant, more patients developed RN in the early (26.0%) versus delayed (3.8%) group (p=0.07). No additional patient or treatment differences were identified. CONCLUSIONS Early concurrentTx was associated with prolonged OS and improved DBF in newly diagnosed MBM patients who did not receive prior CNS-directed therapy. This finding suggests therapeutic synergism related to combined early treatment and should be validated in a prospective clinical trial.
Spondylitis as a Rare Manifestation of Granulomatosis With Polyangiitis
Authors: Matthias H. Busch, Joop P. Aendekerk, Astrid M. L. Oude Lashof, Pieter van Paassen
Journal: Arthritis & Rheumatology (2020)

The patient, a 62-year old woman who had a known disc herniation in 2005, was admitted to the tertiary care center for lumbar spondylitis (at L2–L3) with epidural involvement seen on magnetic resonance imaging (MRI) (A). An infectious cause was suspected, and with empirical antibiotic treatment, clinical and imaging features improved. Three weeks after finishing antibiotic treatment, the patient was readmitted due to increasing pain. MRI showed progressive spondylitis with epidural abscess formation (B). Furthermore, the radiologist noted the intact intervertebral L2–L3 disc (arrows in A and B), which is considered a typical finding for tuberculous spondylitis (1). Fluorodeoxyglucose–positron emission tomography/computed tomography revealed a cavitating lung lesion (arrow in C). Blood, lung, and tissue cultures, polymerase chain reaction, tuberculosis (TB) skin test, and interferon-γ release test results were negative. Tissue biopsy at L2–L3 showed early necrotizing granulomatous inflammation with abundant infiltration of neutrophils (white arrow in D) and histiocytes (black arrow in D). Based on these findings, TB treatment was preemptively initiated while mycobacterial cultures were still pending. The patient’s condition appeared to stabilize, but 3 weeks later she was readmitted with peripheral polyneuropathy, most likely due to tuberculostatic toxicity. Mycobacterial cultures were negative, but caudal compression had worsened (E). Additional testing was positive for antineutrophil cytoplasmic antibodies against proteinase 3 (PR3-ANCAs) (38 IU/ml [normal <2]). Necrotizing granulomatous inflammation and PR3-ANCA positivity are hallmarks of granulomatosis with polyangiitis (GPA) (2). ANCA positivity can also occur in TB (3), but without any evidence of active TB, GPA was diagnosed. Treatment with methylprednisolone (1,000 mg/day for 3 days), followed by oral prednisone in tapering doses and cyclophosphamide (2–3 mg/kg/day) was initiated; treatment was switched to azathioprine (3 mg/kg/day) after 3 months. Symptoms improved, PR3-ANCA was no longer present, and imaging showed marked improvement with minimal residual radiologic abnormalities of L3 and the L2–L3 disc (F). Though extremely rare, this case illustrates that inflammatory spondylitis can be a manifestation of GPA. We thank Dr. Myrurgia Abdul Hamid for the histopathologic images.