Individual Histologic Features Research Articles

Urinary biomarkers associated with pathogenic pathways reflecting histological findings in lupus nephritis.

There is a pressing need to understand the pathogenesis of histological findings and identify the biomarkers for predicting the histological severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histological findings in LN. Urine samples from patients with biopsy-proven active LN were screened for 1305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histological features in LN were quantified to identify the urinary proteins associated with the histological findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localisation of the candidate proteins. Cluster analysis extracted five histological subgroups according to their correlations with each histological finding in LN. Protein groups which correlated with each histological subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), MCP-1, and IGFBP-5 levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localisation of these proteins in each lesion. Renal histological findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histological findings in LN.

Understanding interobserver variability of pathologists to improve oral epithelial dysplasia grading.

This study aimed to understand reasons for interobserver variability in the grading of oral epithelial dysplasia (OED) through a survey of pathologists to provide insight for improvements in the reliability and reproducibility of OED diagnoses. The study design included quantitative and qualitative methodology. A pre-validated 31-item questionnaire was distributed to general, head and neck, and oral and maxillofacial histopathology specialists worldwide. A total of 132 pathologists participated and completed the questionnaire. Over two-thirds used the three-tier grading system for OED, while about a third used both binary and three-tier systems. Regular reporters of OED preferred the three-tier system and grading architectural features. Continuing education significantly aided recognition of architectural and cytological changes. Irregular epithelial stratification and drop-shaped rete ridges had the lowest prognostic value and recognition scores, while loss of epithelial cell cohesion had the highest. Most participants used clinical information and often sought a second opinion when grading OED. Our study has found that frequency of OED reporting and attendance of CME/CPD can play an important role in grading OED. Variations in the prognostic value of individual histological features and the use of clinical information may further contribute to interobserver variability.

Impact of Cutaneous Squamous Cell Carcinoma Histologic Features on Percent Interrater Agreement Regarding Tumor Differentiation.

Poor differentiation predicts adverse outcomes in cutaneous squamous cell carcinoma (CSCC), but there is no standardized, reliable grading system. To explore which histologic features have the greatest impact on CSCC differentiation interrater agreement. In a prior study, 40 raters graded differentiation for 45 squamous cell carcinomas, and percent interrater agreements were calculated. Cases graded as well/moderately differentiated with 100% agreement (10), those graded as poorly differentiated with ≥80% agreement (5), and those that received a variety of grades with ≤60% agreement (7) were pulled for the current study. Three raters graded individual histologic features for each case, and percent interrater agreements were calculated using both the well/moderately/poorly differentiated grading system and a dichotomized system. The percent interrater agreements were 34.8% for mitoses, 53% for pleomorphism, 59.1% for keratinization, 66.7% for cellular cohesion/intercellular bridges, and 78.8% for tumor edges. Percent agreements improved with dichotomous grading; the largest improvement was seen within the group of cases that had been graded as well/moderately differentiated with 100% agreement in the prior study. Future squamous cell carcinoma differentiation grading systems would benefit from eliminating mitotic rate, clearly defining how to grade other features, and dichotomous grading.

Abstract PO1-07-01: Artificial intelligence-based prediction of Oncotype DX Score from whole slide images using human-interpretable features and breast biomarkers

Abstract Background The Oncotype DX Breast Recurrence Score assay (ODX) is a commonly used genomic test for patients with estrogen receptor (ER)-positive, HER2-negative, early-stage invasive breast cancer. While ODX predicts patients’ recurrence risk and benefit from chemotherapy, it is tissue and time-consuming, and expensive. Previous deep-learning or non-linear ODX prediction models achieved promising performance using whole-slide images (WSI) or with other covariates (e.g., ER, progesterone receptor (PR), HER-2, Ki-67 scores and tumor stage) but systematic quantification of the contribution of individual histological features to the ODX score remained challenging. Here, we extracted a rich set of human-interpretable features (HIFs) quantifying nuclear morphology and the distribution of cells and tissues in the tumor microenvironment. We used these HIFs, along with manually assessed ER, PR, HER-2 scores, and tumor stage, to predict ODX scores. We also explored the role of Ki-67 features in augmenting our model predictions Methods We developed machine learning models to extract cell, tissue, and nuclear HIFs from WSI stained with hematoxylin and eosin (H&E) and immunohistochemistry (IHC) against Ki-67. These models were deployed on 353 H&E WSI to extract 276 HIFs quantifying cell densities, tissue areas, relative cell counts, and nuclei size, shape and color. Hierarchical agglomerative clustering was applied to cluster these features into 11 groups. Univariate regression was performed to identify correlations between ODX scores and feature clusters. To predict ODX score using HIFs, a multivariable regression model was fitted to the data where regressors are representative features from each cluster, in addition to ER, PR, HER-2 scores and stage as covariates. The model was fitted on the training set (N=266 slides) and evaluated on the held-out test set (N=87 slides). To examine the utility of Ki-67 IHC features in ODX prediction, a Ki-67 model was deployed on a subset of 194 matched Ki-67 IHC WSI to extract count proportions and densities of Ki-67 positive cells in cancer epithelium and stroma. Results Significant positive correlations were identified between ODX scores and feature clusters corresponding to cancer cell density (p < 10-7), macrophage density (p < 10-4), immune cell density (p < 10-16), and variations in cancer nuclear size (p < 10-5) and color (p < 10-3). Significant negative correlations were observed between ODX scores and clusters related to fibroblast density (p < 10-3), and variations of non-cancer cell nuclear color (p = 0.02). Evaluation of our model’s ability to predict ODX scores revealed an association between predicted and observed scores (Pearson r = 0.74). The AUROC for model predictions of high/low classifications (with reference to a cutoff ODX score of 20) was 0.80. Ki-67 features were clustered together with H&E cancer cell density features and showed a stronger correlation with ODX scores compared to the H&E features alone. Combining Ki-67 cell density features with H&E features led to increased performance of the multivariable regression model on the test set compared to H&E features only (r = 0.62 vs. r = 0.59). However, a model combining Ki-67, H&E and covariates performed similarly to a model with H&E and covariates (r = 0.73), suggesting that Ki-67 features may not be needed for ODX prediction when H&E and covariate information is available. Conclusions Our model predicts ODX recurrence scores with comparable performance to other black-box approaches using WSI and breast biomarker status and without the need for, Ki-67 features. Using readily available information, our model has the potential to be a convenient screening tool for patient stratification, which may lead to better patient care, lower costs, and faster treatment. Citation Format: Nhat Le, John Van Arnam, Christian Kirkup, Ylaine Gerardin, Michael Drage, Neha Khaitan, Anurag Sharma, Georgi Galev, Nicholas Indorf, Emily Sansevere, Ilan Wapinski, Stephanie Hennek, Gloria Zhang. Artificial intelligence-based prediction of Oncotype DX Score from whole slide images using human-interpretable features and breast biomarkers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-07-01.

Nutrition assessment and MASH severity in children using the Healthy Eating Index.

Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD. Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components. In all, 119 children were included (13.3 ± 2.7y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04). In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.

Naturally acquired equine parvovirus-hepatitis is associated with a wide range of hepatic lesions in horses.

Equine parvovirus-hepatitis (EqPV-H) is the causative agent of Theiler's disease, or severe acute hepatic necrosis, in horses. However, it is poorly understood whether EqPV-H is associated with other histologic findings in horses with clinical liver disease. The objective of this study was to examine the prevalence and severity of EqPV-H infections in diagnostic liver samples. Archived formalin-fixed, paraffin-embedded (FFPE) liver samples (n = 98) from Cornell University and University of California, Davis, collected between 2007 and 2022 were evaluated for 15 individual histologic features and by EqPV-H in situ hybridization. EqPV-H was detected in 48% (n = 47) of samples. The most common histologic features of EqPV-H-positive samples included individual hepatocyte death (n = 40, 85%), lobular infiltrates (n = 38, 80%), portal infiltrates (n = 35, 74%), and ductular reaction (n = 33, 70%). Centrilobular necrosis, portal infiltrate, and individual hepatocyte death were positively associated with high viral load. Neutrophil infiltrates, bridging fibrosis, and portal edema were negatively associated with a high viral load. Only 4 of 49 tested samples were positive for equine hepacivirus by polymerase chain reaction (PCR), but the PCR assay was unreliable for FFPE tissues. In summary, this study demonstrates that EqPV-H is common in a variety of liver pathologies and should be considered as a differential diagnosis in cases of hepatitis other than Theiler's disease.

Architectural and cytological features of epithelial dysplasia associated with transformation risk.

This study explored associations between histological features of dysplasia and malignant transformation, as well as genomic copy number alterations. Overall, 201 samples were collected from patients of oral leukoplakia. The associations of dysplastic features with malignant transformation and copy number alterations were investigated by Cox proportional hazards regression analysis and the Mann-Whitney U-test. Eight individual histological features, such as irregular epithelial stratification (p = 0.001), mitoses high in epithelium (p = 0.033), extension of changes along minor gland ducts (p < 0.001), etc., were associated with greater risk of malignant transformation. A model including histological features and age showed good performance for predicting malignant transformation (area under receiver operating characteristic curve: 0.806). Irregular epithelial stratification (p = 0.007), abnormal nuclear shape (p = 0.005), abnormal cell size (p = 0.004), etc. were associated with greater genomic instability. A Cox proportional hazards model using eight histological features and patient age reliably predicted the malignant potential of oral epithelial dysplasia. Identification of these histological features closely related to malignant transformation may aid the management of oral potentially malignant disorders and early detection of oral squamous cell carcinoma.

Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review.

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation. In the United States alone, annual medical costs are approximately 100 billion dollars. Unfortunately, there is no Federal Drug Administration (FDA)-approved medication for its treatment. However, various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD. It is valuable to have a compilation of the data available on their efficacy. To assess the efficacy of cyclophilin inhibitors, fibroblast growth factor 21 analogs (FGF21), and dual and pan peroxisome proliferator-activated receptor (PPAR) agonists for treating NAFLD. A comprehensive literature search using keywords including cyclophilin inhibitor, FGF agonist, pan-PPAR agonists, dual-PPAR agonist, NAFLD, non-alcoholic steatohepatitis, and fatty liver was conducted on October 29, 2022, in PubMed, EMBASE, Cochrane Library, Scopus and Web of Science. Animal and human research, case reports, and published articles in English from all countries with patients aged 18 and above were included. Only articles with a National Institutes of Health (NIH) Quality Assessment score of five or higher out of eight points were included. Articles that were narrative or systematic reviews, abstracts, not in English, focused on patients under 18 years old, did not measure outcomes of interest, were inaccessible, or had a low NIH Quality Assessment score were excluded. Each article was screened by two independent researchers evaluating relevance and quality. Resources were scored based on the NIH Quality Assessment Score; then, pertinent data was extracted in a spreadsheet and descriptively analyzed. Of the 681 records screened, 29 met the necessary criteria and were included in this review. These records included 12 human studies and 17 animal studies. Specifically, there were four studies on cyclophilin inhibitors, four on FGF agonists/analogs, eleven on pan-PPAR agonists, and ten on dual-PPAR agonists. Different investigational products were assessed: The most common cyclophilin inhibitor was NV556; FGF agonists and analogs was Efruxifermin; pan-PPAR agonists was Lanifibranor; and dual-PPAR agonists was Saroglitazar. All classes were found to be statistically efficacious for the treatment of NAFLD, with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan (P < 0.05). The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes, as well as good safety profiles (P < 0.05). We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.

The role of histology in the diagnosis of non-erosive reflux disease: A systematic review and meta-analysis.

Non-erosive reflux disease (NERD) accounts for over half of all gastroesophageal reflux cases and is characterized by reflux symptoms with pathologic acid exposure on pH monitoring but no evidence of erosions on upper endoscopy. Ambulatory pH monitoring is limited by availability and patient tolerance. The utility of performing esophageal mucosal biopsies in diagnosing NERD is unclear. We conducted a systematic review and meta-analysis to determine the sensitivity of esophageal mucosal biopsies in diagnosing NERD. Data were obtained from Embase and Ovid MEDLINE from inception to April 2021. Studies were included if esophageal mucosal biopsies were taken and analyzed using conventional histopathologic analysis in symptomatic NERD patients. Relevant data was including histologic abnormalities and location of the biopsy. Sensitivity and specificity were calculated against healthy controls or those with functional heartburn. The search yielded 2871 studies, of which 10 studies met our inclusion criteria and contained raw data. Histological abnormalities included histologic sum scores, papillary elongation, basal cell hyperplasia, and dilated intraepithelial spaces. When assessing for the presence of any abnormality, biopsies taken <3 cm from the lower esophageal sphincter (LES) had a pooled sensitivity of 0.71 (95% CI 0.64-0.77) and specificity of 0.64 (95% 0.54-0.73); however, analysis of individual histologic features such as the presence of eosinophils improved the sensitivity. Although esophageal mucosal biopsies had poor sensitivity at diagnosing NERD, biopsies taken within 3 cm of the LES had higher sensitivity when pathologists reported upon eosinophils and dilated intraepithelial spaces.

Density of Biopsy Sampling Required to Ensure Accurate Histological Assessment of Inflammation in Active Ulcerative Colitis.

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. 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. 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. 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.

Prediction of malignant transformation and recurrence of oral epithelial dysplasia using architectural and cytological feature specific prognostic models

AbstractOral epithelial dysplasia (OED) is a precursor state usually preceding oral squamous cell carcinoma (OSCC). Histological grading is the current gold standard for OED prognostication but is subjective and variable with unreliable outcome prediction. We explore if individual OED histological features can be used to develop and evaluate prognostic models for malignant transformation and recurrence prediction. Digitised tissue slides for a cohort of 109 OED cases were reviewed by three expert pathologists, where the prevalence and agreement of architectural and cytological histological features was assessed and association with clinical outcomes analysed using Cox proportional hazards regression and Kaplan–Meier curves. Within the cohort, the most prevalent features were basal cell hyperplasia (72%) and irregular surface keratin (60%), and least common were verrucous surface (26%), loss of epithelial cohesion (30%), lymphocytic band and dyskeratosis (34%). Several features were significant for transformation (p < 0.036) and recurrence (p < 0.015) including bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses and nuclear pleomorphism. This led us to propose two prognostic scoring systems including a ‘6-point model' using the six features showing a greater statistical association with transformation and recurrence (bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses, nuclear pleomorphism) and a ‘two-point model' using the two features with highest inter-pathologist agreement (loss of epithelial cohesion and bulbous rete pegs). Both the ‘six point' and ‘two point' models showed good predictive ability (AUROC ≥ 0.774 for transformation and 0.726 for recurrence) with further improvement when age, gender and histological grade were added. These results demonstrate a correlation between individual OED histological features and prognosis for the first time. The proposed models have the potential to simplify OED grading and aid patient management. Validation on larger multicentre cohorts with prospective analysis is needed to establish their usefulness in clinical practice.

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness.

Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. We collected cross-sectional, clinical data including liver biopsies from a derivation ( n = 48) and a validation cohort ( n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84-0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77-0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning ( p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

Low skeletal muscle mass is associated with more severe histological features of non-alcoholic fatty liver disease in male.

Although low skeletal muscle mass is associated with non-alcoholic fatty liver disease (NAFLD), it is currently uncertain whether there are associations between weight-adjusted appendicular skeletal muscle (ASM%), severity of histological features of NAFLD, and the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. Our aim was to test for a possible influence of the PNPLA3 rs738409 variant on the association between ASM% and severity of NAFLD histological features. We enrolled 401 Chinese male with biopsy-proven NAFLD. Using a bioelectrical-impedance body composition analyzer (BIA, Inbody 720, Japan Inc., Tokyo), we calculated the ASM% as the percentage of total appendicular skeletal muscle mass (ASM, kg)/total body mass (kg) × 100. Compared to those with high ASM%, patients with low ASM% (≤ 30.6, i.e., the median value of distribution of the whole sample) had a greater severity of individual histological features of NAFLD. These patients also had a higher risk of severe steatosis and non-alcoholic steatohepatitis (NASH) (adjusted-odds ratio [OR] 2.34, 95% CI 1.39-3.93, and adjusted-OR 2.22, 95% CI 1.30-3.77) even after adjusting for age, body mass index, diabetes, and serum creatinine levels. Carriage of the G allele of PNPLA3 rs738409 plus low ASM% was associated with a higher risk of severe steatosis and presence of liver fibrosis (OR 3.02, 95% CI 1.46-6.26, p = 0.003 and OR 2.18, 95% CI 1.03-4.60, p = 0.041 respectively), and there was a non-significant but borderline increased risk of NASH (OR 2.00, 95% CI 0.98-4.06, p = 0.056). Low ASM% and the presence of a G allele within PNPLA3 rs738409 is associated with more severe histological features of NAFLD.

Coexisting Histopathological Features in Oral Leukoplakia, Quid Induced Lichenoid Lesions and Oral Submucous Fibrosis - An Analysis

Background Oral submucous fibrosis OSMF quid-induced lichenoid lesions QILL and leukoplakia show characteristic individual histological features. However all the three lesions are caused by quid chewing. There is a possibility that these lesions may occur together in the same patient. But sometimes there may be no clinical evidence of concomitant lesions with changes being seen at histopathological level.Aim To determine the presence of concurrent histopathological features in oral leukoplakia OSMF and QILL.Method A retrospective analysis of hematoxylin and eosin-stained slides of OSMF n 60 QILL n 20 and leukoplakia n 60 was done. Slides were analysed for the presence of lichenoid features in OSMF and leukoplakia. Fibrosis was searched for in lichenoid reaction and leukoplakia.Results Fifteen cases 25 of OSMF revealed histopathological features of lichenoid reaction. Eight 40 cases of QILL and two cases 3.3 of leukoplakia revealed the presence of fibrosis in the connective tissue. Ten cases 16.6 of leukoplakia revealed the presence of lichenoid reaction. Lichenoid features included subepithelial band of inflammatory cells basal cell degeneration and reduplication of basement membrane. All cases were associated with some form of betel quid chewing.Conclusion This study aimed to highlight the possibility of overlapping histopathological features of three different lesions despite the clinical presence of only one lesion. This may suggest the initiation of a second disease process. Since all the three lesions have a malignant potential these concurrent features may aid in prevention and adequate diagnosis.nbsp

Treatment-resistant actinic keratoses are characterized by distinct clinical and histological features.

Actinic keratoses (AK) are generally treated to reduce the risk of progression into invasive cutaneous squamous cell carcinoma (cSCC). However, this risk of transformation is low, and rather than focusing on these lesions, current treatment studies report on complete clearance of AKs in an entire field. This study aimed to investigate treatment-resistant AKs (trAK) after field therapy compared to randomly chosen AKs prior to treatment. AKs were clinically assessed according to the grade of hyperkeratosis and pain on palpation, prior to treatment. TrAKs were biopsied and compared to AKs which were biopsied prior to any treatment. AKs were evaluated regarding histological severity (AKI-III), their basal growth grading (PROI-III), acantholysis, elastosis, follicular extension of atypical keratinocytes and accompanying infiltrate. Two hundred eleven AKs in 171 patients were identified. TrAKs (N.=79) were significantly more painful (64.6% vs. 22.0%; P<0.0001), showing acantholysis (57.0% vs. 33.3%; P=0.0007); and with distinct basal proliferation (PROIII) (64.4% vs. 46.2%; P=0.0099) compared to the control group (N.=132). In a multivariate analysis using logistic regression, pain and PRO III graded lesions were significant independent (P<0.0001 and P=0.0179) predictors for trAKs. Focusing on individual histological features in the trAK group, AKs with grade AKIII, PROIII or follicular extension reaching the sebaceous gland were the most common findings with 51.9%, 64.6%, and 59.5% AKs demonstrating this, respectively. TrAKs are often painful, showing a distinct basal proliferation (PROIII) and acantholysis. As these features are also seen in invasive cSCCs, trAKs may represent a subgroup of AKs and, for this reason, it requires further evaluations.

The 2016 Edition of the WHO Classification of Primary Brain Tumors: Applicable to Assess Individual Risk of Recurrence in Atypical Meningioma? A Single-Center Experience

Despite the relevance of molecular criteria for brain tumor diagnosis and prognosis, meningioma grading is still solely based on histologic features. Atypical meningiomas (AMs; WHO grade II) display a great histologic heterogeneity and individual courses of disease can differ significantly. This study aimed to identify clinically aggressive AMs that are prone to early recurrence after gross total resection (GTR) by assessing a specific histologic score. A retrospective analysis of 28 consecutive patients (17 females and 11 males; mean age of 62 years [range: 35-88 years]) treated in our institution between January 2006 and December 2015 was performed. Basic demographic and clinical characteristics were assessed. A scoring scale was designed to address the histologic diversity by summing up the individual histologic features in every tumor sample. According to that, points were awarded as follows: major AM defining criterion (3 points) and minor criterion (1 point). The subclassification based on our specific histologic score revealed no significant difference in frequency of one (46.4%) or two (42.9%) AM defining features; three criteria were less frequently seen (10.7%). Mean follow-up was 61.89 ± 9.03 months. Local recurrence occurred in 35.7% after a mean time of 37.4 ± 22.6 months after primary surgery. Age > 60 years was significantly associated with a shorter progression-free survival (PFS). There was a trend toward shorter PFS with increasing scores, tantamount with the presence of several AM defining histologic criteria in one sample. No tumor relapse was seen when diagnosis was based only on minor criteria. AMs display a histologic diversity. There is a trend toward shorter PFS with increasing numbers of AM defining histologic features. The inclusion of this score in the decision algorithm regarding further treatment for patients >60 years after GTR might be helpful and should be evaluated in further studies.

Association of Weight Changes With Changes in Histological Features and Blood Markers in Nonalcoholic Steatohepatitis

Weight loss is recommended for patients with non-alcoholic steatohepatitis (NASH) but the impact of weight change on disease activity remains unclear. We examined the association between weight change (gain/loss) and changes in biochemical and histological features of NASH. This was an analysis of the PIVENS and FLINT trials in adults with NASH who had liver biopsies at baseline and at either 1.5 years or 2 years. Multivariable regression models examined how weight change was associated with changes in (a) blood liver markers, (b) NASH resolution with no fibrosis worsening, (c) fibrosis improving with no NASH worsening, and (d) individual histological features. The BMI of the 421 participants was 34.3 kg/m2 (SD:6.5) and their mean weight change was+0.5 kg (SD:6.5). Weight change was independently and positively associated with changes in liver enzymes and the Fibrosis-4 score (all P < .001). Each kg of weight loss was associated with 7% (95% CI, 3%-10%; P < .001) increase in odds of achieving NASH resolution with no fibrosis worsening and with 5% (95% CI, 1%-8%; P = .01) increase in odds of achieving fibrosis improvement with no NASH worsening. Weight gain was associated with worsening of disease activity. For every kg of weight lost, the odds of fibrosis improving were 5% (95% CI, 2%-8%; P=.001). There was no evidence that the association between weight change and outcome depended upon pharmacological treatment, trial, body mass index, and baseline fibrosis. Weight change was independently and monotonically associated with changes in biochemical and histological features of NASH. Guidelines for NASH management should incorporate recommendations for both avoidance of weight gain and support to lose weight.

Do Histologic Features Help Predict Colectomy in Pediatric Patients Presenting With Acute Severe Colitis?

Multiple prior studies have looked at clinical and laboratory parameters in ulcerative colitis to predict prognosis, but individual histologic features of inflammation and their prognostic significance have not been well studied. The purpose of our study was to determine whether histologic features at presentation with acute severe colitis predict colectomy in pediatric patients. Patients were identified retrospectively through the gastroenterology and pathology databases. Demographic information, duration of disease, laboratory data, endoscopic appearance at scope, and histologic features of inflammation were reviewed along with medical therapies. Patients who underwent surgery within 90 days of hospitalization were compared to those who did not. Fifty patients with acute severe colitis, defined as Pediatric Ulcerative Colitis Activity Index ≥65, were included. Sixteen patients had colectomies performed within 90 days of presentation. No statistically significant difference was found between the surgery and no-surgery groups for patient age, albumin, hemoglobin, or C-reactive protein, though hemoglobin trended toward significance, P = .05. The endoscopic Mayo score and histologic features of inflammation (architectural changes, chronic inflammation, eosinophils, neutrophils within the lamina propria, neutrophils in epithelium, crypt destruction, and ulceration) were similar between groups. In pediatric patients presenting for hospitalization with acute severe colitis, no histologic features of inflammation predicted colectomy within 90 days.

Age, Diagnostic Category, Tumor Grade, and Mitosis-Karyorrhexis Index Are Independently Prognostic in Neuroblastoma: An INRG Project.

The Children's Oncology Group (COG) stratifies the treatment of patients with neuroblastoma on the basis of a combination of biomarkers that include age and tumor histology classified by age-linked International Neuroblastoma Pathology Classification (INPC) criteria. By definition, this leads to a duplication of the prognostic contribution of age. The individual histologic features underlying the INPC have prognostic strength and are incorporated in the International Neuroblastoma Risk Group classification schema. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons to validate the prognostic strength of the underlying INPC criteria and to determine whether a risk classification devoid of the confounding of age and INPC criteria will identify new prognostic subgroups. Event-free survival of patients diagnosed between 1990 and 2002 (cohort 1; n = 10,104) and between 2003 and 2016 (cohort 2; n = 8,761) was analyzed. Recursive partitioning with univariate Cox models of event-free survival ("survival tree regression") was performed using (1) individual INPC criteria (age at diagnosis, histologic category, mitosis-karyorrhexis index (MKI), grade of differentiation) and (2) factors in (1) plus other COG-risk biomarkers (International Neuroblastoma Staging System [INSS] stage, MYCN status, ploidy). The independent prognostic ability of age, histologic category, MKI, and grade were validated. Four histologic prognostic groups were identified (< 18 months with low v high MKI, and ≥ 18 months with differentiating v undifferentiated/poorly differentiating tumors). Compared with survival trees generated with established COG risk criteria, an additional prognostic subgroup was identified and validated when individual histologic features were analyzed in lieu of INPC. Replacing INPC with individual histologic features in the COG risk classification will eliminate confounding, facilitate international harmonization of risk classification, and provide a schema for more precise prognostication and refined therapeutic approaches.

Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical “proof of concept” study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.