Assessment of programmed death-ligand 1 (PD-L1) expression is a critical part of patient management for immunotherapy. However, studies have shown that pathologist-based analysis lacks reproducibility, especially for immune cell expression. The purpose of this study was to validate reproducibility of the automated machine-based Optra image analysis for PD-L1 immunohistochemistry for both tumor cells (TCs) and immune cells. We compared conventional pathologists’ scores for both tumor and immune cell positivity separately using 22c3 antibody on the Dako Link 48 platform for PD-L1 expression in non–small cell lung carcinoma. We assessed interpretation first by pathologists and second by PD-L1 image analysis scores. Lin’s concordance correlation coefficients (LCCs) for each pathologist were measured to assess variability between pathologists and between pathologists and Optra automated quantitative scores in scoring both tumor and immune cells. Lin’s LCCs to evaluate the correlation between pathologists for TC was 0.75 [95% confidence interval (CI), 0.64-0.81] and 0.40 (95% CI, 0.40-0.62) for immune cell scoring. Pathologists were highly concordant for tumor scoring, but not for immune cell scoring, which is similar to previously reported studies where agreement is higher in TCs than immune cells. The LCCs between conventional pathologists’ read and the machine score were 0.80 (95% CI, 0.74-0.85) for TCs and 0.70 (95% CI, 0.60-0.76) for immune cell population. This is considered excellent agreement for TCs and good concordance for immune cells. The automated scoring methods showed concordance with the pathologists’ average scores that were comparable to interpathologist scores. This suggests promise for Optra automated assessment of PD-L1 in non–small cell lung cancer.

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Data in both humans and preclinical animal models clearly indicate drug exposure during adolescence, when the “reward” circuitry of the brain develops, increases the risk of substance use and other mental health disorders later in life. Human data indicate that different neural and behavioral sequelae can be observed in early versus late adolescence. However, most studies with rodent models examine a single adolescent age compared to a mature adult age, and often only in males. Herein, we sought to determine whether the acute response to the opioid morphine would also differ across adolescence, and by sex. By quantifying Fos positive cells, a proxy for neural activity, at different stages during adolescence (pre‐, early, mid‐, and late adolescence) and in multiple reward regions (prefrontal cortex, nucleus accumbens, caudate/putamen), we determined that the neural response to acute morphine is highly dependent on adolescent age, sex, and brain region. These data suggest that heterogeneity in the consequences of adolescent opioid exposure may be due to age‐ and sex‐specific developmental profiles in individual reward processing regions. In future studies, it will be important to add age within adolescence as an independent variable for a holistic view of healthy or abnormal reward‐related neural development.

Drug and alcohol use during adolescence is common, and data in both humans and preclinical animal models clearly indicate drug exposure during adolescence increases the risk of substance use and other mental health disorders later in life. Adolescence is a period of social, emotional, and cognitive development, and is characterized by increased exploratory behavior, risk-taking, and peer-centered social interactions. These are thought to be behavioral manifestations of developmental plasticity in ‘reward’ regions of the brain. Human data indicate that adolescence is not a unitary developmental period, but rather different neural and behavioral sequelae can be observed in early vs. late adolescence. However, most studies with rodent models examine a single adolescent age compared to a mature adult age, and often only in males. Herein, we sought to determine whether the acute response to the opioid morphine would also differ across adolescence, and by sex. By quantifying c-Fos positive cells, a proxy for neural activity, at different stages during adolescence (pre-, early, mid-, and late adolescence) and in multiple reward regions (prefrontal cortex, nucleus accumbens, caudate/putamen), we determined that acute morphine can either reduce or increase c-Fos expression dependent on adolescent age, sex, and brain region. These data suggest that heterogeneity in the consequences of adolescent opioid exposure may be due to the interaction between age- and sex-specific developmental profiles of reward processing in individual brain regions. In future studies, it will be important to add age within adolescence as an independent variable to fully capture the consequences of healthy or abnormal reward-related neural development.

Purpose: Assessment of PD-L1 expression is a critical part of patient management for immunotherapy. However, studies have shown that pathologist-based analysis lacks reproducibility, especially for immune cell expression. The purpose of this study was to validate and to assess reproducibility of the automated Optra image analysis for PD-L1 IHC for both tumor cells and immune cells. Experimental Design: We compared conventional pathologists' scores (3 board-certified pathologists active in routine signout of these cases) for both tumor and immune cell positivity separately, using 22c3 antibody on the Dako Link 48 platform for PD-L1 expression in non-small cell lung carcinoma (NSCLC). We examined interpathologist PD-L1 expression scoring variability for both, tumor and immune cells using ordinal tumor proportion scores for tumor cells and continuous percentage positive scores. The cohort included 230 NSCLCs obtained from Yale School of Medicine, Department of Pathology archives. We assessed interpretation first by pathologists and secondly by the Optra PD-L1 image analysis scores for both tumor and immune cells. The Intra Class Correlation (ICC) for each pathologist was measured to assess variability between pathologists in scoring both tumor and immune cells. The concordance between pathologists using digital manual reads of PD-L1 staining percentages and Optra PD-L1 image analysis quantitative scores was then assessed using the Lin's concordance correlation coefficient for both tumor and immune cells. Results: Intraclass correlation coefficients to evaluate the correlation between pathologists for tumor cell (ICC = 0.750) showed an excellent concordance but lower concordance for immune cell scoring (ICC = 0.4). To compare the pathologist scores to the Optra automated system, the scores from the 3 pathologists were averaged to produce a single conventional read score. The Lin's concordance correlation coefficient between the conventional read and the machine score was 0.83 for tumor cells and 0.6 for immune cell population in intra- and peritumoral compartments. This is considered excellent agreement for tumor cells and good concordance for immune cells. Conclusion: The interpathologist assessment seen in this study is similar to previously reported studies where agreement is higher in tumor cells than immune cells. The Optra PD-L1 image analysis showed concordance with the pathologists' average scores that were comparable to interpathologist scores. This suggests promise for automated assessment of PD-L1 in NSCLC. These results justify similar studies with immunotherapy-treated patients with known outcomes. Citation Format: Clive Taylor, Anagha P. Jadhav, Abhi Gholap, Gurunath Kamble, Jiaoti Huang, Allen Gown, Isha Doshi, David Rimm. A multi-institutional study to evaluate automated scoring of immunohistochemistry slides for assessment of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1695.