Abstract
BACKGROUND: The VENTANA PD-L1 (SP142) Assay (SP142 assay) is the FDA-approved companion diagnostic for the combination of TECENTRIQ (atezolizumab) and nab-paclitaxel for the treatment of ...patients with unresectable, locally advanced, or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 - defined as PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥ 1 percent of the tumor area. Accurate and reproducible assessment of IC PD-L1 staining with the SP142 assay by pathologists is important to ensure the right treatment decisions for patients are made. Analytical studies have demonstrated variable agreement rates for PD-L1 IC scoring with the SP142 assay, ranging from low, moderate, strong and near-perfect agreement depending on tumor type, cut-off and prior training. The Roche International Pathologist Training Program has trained over 1000 pathologists globally for the SP142 assay in the indications of non-small cell lung cancer, urothelial carcinoma and TNBC. Here we present results from the TNBC training program. METHODS: The glass-slide based training program for pathologists participating in clinical trials leading to the approval of the SP142 assay was adapted to enable live training to be conducted using a novel digital training platform (Pathomation) which was customized for Roche with a rapid, user-friendly interface, facilitating monitoring of scores and reporting. Feedback and endorsement from a Pathologist Training Expert Committee led to a global Train-the Trainer program which enabled regional training sessions to be conducted using the digital platform. Training content was developed around the FDA-approved 1% IC cut-off and was conducted over a 1-day program. Didactic instruction was followed by case reviews and a final proficiency test consisting of 28 cases, with a passing score of ≥85%. RESULTS: Between 17th November, 2018 and 19th June 2019, 432 pathologists from 58 countries participated in the TNBC training program for the SP142 assay. This includes 1 PTEC, 10 Train-the Trainer Sessions and 24 Regional Training sessions. The passing rate for trainees was 99.1%. Overall percent agreement (OPA) was 98.2%, with positive percent agreement (PPA) 99.4% and negative percent agreement (NPA) 96.6%. CONCLUSION: This is the first formal PD-L1 training program for practicing pathologists to be developed for the assessment of PD-L1 on ICs in TNBC. The SP142 assay training utilizing a novel digital platform demonstrates robust, reproducible and excellent pathologist concordance scores in this real-world program.
Citation Format: Eslie Dennis, Mark Kockx, Greg Harlow, Zhuangyu Cai, Ken Bloom, Ehab ElGabry. Effective and globally reproducible digital pathologist training program on PD-L1 immunohistochemistry scoring on immune cells as a predictive biomarker for cancer immunotherapy in triple negative breast cancer abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-02.
Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as ...many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
Academic industry partnership (AIP) represents an important alliance between academic researchers and industry that helps translate technology and complete the innovation cycle within academic health ...systems. Despite diverging missions and skillsets the culture for academia and industry is changing in response to the current digital era which is spawning greater collaboration between physicians and businesses in this marketplace. In the field of pathology, this is further driven by the fact that traditional funding sources cannot keep pace with the innovation needed in digital pathology and artificial intelligence. This concept article from the Digital Pathology Association (DPA) describes the rules of engagement for pathology innovators in academia and for their corporate partners to help establish best practices in this critical area. Stakeholders include pathologists, basic and translational researchers, university technology transfer and sponsored research offices, as well as industry relations officers. The article discusses the benefits and pitfalls of an AIP, reviews different partnership models, examines the role of pathologists in the innovation cycle, explains various agreements that may need to be signed, covers conflict of interest and intellectual property issues, and offers recommendations for ensuring successful partnerships.
* Context.--Delta-like protein 3 (DLL3) is a protein that is implicated in the Notch pathway. Objective.--To present data on DLL3 prevalence in small cell lung cancer and staining characteristics of ...the VENTANA DLL3 (SP347) Assay. In addition, the assay's immunoreactivity with other neoplastic and nonneoplastic tissues is outlined. Design.--Individual formalin-fixed, paraffin-embedded specimens of small cell lung cancer and tissue microarrays comprising neoplastic and nonneoplastic tissues were procured. Sections were cut and stained with DLL3 (SP347) assay. The slides were examined to determine prevalence, staining characteristics, and immunoreactivity. Results.--Cytoplasmic and/or membranous staining was observed in 1040 of 1362 specimens of small cell lung cancer (76.4%). Homogenous and/or heterogeneous and partial and/or circumferential granular staining with varied intensities was noted. Immunoreactivity was also observed in other neoplastic and nonneoplastic tissues. Conclusions.--Our study findings provided the profile of DLL3 staining characteristics that can be used for determining the level of DLL3 expression in small cell lung cancer. (Arch Pathol Lab Med. 2019;143:1373-1377; doi: 10.5858/arpa.2018-0497-OA)
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background Silver nanoparticles (AgO-NPs) have shown antimicrobial effects against a broad spectrum of microorganisms.
Objectives To assess the antimicrobial effects of AgO-NPs prepared using an ...eco-friendly green method against multidrug-resistant Escherichia coli in vivo after inducing endometritis in rats.
Materials and methods In female mice, LD50 of AgO-NPs was determined, followed by a chronic toxicity in female rats by oral administration of 0, 20, 30, and 40 mg of AgO-NPs daily for 4 weeks. The induced endometritis model in female rats was performed by inoculating two doses of E. coli (100 μl of 10×105 CFU) intravaginally. Seven days later, vaginal swabs were stained with Wright stain to confirm the development of endometritis and used to re-isolate the inoculated microorganism. Two doses of 100 μl containing 10 mg AgO-NPs were inoculated intravaginally. Estradiol, progesterone, liver and kidney functions, oxidants and antioxidants, and zinc were measured in collected blood samples of chronic toxicity and induced endometritis model.
Results and conclusion LD50 of AgO-NPs was 800 mg/kg body weight (BW). The use of 40 (1 : 20 LD50), 30 (1 : 26.67 LD50), and 20 (1 : 40 LD50) mg/kg BW during the chronic toxicity experiment was safe as indicated by blood biochemical analyses. The chronic toxicity experiment resulted in normal liver and kidney functions, oxidant-antioxidant status, acute-phase proteins, and ovarian hormones. The green method-synthesized AgO-NPs showed efficacy against E. coli-induced endometritis, and rats responded to the treatment as indicated by the uterine cytology and the clinical analysis with mild adverse effects on both liver and kidney. In conclusion, AgO-NPs showed treatment of experimental uterine infections induced by E. coli in rats and were safe for longer administration in concentrations lower than 50 mg/kg BW.
PDF
