Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: 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

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Colonisation of basal cell carcinoma and actinic keratosis by malignant melanoma in situ in a patient with xeroderma pigmentosum variant

Although malignant melanoma (MM) and both basal cell carcinoma (BCC) and actinic keratosis (AK) are sun-induced lesions, the coexistence of these entities at the same anatomical site (collision tumour) is exceedingly rare. We report the case of a 54-year-old woman with a known history of xeroderma pigmentosum variant (XPV) who presented with 2 separate skin lesions over the middle and upper right forearm, respectively. The clinical impression was that of BCCs or squamous cell lesions. On histological examination, both specimens showed features of melanoma in situ (MIS). In the first lesion, MIS merged with and colonised a superficial and focally invasive BCC. In the second lesion, MIS merged with an AK. No separate invasive nests of malignant melanoma were seen in either specimen. The atypical melanocytes were highlighted by Melan-A and HMB-45 immunostaining, whereas the epithelial cells in both the BCC and AK stained with the pancytokeratin MNF-116. The patient had a previous history of multiple MMs and non-melanomatous skin cancers and finally developed widespread metastatic malignant melanoma, which proved fatal. The rare and interesting phenomenon of collision tumours may pose diagnostic difficulties. To our knowledge, this is the first reported simultaneous presentation of cytologically malignant collision tumours in a patient with XPV

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

<p>Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.</p

Analysing the influence of ground granulated blast furnace slag and steel fibre on RC beams flexural behaviour

Abstract This study examines the effect of Ground Granulated Blast Furnace Slag (GGBS) and steel fibers on the flexural behaviour of RC beams under monotonic loading. Various percentages of GGBS were used to substitute cement, namely 0%, 20%, 40%, 60%, and 80% and fibers were added to the concrete mix as 0%, 0.5%, 1%, and 1.5% of the volume of concrete. The load–deflection behaviour of GGBS-incorporated RC beams with fibers was compared with the control RC beam. Beams were tested under load control for 28 days and 180 days. The ultimate load of the GGBS-incorporated RC beam up to 40% cement replacement was found to higher than that of the control beam. The strength of concrete is reduced by 28% and 19% when cement was partially replaced by 80% of GGBS at 28 and 180 days, respectively, compared to control concrete without fibres. Further, the analytical load–deflection response of GGBS-incorporated RC beams was determined by using several codes of practice, namely, ACI 318-11(2011), CSA A23.3-04 (2004), EC-04 (2004), and IS 456 (2000). The Codal provisions were primarily based on the effective moment of inertia, Young’s modulus, and modulus of rupture, stiffness, and cracking. Average load–deflection plots obtained from experiments were compared with the computed load–deflection of analytical studies. It was found that the analytically predicted load–deflection behaviour is comparable with the corresponding average experimental load–deflection response. Moment curvature relations were also developed for RC beams

PUBLIC AWARENESS TOWARDS HEPATITIS B AMONG GENERAL POPULATION, IN SAUDI ARABIA

Background: Hepatitis Virus B is a major health problem worldwide as well as in Kingdom of Saudi Arabia (KSA) as it is one of the most common contagious infection and cost effective. Objectives: To Evaluate the knowledge, attitude and practice (KAP) of general population toward hepatitis B infection in KSA. Methods: A cross-sectional study was conducted among 500 Saudi participants aged between 20-60 years old. Participants were conducted during the period from December 2018 till January 2019 and the questionnaire was consisted of 4 parts including the demographics information and KAP. Results: 500 participants have filled the surveys. The age of the participants were from 20-60 years/old and the majority were between 20- and 30 years old (33.8%). Regarding the knowledge, (87%) have heard about hepatitis disease and (81%) know that hepatitis B affects the liver. Regarding the attitude, (82.8%) will visit physician if they get hepatitis. But unfortunately, only (56%) have been vaccinated against hepatitis B. Conclusion: The level of KAP toward hepatitis B was moderately acceptable in most of our sample but with insufficient practice among most of participants. More campaigns should be conducted increase the level of awareness towards the disease. Keywords: KAP, Hepatitis B, Saudi Arabia

Metastatic-niche labelling reveals parenchymal cells with stem features.

Direct investigation of the early cellular changes induced by metastatic cells within the surrounding tissue remains a challenge. Here we present a system in which metastatic cancer cells release a cell-penetrating fluorescent protein, which is taken up by neighbouring cells and enables spatial identification of the local metastatic cellular environment. Using this system, tissue cells with low representation in the metastatic niche can be identified and characterized within the bulk tissue. To highlight its potential, we applied this strategy to study the cellular environment of metastatic breast cancer cells in the lung. We report the presence of cancer-associated parenchymal cells, which exhibit stem-cell-like features, expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. In ex vivo assays, lung epithelial cells acquire a cancer-associated parenchymal-cell-like phenotype when co-cultured with cancer cells and support their growth. These results highlight the potential of this method as a platform for new discoveries.This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001112), the UK Medical Research Council (FC001112), and the Wellcome Trust (FC001112) and the European Research Council grant (ERC CoG-H2020-725492); and by the Wellcome Trust – MRC Stem Cell Institute which receives funding from the Sir Henry Dale Fellowship from Wellcome and the Royal Society (107633/Z/15/Z) and the European Research Council Starting Grant (679411)