Determination of programmed death-ligand 1 (PD-L1) protein expression level in tumor cells and tumor-associated immune cells is critical for identifying patients eligible for immunotherapy. PD-L1 ...manual scoring algorithms can generally be divided into two categories: cell counting and visual estimation. Cell counting can be time-consuming and is not in sync with pathology practice, which classically uses a Gestalt approach based on pattern recognition and visual estimation. In this study, we introduce the Tumor Area Positivity (TAP) score, which is a novel, straightforward method for scoring tumor cells and immune cells together using visual estimation.
To demonstrate the reproducibility of TAP scoring among pathologists, between- and within-reader precision studies were performed both within (internal) and outside of (external) our organization. We also compared the TAP score to the Combined Positive Score (CPS), which is based on cell counting, for concordance and time efficacy.
The average positive agreement, average negative agreement, and overall percent agreement between and within readers were all above 85% for both internal and combined external reader precision studies. TAP score had high concordance rate at 5% cutoff compared with CPS at cutoff 1: positive percent agreement, negative percent agreement, and overall percent agreement were all above 85%.
Our study showed the TAP scoring method to be straightforward, significantly less time-consuming, and highly reproducible with a high concordance rate between TAP score and CPS.
Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new ...methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change.
To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development.
Sources were a literature review and the personal experience of authors and educators.
High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward ...providing more quantitative scores for these biomarkers. The application of quantitative image analysis has thus become an indispensable tool for in-depth tissue biomarker interrogation in these contexts. This white paper reviews current technologies being employed for quantitative image analysis, their application and pitfalls, regulatory framework demands, and guidelines established for promoting their safe adoption in clinical practice.
Delta-like protein 3 (DLL3) is a protein that is implicated in the Notch pathway.
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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The COVID-19 pandemic presented numerous challenges to the continuity of programmed cell death ligand 1 (PD-L1) assay training events conducted by our organization. Under typical conditions, these ...training events are face-to-face affairs, where participants are trained to assay algorithms on glass slides during multi-headed scope sessions. Social distancing measures undertaken to slow pandemic spread necessitated the adaptation of our training methods to facilitate assay training and subsequent continuation of clinical trials. The present report details the creation and use of the Roche pathology training portal (PTP) that allowed for remote training to diagnostic assay algorithms. The PTP is a web-based system comprised of a learning management system (LMS) coupled to an image management system (IMS). Whole slide images (WSIs) were produced using a DP200 instrument (Roche, Pleasanton, CA) and these scan files were then uploaded to an IMS. Courses were created on the LMS using annotated WSIs that were shared with enrolled pathologists worldwide during assay training events. These courses culminated in assay certification examinations, where pathologists evaluated test-case WSIs and evaluated these cases within the LMS. Trainee submissions were analyzed for pass/fail status by comparing user data entries with consensus scores on these test-case WSIs. To date, 47 pathologist trainings have occurred and of these, 44 have successfully passed the associated assay certification exam on the first attempt (93% 1st-try pass rate). The PTP allowed roche to continue training sites during the COVID-19 pandemic, and these early results demonstrate the capability of this digital solution regarding PD-L1 diagnostic assay training events.
Atezolizumab (anti-programmed cell death ligand 1 PD-L1) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer ...(mTNBC) has not been reported.
To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC.
Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression.
Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit.
Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups.
Among 116 evaluable patients (median age, 53 years range, 29-82 years), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 24%) than in second-line or greater patients (6 of 94 6%). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% 11 of 91; 10.1 95% CI, 7.0-13.8 months, respectively) than those with less than 1% ICs (0 of 21; 6.0 95% CI, 2.6-12.6 months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS.
Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment.
ClinicalTrials.gov identifier: NCT01375842.
Background Determination of programmed death-ligand 1 (PD-L1) protein expression level in tumor cells and tumor-associated immune cells is critical for identifying patients eligible for ...immunotherapy. PD-L1 manual scoring algorithms can generally be divided into two categories: cell counting and visual estimation. Cell counting can be time-consuming and is not in sync with pathology practice, which classically uses a Gestalt approach based on pattern recognition and visual estimation. In this study, we introduce the Tumor Area Positivity (TAP) score, which is a novel, straightforward method for scoring tumor cells and immune cells together using visual estimation. Methods To demonstrate the reproducibility of TAP scoring among pathologists, between- and within-reader precision studies were performed both within (internal) and outside of (external) our organization. We also compared the TAP score to the Combined Positive Score (CPS), which is based on cell counting, for concordance and time efficacy. Results The average positive agreement, average negative agreement, and overall percent agreement between and within readers were all above 85% for both internal and combined external reader precision studies. TAP score had high concordance rate at 5% cutoff compared with CPS at cutoff 1: positive percent agreement, negative percent agreement, and overall percent agreement were all above 85%. Conclusions Our study showed the TAP scoring method to be straightforward, significantly less time-consuming, and highly reproducible with a high concordance rate between TAP score and CPS. Keywords: Programmed death-ligand 1 (PD-L1), Tumor area positivity, Tumor cells, Immune cells, Scoring method
Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell-redirecting antibody (TRAB) is one ...such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens. Its clinical efficacy has been exemplified by blinatumomab, a bispecific T cell engager targeting CD19 and CD3, which has shown marked clinical responses against hematological malignancies. However, the success of TRAB in solid tumors has been hampered by the lack of a target molecule with sufficient tumor selectivity to avoid "on-target off-tumor" toxicity. Glypican 3 (GPC3) is a highly tumor-specific antigen that is expressed during fetal development but is strictly suppressed in normal adult tissues. We developed ERY974, a whole humanized immunoglobulin G-structured TRAB harboring a common light chain, which bispecifically binds to GPC3 and CD3. Using a mouse model with reconstituted human immune cells, we revealed that ERY974 is highly effective in killing various types of tumors that have GPC3 expression comparable to that in clinical tumors. ERY974 also induced a robust antitumor efficacy even against tumors with nonimmunogenic features, which are difficult to treat by inhibiting immune checkpoints such as PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T lymphocyte-associated protein-4). Immune monitoring revealed that ERY974 converted the poorly inflamed tumor microenvironment to a highly inflamed microenvironment. Toxicology studies in cynomolgus monkeys showed transient cytokine elevation, but this was manageable and reversible. No organ toxicity was evident. These data provide a rationale for clinical testing of ERY974 for the treatment of patients with GPC3-positive solid tumors.