The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients.

BACKGROUND/OBJECTIVE: Proto-oncogenes (HER-2) and tumor suppressor genes (p53) are commonly deregulated in gallbladder cancer (GBC). Available literature discloses skewed data from endemic Asian countries, especially north India. This study evaluates the prognostic significance of HER-2 and p53 in GBC patients from two major hospitals. METHODS: Sixty resectable tumor and control specimens were prospectively collected from December 2012 to January 2016. Immunohistochemical staining was done using monoclonal antibodies to semiquantitatively evaluate HER-2 and p53 protein expression. The criterion for HER-2 positivity was set at >30% tumor cells showing complete, membranous staining while p53 positivity was established at <50% tumor cells showing complete nuclear staining. Clinicopathological correlations were drawn with major clinical outcomes. RESULTS: It was observed that 36.67% (22/60) tumor cases and 5% (3/60) control cases showed strong HER-2 overexpression significantly correlating with sex, T-stage, nodal spread and distant metastasis (p < 0.05), while 33.3% (20/60) positivity was observed for p53 in tumor cases and 1.7% (1/60) in control cases. Multivariate analysis showed HER-2 (p = 0.04; hazard ratio: 2.36; 95% confidence interval: 1.04-5.33) and p53 (p = 0.03; hazard ratio: 5.63; 95% confidence interval: 1.21-26.26) expression to be independent prognostic factors. CONCLUSION: Our study thus suggests the plausible role of HER-2 and p53 expression in worse prognosis of GBC in a north Indian population.

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Tiger Man Sign-F-18 FDG PET CT Scan Pattern in Muscular and Cutaneous Sarcoidosis: A Case Report and Literature Survey.

Sarcoidosis is a chronic granulomatous disorder of unknown etiology which primarily affects the respiratory system. However, 0.5%-2.5% of patients with sarcoidosis show muscle involvement, namely sarcoid myopathy. F-18 Fluorodeoxyglucose positron-emission tomography (F-18 FDG PET) has become an important component of the diagnostic algorithm of these patients, owing to its ability to assess disease extent and identify occult sites of disease involvement and guiding sites of biopsy. Awareness of pattern of FDG uptake in sarcoid myopathy not only helps in identifying muscular involvement in already known cases but also helps in the initial diagnosis of sarcoidosis as in the present case.

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

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.

Gastrointestinal Biopsies for Evaluation of Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Graft-versus-host disease (GVHD) is the major complication post hematopoeitic stem cell transplantation (HSCT) causing significant morbidity and mortality. Colonic biopsies were performed in 25 post HSCT patients presenting the diarrhea for diagnosis of acute graft versus host disease (A-GVHD). The present study was undertaken to evaluate and illustrate histomorphological features of A-GVHD in GI biopsies and to grade them. Histopathological features of gastrointestinal biopsies from 25 allogeneic HSCT patients having clinical suspicion of A-GVHD were evaluated and compared with colonic biopsies from negative controls. A-GVHD was observed in 17 cases, CMV colitis was present in 3 cases and one case had herpes simplex infection diagnosed in conjunction with serological findings. A-GVHD was graded as grade 1 and 2 in 10 cases and grade 3 and 4 in 7 cases. Apoptosis of crypt epithelial cells was the cardinal feature for diagnosis. Grade 1 and grade 2 A-GVHD cases showed crypt apoptosis in all cases as well as pericryptal apoptosis in lamina propria in many cases. Occasional crypt loss was seen in grade 2 GVHD. Inflammatory infiltrate was composed of lymphocytes and plasma cells. Neutrophils were inconspicuous. Grade 3 and grade 4 A-GVHD cases showed contiguous areas of multiple crypt loss and ulceration with inflammatory infiltrate predominantly composed of lymphocytes and plasma cells, but neutrophils were more prominent than in grade 1 and 2 A-GVHD. Apoptosis of crypt epithelial cells was present in all grade 3 &4 cases except one case. CMV cases were diagnosed by CMV inclusions and IHC stain. Several factors including drug-induced side effects and infections can cause difficulty in histologic interpretation of gastrointestinal biopsies for GVHD. Proper histomorphological interpretation of intestinal A-GVHD is critical for clinical management. A-GVHD is treated with immunosuppression which may worsen infective condition, if present.