A Gene Panel for Early Identification of Future Responders to Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB), therapies that target the PD-1 pathway, CTLA-4 pathway, and other checkpoint pathways, lead to durable responses in many cancer types. Since only a minority of patients respond to ICB, it may be useful to identify the future responders early in the course of treatment. In this study we evaluated a small (15 genes) biologically motivated panel, consisting of genes involved in immune activation and checkpoint pathways, for early identification of future responders to ICB. The panel passed consistency check, pathological and in-silico validations, and was an excellent predictor (area under ROC curve >0.95) of eventual response to ICB, both CTLA-4 and PD-1 blockade, when applied to metastatic melanoma patients undergoing ICB (i.e., "on-treatment") in a publicly available dataset. These results suggest that this small biologically motivated panel may be useful for early identification of future responders to ICB.

Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors.

PURPOSE: An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels. METHODS: WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy. RESULTS: We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments. CONCLUSION: In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.

Left ventricular epicardial hydatid cyst compressing the left circumflex artery.

Cardiac hydatid is a rare disease with varied presentation. We report a unique case of left ventricular epicardial hydatid cyst causing left circumflex artery compression. Cardiac hydatids have to be surgically treated on diagnosis because of the high risk of catastrophic rupture. We discuss the surgical principles and the other adjuncts to avoid recurrence.