Purpose Tumor mutational burden detected by tissue next generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hyper-mutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response. Experimental Design We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived circulating tumor DNA (ctDNA) NGS testing (54–70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), as well as progression-free survival (PFS) and overall survival (OS) were assessed based on total and VUS alterations. Results Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD≥6 months/PR/CR 45% versus 15%, respectively; p = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 versus <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus non-responders with VUS>3 had a median PFS of 23 versus 2.3 months (p = 0.0004). Conclusion Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hyper-mutated ctDNA as a predictive biomarker is warranted.

With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgkin's lymphoma, and urothelial cancer. Though FDA-approved indications for use of some of these novel agents depend on current, protein-based PD1 and PD-L1 assays, detection methods come with several caveats. Additional predictive tools must be interrogated to discern responders from non-responders. Some of these include measurement of microsatellite instability, PD-L1 amplification, CD8 infiltrate density, and tumor mutational burden. This review serves to synthesize biomarker detection at the DNA, RNA, and protein level to more accurately forecast benefit from these novel agents.

Background Heart rate and rhythm disturbances are common after cardiac surgery. This study tests the hypothesis that inflammation caused by cardiac surgery is an underlying mechanism for postoperative changes in heart rate (HR), rhythm, and heart rate variability (HRV). Method and Results Normal canines (n=6/group) were divided into four groups: 1. anesthesia, 2. sternotomy and pericardiotomy, 3. atriotomy, and 4. corticosteroids combined with an atriotomy. Continuous ECG recordings were done preoperatively and for three post-operative days. Electrophysiologic testing was done at the initial and terminal surgeries. C-reactive protein (CRP) was assessed at each study day and tissue myeloperoxidase activity (MPO) was assessed at the terminal study. Measurements of HRV were determined daily to detect changes in autonomic tone. Postoperatively HR increased in the pericardiotomy (p=0.0005) and atriotomy (p=0.001) groups and HRV decreased in both groups. No significant change occurred in HR or HRV in the anesthesia (p=0.52) and steroid groups (p=0.16). HRV (triangular index) on POD3 was correlated with the tissue MPO levels (r= −0.83, p=0.0004) Autonomic blockade with atropine and esmolol resulted in a HR and HRV which were not significantly different between groups. Atrial premature beats occurred postoperatively in the all the groups except the anesthesia group and were independent of the degree of inflammation. Conclusion Cardiac surgery increases postoperative heart rate by reducing heart rate variability, due in most part to a reduction in vagal tone. Furthermore, the magnitude of these changes is dependent upon the degree of inflammation and is normalized by corticosteroids.

Multiple myeloma is the second most common hematologic malignancy in the US. Treatments utilizing alkylating agents, corticosteroids, proteasome inhibitors, and immunomodulatory drugs have resulted in significant survival benefits, however, despite the advances, relapse is inevitable. Decreased depth and duration of response obtained with each successive relapse of disease is typical of the disease course, thereby highlighting a continuing need for new treatment options. With the introduction of monoclonal antibodies for multiple myeloma, new options for treatment in the relapsed setting are on the horizon. Among the new immunologic agents is daratumumab (DARA), a humanized antibody to CD38 with potent multifaceted antitumor activity. Phase I and II clinical trials have demonstrated significant reduction in serum M-protein and bone marrow plasma cell percentage in refractory patients, with an acceptable toxicity profile. Moreover, ex vivo studies have shown that DARA may be particularly useful in combination with currently used anti-myeloma agents. With a recent breakthrough drug designation by the US Food and Drug Administration, DARA shows promise as mono- and combination therapy for the treatment of relapsed/refractory multiple myeloma.