The Benefit of Percutaneous Coronary Intervention Before Transcatheter Aortic Valve Replacement: A Multicenter Retrospective Outcome-Based Study.

There is inadequate evidence regarding the role of percutaneous coronary intervention (PCI) in patients who underwent transcatheter aortic valve replacement (TAVR). The current American Heart Association/American College of Cardiology guidelines are limited to class 2A recommendations for pre-TAVR revascularization in the setting of hemodynamically significant left main (LM), proximal left anterior descending (pLAD), or extensive bifurcation disease regardless of angina status. We performed a multicenter, retrospective, observational study assessing the benefit of PCI in patients with coronary artery disease who underwent transfemoral TAVR for severe symptomatic aortic stenosis. Patients were divided into 2 cohorts: (1) patients who did not undergo pre-TAVR PCI within the preceding 12 months (no-PCI group) and (2) patients who received pre-TAVR PCI within the preceding 12 months (PCI group). The primary outcome was defined as the composite end point of in-hospital and 30-day adverse events, including all-cause mortality, cardiac arrest, and myocardial infarction. Subgroup analyses were performed on patients with LM and/or pLAD disease and other high-risk features, including angina and heart failure. Comparisons were made between 1,809 consecutive patients (1,364 in the no-PCI group and 445 in the PCI group). There were no differences between the 2 cohorts regarding the primary composite outcome (2.0% vs 2.8%, p = 0.918) or individual secondary outcomes. Although LM/pLAD disease, New York Heart Association classes III to IV, and Society of Thoracic Surgeons risk score ≥8 were all independent predictors of the primary outcome, none of the subgroups demonstrated a benefit favoring PCI. In conclusion, there is no observed benefit from PCI within 12 months pre-TAVR in patients with severe aortic stenosis and concomitant coronary artery disease, including patients with LM/pLAD disease.

Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.

BACKGROUND: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients.

BACKGROUND: While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling. METHODS: We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti-CTLA-4 or anti-PD-1 therapy. Using a panel of ~ 40 surface and intracellular markers, we performed in-depth phenotypic and functional immune profiling to identify potential predictive biomarker candidates. RESULTS: Immune profiling of baseline peripheral blood samples using CyTOF revealed that anti-CTLA-4 and anti-PD-1 therapies have distinct sets of candidate biomarkers. The distribution of CD4+ and CD8+ memory/non-memory cells and other memory subsets was different between responders and non-responders to anti-CTLA-4 therapy. In anti-PD-1 (but not anti-CTLA-4) treated patients, we discovered differences in CD69 and MIP-1ß expressing NK cells between responders and non-responders. Finally, multivariate analysis was used to develop a model for the prediction of response. CONCLUSIONS: Our results indicate that anti-CTLA-4 and anti-PD-1 have distinct predictive biomarker candidates. CD4+ and CD8+ memory T cell subsets play an important role in response to anti-CTLA-4, and are potential biomarker candidates. For anti-PD-1 therapy, NK cell subsets (but not memory T cell subsets) correlated with clinical response to therapy. These functionally active NK cell subsets likely play a critical role in the anti-tumor response triggered by anti-PD-1.

Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.

Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480-92. ©2017 AACR.

Human cytomegalovirus is protected from inactivation by reversible binding to villous trophoblasts.

Human cytomegalovirus (HCMV) is the leading cause of congenital disease in the developed world. Transmission of HCMV to the fetus can occur through the villous placenta. Previously, we have shown that although syncytiotrophoblast (ST) can be productively infected, it is more likely that HCMV reaches the fetus through breaks in the ST than through basal release of progeny virus from infected ST. Progeny virus released on the maternal side could interact back with the ST and accumulate. In pregnancy, the organ distribution of disease burden is dramatically shifted, with the placenta reported as a reservoir for some pathogens. Thus, we propose that the ST layer functions as a viral reservoir, where HCMV is harbored and ultimately protected from degradation. Using primary cytotrophoblasts differentiated into an ST culture in vitro and challenged with HCMV, we have defined reversible binding between the virus and trophoblasts that protects the virus from degradation. This is blocked by treatment with low pH and neutralizing intravenous immunoglobulin. This reversible binding likely is to heparan sulfate proteoglycans, because heparin treatment blocks it. Importantly, we show that bound and released virus maintained in culture for at least 48 h results from inoculum and not progeny virus. Thus, the placenta has the potential to accumulate a relatively high steady-state level of virus within the intervillous space resulting from localized binding and release at the ST. A better understanding of the molecular interactions between HCMV and ST will provide insights regarding interventions to prevent or minimize congenital transmission.