Photodynamic therapy-induced angiogenic signaling: consequences and solutions to improve therapeutic response.

Photodynamic therapy (PDT) can be a highly effective treatment for diseases ranging from actinic keratosis to cancer. While use of this therapy shows great promise in preclinical and clinical studies, understanding the molecular consequences of PDT is critical to designing better treatment protocols. A number of publications have documented alteration in angiogenic factors and growth factor receptors following PDT, which could abrogate treatment effect by inducing angiogenesis and re-establishment of the tumor vasculature. In response to these findings, work over the past decade has examined the efficacy of combining PDT with molecular targeting drugs, such as anti-angiogenic compounds, in an effort to combat these PDT-induced molecular changes. These combinatorial approaches increase rates of apoptosis, impair pro-tumorigenic signaling, and enhance tumor response. This report will examine the current understanding of PDT-induced angiogenic signaling and address molecular-based approaches to abrogate this signaling or its consequences thereby enhancing PDT efficacy.

High-risk patients with inoperative aortic stenosis: use of transapical, transaortic, and transcarotid techniques.

BACKGROUND: Patient characteristics and procedural outcomes from nontransfemoral (non-TF) transcatheter aortic valve replacement (TAVR) in high-risk or inoperable patients with aortic stenosis have been incompletely reported. The purpose of this study was to compare outcomes with non-TF TAVR access techniques including transapical (TA), transaortic (TAo), and transcarotid (TC) TAVR with a balloon-expandable valve. METHODS: A retrospective review was performed of all patients undergoing TA, TAo, and TC TAVR from 2007 to 2013 at Emory University. Preoperative risk factors and postoperative outcomes were evaluated using Valve Academic Research Consortium-2 definitions. RESULTS: Of 469 patients undergoing TAVR during that period at our institution, 139 underwent TA TAVR, 35 had Tao TAVR, and 11 had TC TAVR. Patients undergoing TC TAVR were younger than those undergoing TA TAVR and TAo TAVR (mean ages: TC, 68.9 ± 23.6 years; TA, 81.3 ± 7.7 years; Tao, 83.8 ± 8.3 years; p = 0.017). Most patients undergoing TAo TAVR were women (82.9%), whereas patients undergoing TA TAVR were more likely to be men (62.6%). Slightly more than half of patients undergoing TA TAVR (54.7%) and TC (54.6%) TAVR had undergone previous coronary artery bypass grafting (CABG), whereas no patients underwent TAo TAVR (0%). There was no preoperative difference in ejection fraction, New York Heart Association classification, significant chronic obstructive pulmonary disease, and The Society of Thoracic Surgeons predicted risk of mortality between TA TAVR, Tao TAVR, and TC TAVR, respectively. Average postoperative length of stay was 9 to 11 days and was similar among groups (p = 0.22). There were 13 (9.4%) TA TAVR operative deaths and 4 (11.4%) operative deaths in the TAo TAVR group. There were no deaths in the TC TAVR group. CONCLUSIONS: In high-risk and inoperable patients who are not candidates for TF TAVR, careful selection of alternative access options can lead to excellent and comparable postoperative outcomes.

Tumor vascular microenvironment determines responsiveness to photodynamic therapy.

The efficacy of photodynamic therapy (PDT) depends upon the delivery of both photosensitizing drug and oxygen. In this study, we hypothesized that local vascular microenvironment is a determinant of tumor response to PDT. Tumor vascularization and its basement membrane (collagen) were studied as a function of supplementation with basement membrane matrix (Matrigel) at the time of tumor cell inoculation. Effects on vascular composition with consequences to tumor hypoxia, photosensitizer uptake, and PDT response were measured. Matrigel-supplemented tumors developed more normalized vasculature, composed of smaller and more uniformly spaced blood vessels than their unsupplemented counterparts, but these changes did not affect tumor oxygenation or PDT-mediated direct cytotoxicity. However, PDT-induced vascular damage increased in Matrigel-supplemented tumors, following an affinity of the photosensitizer Photofrin for collagen-containing vascular basement membrane coupled with increased collagen content in these tumors. The more highly collagenated tumors showed more vascular congestion and ischemia after PDT, along with a higher probability of curative outcome that was collagen dependent. In the presence of photosensitizer-collagen localization, PDT effects on collagen were evidenced by a decrease in its association with vessels. Together, our findings show that photosensitizer localization to collagen increases vascular damage and improves treatment efficacy in tumors with greater collagen content. The vascular basement membrane is thus identified to be a determinant of therapeutic outcome in PDT of tumors.