A senescence-mimicking (senomimetic) VEGFR TKI side-effect primes tumor immune responses via IFN/STING signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ('senomimetic') VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. Using a live-cell sorting method to detect beta-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened interferon (IFN) signaling and increased expression of IFN-stimulated genes (ISGs). These ISG increases were under the control of the STimulator of INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host:tumor cell contact while tumors grown from SM+ cells were more sensitive to PD-L1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side-effects may help identify TKIs that uniquely 'prime' tumors for enhanced sensitivity to PD-L1 targeted agents.

A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) not only disrupt tumor angiogenesis but also have many unexpected side effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ("senomimetic") VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. By using a live cell sorting method to detect ß-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened IFN signaling and increased expression of IFN-stimulated genes (ISGs). These ISGs increase under the control of the STimulator of the INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host-tumor cell contact while tumors grown from SM+ cells were more sensitive to PDL1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side effects may help identify TKIs that uniquely "prime" tumors for enhanced sensitivity to PDL1-targeted agents.

Novel pilot films providing indispensable information in pharmaco-cavernosography.

BACKGROUND: Conventional pharmaco-cavernosography provides little information on penile venous anatomy, although it is indispensible in documenting veno-occlusive erectile dysfunction (ED). We propose an innovative method, which may provide additional insight into the penile venous structure. METHODS: From July 2010 to November 2012, 96 impotent men, aged 20 to 75 years, underwent this method of pharmaco-cavernosography in which two sets of 60 mL of 50% omnipaque solution administered intracavernously by themselves. The first set of pilot cavernosograms was taken at intervals of five, ten, twenty and thirty seconds after the commencement of the injection. The second set of cavernosograms was taken in the same intervals within 30 minutes following the pilot set, preceded by the injection of 20 µg prostaglandin E1 (PGE1). Analysis was conducted on the drainage veins including deep dorsal vein (DDV), cavernosal veins (CVs) and para-arterial veins (PAVs) accordingly. The veins demonstrated in the pilot cavernosograms, and the second set, were compared in terms of venous numbers and presentation percentage. RESULTS: There was a statistically significant difference (P<0.001) between the total number of independent venous drainage channels and the presentation percentage of DDV, CVs and PAVs observed in the pilot cavernosograms, and those in second set (4.5 vs. 2.1; 97.47%, 60.33%, and 38.91% vs. 57.06%, 29.34%, and 19.08%, respectively). CONCLUSIONS: Compared with conventional pharmaco-cavernosography methods, pilot cavernosograms are readily able to show detailed penile venous anatomy. It is therefore may be concluded that pilot cavernosograms is a valuable addition to conventional protocols of pharmaco-cavernosography.

Venous ligation: a novel strategy for glans enhancement in penile prosthesis implantation.

Although penile implantation remains a final solution for patients with refractory impotence, undesirable postoperative effects, including penile size reduction and cold sensation of the glans penis, remain problematic. We report results of a surgical method designed to avoid these problems. From 2003 to 2013, 35 consecutive patients received a malleable penile implant. Of these, 15 men (the enhancing group) were also treated with venous ligation of the retrocoronal venous plexus, deep dorsal vein, and cavernosal veins. The remaining 20 men formed the control group, treated with only a penile implant. Follow-up ranged from 1.1 to 10.0 years, with an average of 6.7 ± 1.5 years. Although preoperative glanular dimension did not differ significantly between the two groups, significant respective difference at one day and one year postoperatively was found in the glanular circumference (128.8 ± 6.8 mm versus 115.3 ± 7.2 mm and 130.6 ± 7.2 mm versus 100.5 ± 7.3 mm; both P<0.05), radius (38.8 ± 2.7 mm versus 37.1 ± 2.8 mm and 41.5 ± 2.6 mm versus 33.8 ± 2.9 mm; latter P<0.01), and satisfaction rate (91.7% versus 53.3%, P<0.01) as well. Based on our results, selective venous ligation appears to enhance the glans penis dimension in implant patients.