Combination of yttrium-90 radioembolization with stereotactic body radiation therapy in the treatment of portal vein tumor thrombosis

Purpose@#Portal vein tumor thrombosis (PVTT) from cancer involving the liver carries a dismal prognosis, with median overall survival (OS) ranging from 2 to 5 months. While treatment with yttrium-90 (90Y) radioembolization alone may improve outcomes, overall prognosis remains poor. We hypothesize that the combination of 90Y radioembolization to the parenchymal component of the tumor and stereotactic body radiation therapy (SBRT) to the vascular component is a safe and effective means of improving outcomes. @*Materials and Methods@#A single center retrospective review identified 12 patients with cancers involving the liver who received both 90Y radioembolization and SBRT to the PVTT between May 2015 to August 2020. Primary endpoint was the 90-day toxicity rate by the Common Terminology Criteria for Adverse Events version 5.0. Secondary endpoints were the best response rate based on the Response Evaluation Criteria in Solid Tumors v1.1, local control rate, portal vein (PV) patency rate, and median OS. @*Results@#Patients received a median 90Y dose of 104.3 Gy (range, 83.3 to 131.7 Gy) and a median 5-fraction SBRT dose of 32.5 Gy (range, 27.5 to 50 Gy). There were no late toxicities reported, and only 7 acute grade 1 toxicities reported: elevation of liver function tests (17%), nausea (17%), fatigue (17%), and esophagitis (8%). Local control was 83%. 58% of patients had a patent PV after treatment. With a median follow-up time of 28 months, 1-year OS was 55% with a median OS of 14 months. @*Conclusion@#Combination 90Y radioembolization and SBRT appears to be safe and effective in the treatment of PVTT. Larger prospective studies are warranted to better evaluate this combination treatment approach.

Combination of yttrium-90 radioembolization with stereotactic body radiation therapy in the treatment of portal vein tumor thrombosis

Purpose@#Portal vein tumor thrombosis (PVTT) from cancer involving the liver carries a dismal prognosis, with median overall survival (OS) ranging from 2 to 5 months. While treatment with yttrium-90 (90Y) radioembolization alone may improve outcomes, overall prognosis remains poor. We hypothesize that the combination of 90Y radioembolization to the parenchymal component of the tumor and stereotactic body radiation therapy (SBRT) to the vascular component is a safe and effective means of improving outcomes. @*Materials and Methods@#A single center retrospective review identified 12 patients with cancers involving the liver who received both 90Y radioembolization and SBRT to the PVTT between May 2015 to August 2020. Primary endpoint was the 90-day toxicity rate by the Common Terminology Criteria for Adverse Events version 5.0. Secondary endpoints were the best response rate based on the Response Evaluation Criteria in Solid Tumors v1.1, local control rate, portal vein (PV) patency rate, and median OS. @*Results@#Patients received a median 90Y dose of 104.3 Gy (range, 83.3 to 131.7 Gy) and a median 5-fraction SBRT dose of 32.5 Gy (range, 27.5 to 50 Gy). There were no late toxicities reported, and only 7 acute grade 1 toxicities reported: elevation of liver function tests (17%), nausea (17%), fatigue (17%), and esophagitis (8%). Local control was 83%. 58% of patients had a patent PV after treatment. With a median follow-up time of 28 months, 1-year OS was 55% with a median OS of 14 months. @*Conclusion@#Combination 90Y radioembolization and SBRT appears to be safe and effective in the treatment of PVTT. Larger prospective studies are warranted to better evaluate this combination treatment approach.

Modulation of Immunosuppression by Oligonucleotide-Based Molecules and Small Molecules Targeting Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exert suppressive function on the immune response. MDSCs expand in tumor-bearing hosts or in the tumor microenvironment and suppress T cell responses via various mechanisms, whereas a reduction in their activities has been observed in autoimmune diseases or infections. It has been reported that the symptoms of various diseases, including malignant tumors, can be alleviated by targeting MDSCs. Moreover, MDSCs can contribute to patient resistance to therapy using immune checkpoint inhibitors. In line with these therapeutic approaches, diverse oligonucleotide-based molecules and small molecules have been evaluated for their therapeutic efficacy in several disease models via the modulation of MDSC activity. In the current review, MDSC-targeting oligonucleotides and small molecules are briefly summarized, and we highlight the immunomodulatory effects on MDSCs in a variety of disease models and the application of MDSC-targeting molecules for immuno-oncologic therapy.

Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs)

Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate NF-κB signaling. Moreover, expression of PD-L1 and CD80 on PD-1+ MDSCs was higher than on PD-1− MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in PD-1+ MDSCs than in PD-1− MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that PD-1+ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.