Disruption of the molecular interaction between CD93 and IGFBP7 improves tumor vascular functions and thereby facilitates therapeutic interventions.

Immunotherapy is a rapidly growing field and represents a paradigm shift in the treatment of malignancies as it offers a new therapeutic approach beyond surgery, conventional chemotherapy, and radiation treatment. Targeting immune checkpoints, such as cytotoxic T‐lymphocyte‐associated antigen 4 and programmed death 1/programmed death ligand 1 has had immense clinical success resulting in sustained treatment response for a subset of patients with certain malignancies such as melanoma, non‐small‐cell lung cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, renal cell cancer, hepatocellular cancer, and metastatic colorectal cancer. Importantly, there has been limited success in the use of immunotherapy in the treatment of pancreatic cancer. Investigation into the complex tumor microenvironment of pancreatic cancer that is composed of immune cells, stromal cells, and extracellular matrix proteins has begun to shed light on important attributes of this microenvironment that act as barriers to the effective use of immunotherapy. In this review, we will discuss the progress that has been made in treating pancreatic cancer with immunotherapy, the barriers that have limited treatment success, and breakthroughs with combination treatments that hold promise for the future.

Objective: To compare short-term and oncologic outcomes of patients with cancer who underwent open pancreaticoduodenectomy (OPD) versus minimally invasive pancreaticoduodenectomy (MIPD) using the National Cancer Database. Summary Background Data: MIPD, including laparoscopic and robotic approaches, has continued to gain acceptance despite prior reports of increased short-term mortality when compared with OPD. Methods: Patients with pancreatic cancer diagnosed from 2010 to 2015 undergoing curative intent resection were selected from the National Cancer Database. Patients submitted to OPD were compared with those submitted to MIPD. Laparoscopic and robotic approaches were included in the MIPD cohort. The primary outcome was 90-day mortality; secondary outcomes included 30-day mortality, hospital length of stay, unplanned 30-day readmission, surgical margins, number of lymph nodes harvested, and receipt of adjuvant chemotherapy. Propensity score-weighted random effects logistic regression models were used to examine the adjusted association between surgical approach and the specified outcomes. Results: Between 2010 and 2015, 22,013 patients underwent OPD or MIPD for pancreatic cancer and 3754 (17.1%) were performed minimally invasively. On multivariable analysis, there was no difference in 90-day mortality between MIPD and OPD (OR, 0.92; 95% CI, 0.75–1.14). Patients undergoing MIPD were less likely to stay in the hospital for a prolonged time (OR, 0.75; 95% CI, 0.68–0.82). 30-day mortality, unplanned readmissions, margins, lymph nodes harvested, and receipt of adjuvant chemotherapy were equivalent between groups. Regardless of surgical approach, patients operated on at high volume centers had reduced 90-day mortality. Conclusion: Patients selected to receive MIPD for cancer have equivalent short-term and oncologic outcomes, when compared with patients who undergo OPD.

Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (αMHC‐CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte‐ vs. endothelial‐derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2‐CYP2C8 Tr and Tie2‐CYP2J2 Tr) or EET hydrolysis (Tie2‐sEH Tr). Compared to wild‐type (WT), αMHC‐CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2‐CYP2J2 Tr and Tie2‐sEH Tr hearts. Surprisingly, compared to WT, Tie2‐CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14%) and increased infarct size after I/R (from 51 to 61%). Tie2‐CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2‐CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10‐DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31%, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.—Edin, M. L., Wang, Z. J., Bradbury, J. A., Graves, J. P., Lih, F. B., DeGraff, L. M., Foley, J. F., Torphy, R., Ronnekleiv, O. K., Tomer, K. B., Lee, C. R., Zeldin, D. C. Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia‐reperfusion injury in isolated mouse heart. FASEB J. 25, 3436–3447 (2011). www.fasebj.org