The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer.

Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer.

Enhanced recovery pathway after open pancreaticoduodenectomy reduces postoperative length of hospital stay without reducing composite length of stay.

BACKGROUND/PURPOSE: There is no data regarding the impact of enhanced recovery pathways (ERP) on composite length of stay (CLOS) after procedures with increased risk of morbidity and mortality, such as pancreaticoduodenectomy. METHODS: Patients undergoing open pancreaticoduodenectomy before and after implementation of ERP were prospectively followed for 90 days after surgery and complications were severity graded using the Modified Accordion Grading System. A retrospective analysis of patient outcomes were compared before and after instituting ERP. 1:1 propensity score matching was used to compare ERP patient outcomes to those of matched pre-ERP patients. CLOS is defined as postoperative length of hospital stay (PLOS) plus readmission length of hospital stay within 90 days after surgery. RESULTS: 494 patients underwent open pancreaticoduodenectomy - 359 pre-ERP and 135 ERP. In a 1:1 propensity-score-matched analysis of 110 matched pairs, ERP patients had significantly decreased superficial surgical site infections (5.5% vs 15.5% p = 0.015) and significantly increased rates of urinary retention (29.1% vs 7.3% p < 0.0001) compared to matched pre-ERP patients. However, overall complication rate and 90-day readmission rate were not significantly different between matched groups. Propensity score-matched ERP patients had significantly decreased PLOS (7 days vs 8 days p = 0.046) compared to matched pre-ERP patients, but CLOS was not significantly different (9 days vs 9.5 days p = 0.615). CONCLUSION: ERP may reduce PLOS but might not impact the total postoperative time spent in the hospital (i.e. CLOS) within 90 days after pancreaticoduodenectomy.

Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer.

PURPOSE: FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). RESULTS: Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27-Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. CONCLUSIONS: Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.

Extending Enhanced Recovery after Surgery Protocols to the Post-Discharge Setting: A Phone Call Intervention to Support Patients after Expedited Discharge after Pancreaticoduodenectomy.

The goal of this pilot study was to track patient outcomes after an expedited discharge after enhanced recovery after surgery (ERAS) pathway for pancreaticoduodenectomy (PD). A quantitative content analysis approach was used. All PD patients in a single academic medical center between February 2017 and June 2018 were called twice by specialized physician extenders after discharge. A semi-structured interview approach was used to identify patient's symptoms or concerns, proactively educate them, and provide outpatient management when indicated. A detailed narrative of the conversation was documented. Ninety patients (mean age 66.3; 58.1% males) were included in the study. Of all, 88.9 per cent of the patients received follow-up phone calls in accordance with our PD ERAS protocol. Among the 80 patients called, 71 (88.8%) reported at least one symptom, issue, or self-care need. The most common issues involved bowel movements and nutrition. A total of 147 interventions were performed to address patient needs including medication management, local care coordination, and outpatient referral to a healthcare provider. The intervention led to the identification of 15 patients for earlier evaluation. This identification was associated with the total number of reported symptoms (X² = 15.6, P = 0.004). Most patients require additional care after discharge after traditional ERAS pathways. ERAS transitional care protocols uncovered an unmet need for additional patient support after PD.