Natalia Paez Arango’s research while affiliated with University of Texas MD Anderson Cancer Center and other places

Background Previous implementation of risk-stratified pancreatectomy clinical pathways (RSPCPs) decreased length of stay (LOS) following pancreaticoduodenectomy (PD). This study’s primary aim was to measure the association of iterative RSPCP revisions with accelerated discharge and early postoperative outcomes.Methods This is a retrospective cohort study of a prospectively maintained surgical database (10/2016–9/2020). In February 2019, revised RSPCPs were implemented with earlier nasogastric tube (NGT) removal (postoperative day [POD] 1 for low risk; POD 2 for high risk) and updated drain fluid amylase cutoffs for POD 1/POD 3 removal. Perioperative outcomes between original and revised pathways were compared. Predictors of accelerated discharge (defined as ≤ POD 5 for low risk; ≤ POD 6 for high risk) were identified.ResultsThere were 233 (36% high risk) patients in original and 131 (32% high risk) in revised RSPCPs. After revision, the rate of POD 1 NGT removal was higher while POD ≤ 3 drain removal was similar. Median LOS decreased for low risk (5 vs. 6 days, p = 0.011) and high risk (6 vs. 9 days, p = 0.005) with no increase in delayed gastric emptying, postoperative pancreatic fistula, or readmissions. With POD 1 NGT removal, diet tolerance was earlier without increased NGT reinsertions. In low-risk patients, younger age, POD 1 NGT removal, and POD ≤ 3 drain removal were independent predictors of accelerated discharge. In high-risk patients, POD 1 NGT removal and POD ≤ 3 drain removal were independent predictors of accelerated discharge.Conclusions Following iterative revisions in RSPCPs, LOS after PD decreased further without increasing readmissions, and NGTs were removed earlier without increased reinsertions. Early NGT and drain removal are modifiable practices within RSPCPs that are associated with accelerated discharge.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. Significance These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.

Background Delayed gastric emptying (DGE) is a frequent complication after pancreaticoduodenectomy (PD) that impairs recovery and quality of life. The purpose of this study was to assess the impact risk-stratified pancreatectomy clinical pathways (RSPCPs) had on delayed gastric emptying (DGE) and identify factors associated with DGE in a contemporary period.MethodsA single-institution, prospective database was queried for consecutive PDs during July 2011–November 2019. Using international definitions, DGE rates were compared between periods before and after RSPCPs were implemented in 2016, classifying patients according to their postoperative pancreatic fistula (POPF) risk. Risk factors were analyzed to identify modifiable targets.ResultsAmong 724 elective PDs, 552 (76%) were for adenocarcinoma and 172 (24%) for other diagnoses. Of the 197 (27%) patients with DGE, 119 (16%) had type A, 41 (6%) type B, and 38 (5%) type C. In the overall cohort, DGE rates were higher with pylorus-preserving vs. classic hand-sewn reconstruction (odds ratio [OR] − 1.84; p < 0.001), postoperative abscess (OR − 2.54; p = 0.003), and non-white patients (p = 0.007), but lower after implementation of RSPCPs (OR − 0.34, p < 0.001). In the 374 patients treated with RSPCPs, only 17% (n = 65/374) developed DGE. Patients with protocol-compliant NGT removal ≤ 48 h were less likely to experience DGE (OR − 1.46, p = 0.042).Conclusion Our data suggest that implementation of preoperatively assigned RSPCPs as a care bundle was the most important factor in decreasing DGE. These gains were accentuated in patients who underwent early nasogastric tube removal and had a classic hand-sewn gastro-jejunostomy reconstruction. Application of these modifiable factors is generalizable with low implementation barriers.

There is a pressing need to identify improved therapies for triple negative breast cancers (TNBC) resistant to standard chemotherapy. To identify potential molecular targets, we performed RNA sequencing of pre-treatment biopsies from 43 patients with operable TNBC who received neoadjuvant anthracycline and taxane-based chemotherapy. Ingenuity pathway analysis demonstrated that the top canonical pathway associated with higher likelihood of recurrence was higher expression of oxidative phosphorylation (OXPHOS) signature. We therefore sought to determine the efficacy of IACS-10759, a potent inhibitor of OXPHOS, in 10 TNBC patient-derived xenografts (PDX), 8 generated from chemotherapy-resistant tumors. Partial response was observed in one PDX model and prolonged disease stabilization in 5 of 10 PDXs. PDXs with higher expression of protein coding mitochondrial genes were more sensitive to IACS-10759. AXL overexpression was associated with intrinsic and acquired IACS-10759 resistance. The combination of cabozantinib, a multi-kinase inhibitor targeting AXL, with IACS-10759 significantly improved responses in TNBC PDXs. In contrast, selective AXL inhibitor BGB324 or knockdown of AXL did not enhance IACS-10759 sensitivity. In addition, an in vivo synthetic lethality screen identified CDK4, PARP1 and PARP2 as potential combination targets for IACS-10759. Palbociclib as well as talazoparib enhanced growth inhibitory effect of OXPHOS inhibition in vitro and Our data suggests that OXPHOS is a promising target in chemoresistant TNBC. IACS-10759 is currently in Phase 1 testing, including TNBC. Further work is needed to determine the optimal biomarker-driven combination partners. Citation Format: Kurt Evans, Stacy Moulder, Erkan Yuca, Stephen Scott, Natalia Paez Arango, Maryam Shariati, Christopher P Vellano, Turcin Saridogan, Xiaofeng Zheng, Ana Maria Gonzalez-Angulo, Ming Zhao, Xiaoping Su, Coya Tapia, Ken Chen, Argun Akcakanat, Charles M Perou, Bora Lim, Debu Tripathy, Timothy A Yap, Maria E Di Francesco, Giulio Draetta, Philip Jones, Joe Marszalek, Funda Meric-Bernstam. Oxidative phosphorylation is a metabolic vulnerability in chemotherapy resistant triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C016. doi:10.1158/1535-7163.TARG-19-C016

[This corrects the article DOI: 10.18632/oncotarget.16018.].