Iterative Changes in Risk-Stratified Pancreatectomy Clinical Pathways and Accelerated Discharge After Pancreaticoduodenectomy.

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. RESULTS: There 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.

Risk-Stratified Pancreatectomy Clinical Pathway Implementation and Delayed Gastric Emptying.

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. METHODS: A 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. RESULTS: Among 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.

Correction: A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

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

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors.

Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy.Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents.Results: Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple-negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDXs also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR, and MEK inhibitors repressed growth but did not cause tumor regression. The PARP inhibitor talazoparib caused dramatic regression in five of 12 PDXs. Notably, four of five talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations.Conclusions: PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers. Clin Cancer Res; 23(21); 6468-77. ©2017 AACR.

Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer.

BACKGROUND: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. METHODS: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy. In vivo efficacy was tested both as a single agent and in combination therapy in TNBC patient-derived xenografts (PDXs). RESULTS: Selinexor demonstrated growth inhibition in all 14 TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44 nM, range 11 to 550 nM) than were estrogen receptor (ER)-positive breast cancer cell lines (median IC50 > 1000 nM, range 40 to >1000 nM; P = 0.017). In multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin, and doxorubicin in vitro. Selinexor as a single agent reduced tumor growth in vivo in four of five different TNBC PDX models, with a median tumor growth inhibition ratio (T/C: treatment/control) of 42% (range 31 to 73%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin (average T/C ratios of 27% and 12%, respectively). CONCLUSIONS: Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy.

A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

PURPOSE: Molecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment. EXPERIMENTAL DESIGN: 1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform. RESULTS: 527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials. CONCLUSION: Expanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.