Pancreatic Cancer CT: Prediction of Resectability according to NCCN Criteria.

Purpose To evaluate the diagnostic performance of CT in the determination of pancreatic cancer resectability according to the National Comprehensive Cancer Network (NCCN) criteria to predict R0 resection. Materials and Methods Structured reports of pancreatic CT clinically prepared by board-certified abdominal radiologists from January 2014 to March 2017 were retrospectively reviewed to assess resectability (resectable, borderline resectable, or unresectable) according to NCCN criteria (version 1.2017) in 616 patients (369 men, 247 women; mean age, 63 years ± 10 [standard deviation]) with pancreatic cancer. Negative resection margin (R0) rates were assessed based on CT resectability status in patients who underwent upfront surgery. R0 resection-associated factors were identified by using logistic regression analysis. Results In 371 patients who underwent surgery, R0 resection rates were 73% (171 of 235), 55% (57 of 104), and 16% (five of 32) for resectable, borderline resectable, and unresectable disease, respectively (P < .001). At multivariable analysis, tumor diameter larger than 4 cm (P < .001) and abutment to the portomesenteric vein (P < .001) were significantly associated with margin-positive resection in patients with resectable disease at CT. R0 resection rates were 80% (123 of 154) for resectable disease without portomesenteric vein abutment, 59% (48 of 81) for resectable disease with portomesenteric vein abutment, 83% (57 of 69) for resectable disease 2 cm or smaller, and 29% (five of 17) for tumors larger than 4 cm. Conclusion CT resectability is used to stratify patients with pancreatic cancer according to the possibility of R0 resection. Larger tumor size and tumor abutment to the portomesenteric vein are associated with margin-positive resection in patients with resectable pancreatic cancer. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Fowler in this issue.

Outcomes after endoscopic ultrasound-guided ethanol-lipiodol ablation of small pancreatic neuroendocrine tumors.

BACKGROUND AND AIM: Little is known about the standard care of small (<2 cm in diameter) pancreatic neuroendocrine tumors (PNET). The aim of the present study was to determine the clinical outcomes of small PNET after endoscopic ultrasound (EUS)-guided ethanol-lipiodol ablation (EUS-ELA). METHODS: In this prospective cohort study, consecutive patients who underwent EUS-ELA for PNET were enrolled and were followed for ≥3 years. Treatment efficacy was the primary outcome measure. RESULTS: In total, 33 patients who had 40 pathologically confirmed PNET (<2 cm in diameter) were enrolled for final analysis. A total of 63 EUS-ELA sessions were successfully carried out (mean, 1.9 sessions per patient, 1.6 sessions per tumor), which included 40 initial sessions and 23 repeated sessions owing to incomplete ablation. Median actual volume of ethanol-lipiodol mixture injected per session was 1.1 mL (IQR 0.8-1.9 mL). Complete ablation was achieved in 24 of 40 tumors (60%) with one (18 tumors, 45%) or two (24 tumors, 60%) sessions of EUS-ELA. Lipiodol retention within tumor had better treatment outcomes (P = 0.004). Rate of procedure-related adverse events was 3.2%. No malignancy or lymph node metastasis was discovered during a median follow up of 42 months (IQR 39-46 months). CONCLUSIONS: We found that EUS-ELA was a safe and effective alternative option in the management of PNET <2.0 cm in diameter; 60% of patients achieved complete ablation. Lipiodol retention within tumor may be a useful early predictor of treatment effectiveness. Trial registered at ClinicalTrials.gov (NCT 01902238).

Intravoxel incoherent motion MRI for monitoring the therapeutic response of hepatocellular carcinoma to sorafenib treatment in mouse xenograft tumor models.

Background With the introduction of targeted therapies, there has been a growing need for non-invasive imaging methods which accurately evaluate therapeutic effects and overcome the limitations of tumor size-based therapeutic response assessments. Purpose To assess diagnostic values of intra-voxel incoherent motion (IVIM) imaging in evaluating therapeutic effects of sorafenib on hepatocellular carcinoma (HCC) using mouse xenograft model. Material and Methods Twenty-four mice bearing Huh-7 were divided into a control group and two treatment groups received sorafenib doses of 5 mg/kg (5 mg-Tx) or 30 mg/kg (30 mg-Tx). IVIM imaging was performed using 10 b-values (0-900 s/mm2). The apparent diffusion coefficient (ADC), diffusion coefficient ( D), and perfusion fraction ( f) were measured for whole tumors and tumor periphery. Changes between baseline and post-treatment parameters ( Δ ADC, Δ D, and Δ f) were calculated, and these parameters were compared with microvessel density (MVD) and area of tumor cell death. Results The post-treatment f and Δ f for tumor periphery were significantly higher in control group, followed by 5 mg-Tx and 30 mg-Tx ( P < 0.001). MVD showed significant positive correlation with post-treatment f ( r = 0.584, P = 0.003) and negative correlation with D ( r = -0.495, P = 0.014) for tumor periphery, while no parameter showed significant correlation with area of tumor cell death. Conclusion The f is significantly correlated with MVD of HCC, and could potentially be used to evaluate the anti-angiogenic effects of sorafenib.

Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature.

Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC.

The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) arises in the backdrop of reflux-induced metaplastic phenomenon known as Barrett esophagus. The prognosis of advanced EAC is dismal, and there is an urgent need for identifying molecular targets for therapy. Serial Analysis of Gene Expression (SAGE) was performed on metachronous mucosal biopsies from a patient who underwent progression to EAC during endoscopic surveillance. SAGE confirmed significant upregulation of Axl "tags" during the multistep progression of Barrett esophagus to EAC. In a cohort of 92 surgically resected EACs, Axl overexpression was associated with shortened median survival on both univariate (p < 0.004) and multivariate (p < 0.036) analysis. Genetic knockdown of Axl receptor tyrosine kinase (RTK) function was enabled in two EAC lines (OE33 and JH-EsoAd1) using lentiviral short hairpin RNA (shRNA). Genetic knockdown of Axl in EAC cell lines inhibited invasion, migration, and in vivo engraftment, which was accompanied by downregulation in the activity of the Ral GTPase proteins (RalA and RalB). Restoration of Ral activation rescued the transformed phenotype of EAC cell lines, suggesting a novel effector mechanism for Axl in cancer cells. Pharmacological inhibition of Axl was enabled using a small molecule antagonist, R428 (Rigel Pharmaceuticals). Pharmacological inhibition of Axl with R428 in EAC cell lines significantly reduced anchorage-independent growth, invasion and migration. Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, indicative of receptor crosstalk. Axl RTK is an adverse prognostic factor in EAC. The availability of small molecule inhibitors of Axl function provides a tractable strategy for molecular therapy of established EAC.

Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer.

Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-kappaB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.