Citations

Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.

Background. Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. Methods. Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. Results. Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. Conclusions. Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

Abstract Background The neo-squamous epithelium that replaces columnar epithelium after successful endoscopic ablation of Barrett's esophagus (BE) has not been fully characterized in regard to its structural and functional integrity. Intercellular space is a surrogate marker for epithelial structural integrity and mucosal impedance (MI) is a surrogate for transepithelial resistance and thus epithelial functional integrity. Impairment of the structural and functional integrity may influence recurrence following successful ablation. We aimed to measure the esophageal epithelial intercellular space diameter and MI in the neo-squamous and normal squamous epithelium of patients who underwent successful radiofrequency ablation for dysplastic BE. Methods Forty patients with complete remission of intestinal metaplasia (CRIM) (defined as two negative surveillance endoscopies for intestinal metaplasia) were prospectively recruited. Patients were excluded if they had endoscopic evidence of esophagitis. MI measurements were taken at 1 cm above the GE junction and 2 cm above the prior BE segment (targeting uninvolved squamous epithelium), using a novel through the scope MI probe. Endoscopic biopsies were also taken at these corresponding sites to assess intercellular space diameter using transmission electron microscopy (TEM) using standard techniques. Results 80% of patients were male with a mean age of 69 years. Mean follow since achieving CRIM was 30 months. 39 patients underwent RFA for dysplasia. The mean intercellular space diameter was higher in the neo-squamous epithelium (1.01 μm) when compared to the untreated native squamous epithelium (0.96 μm) [Difference of 0.056 μm, 95% CI of -0.036 to 0.148, P = 0.228]. The mean MI was significantly lower in the neosquamous epithelium (4001.3 Ω) when compared to the untreated native epithelium (5168.1 Ω) [Difference of 1166.7 Ω, 95% CI 418.8 to 1914.6, P = 0.003]. Conclusion Neo-squamous epithelium that replaces BE epithelium following successful endoscopic therapy for BE appears to be functionally and likely structurally deficient with regards to acid reflux barrier function, when compared to native squamous esophageal epithelium. This impairment may be associated with recurrence following successful ablation. Disclosure All authors have declared no conflicts of interest.

e15641 Background: CC pts with biliary stents or catheters are prone to have obstruction/infection and studies show 20-40% present with fever/or jaundice requiring urgent treatment for which there is no uniform guideline. We aimed to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: We recruited 13 physician experts from relevant specialty, geography, and practice settings. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a 1-9 scale and classified as appropriate, inappropriate, or uncertain. Scenarios with > 2 ratings of 1-3 (inappropriate) and > 2 ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions (92%) and the UK (8%); had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting, but re-rated only 288 clinical scenarios as they felt that ongoing treatment with chemotherapy did not influence decision-making. Disagreement decreased from 37.5% before the meeting to 10.4% after. Consensus statements are summarized in the table below. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in urgent management of ascending cholangitis in pts with CC. (Support: The Cholangiocarcinoma Foundation). [Table: see text]

Abstract SIAH is a new and potent anti-K-RAS drug target in human cancer. The oncogenic EGFR/HER2/K-RAS pathway activation is pivotal in driving uncontrolled tumor growth and systemic metastasis. Thus, counteracting ERBB/K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor growth is an important area for new therapy development against late-stage and metastatic cancer. Guided by Drosophila studies, we found that SIAH (Seven-In-Absentia Homologue) is the most downstream “gatekeeper” required for proper K-RAS signaling. Based on its extraordinarily evolutionary conservation, SIAH E3 ligase is well positioned to serve as an ideal drug target for developing new anti-K-RAS and anticancer therapy. We have shown that anti-SIAH-based therapy is indeed effective in inhibiting tumorigenesis and metastasis of pancreatic, lung and breast cancer cells in xenograft models. Importantly, we have shown that anti-SIAH-based anti-K-RAS strategy is effective against well-established, super-large and late-stage pancreatic and triple-negative breast tumors in a xenograft model in vivo. Through these studies, we have successfully identified a new oncogenic K-RAS "vulnerability," SIAH, in high-grade metastatic cancer. We aim to design and develop potent SIAH inhibitor, and translate these findings to the clinic to benefit more cancer patients with therapy-refractory, relapsed and metastatic diseases in the future. SIAH is a therapy-responsive and prognostic biomarker in human cancer: SIAH expression can be used to monitor tumor responses, and identify resistant tumor clones post-NST. SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two robust, sensitive and prognostic biomarkers to predict survival in breast cancer patients with lymph node metastases. The prognostic power of SIAH and EGFR, alone or in combination, is comparable to the clinical gold standards of clinical predictors (LN positivity, mammary tumor size, grade, stage and molecular subtypes in combination), and imaging-guided technology. A marked reduction in SIAH/EGFR expression post-NST would indicate effective therapy and increased survival, while persistent high SIAH/EGFR expression post-NST would indicate ineffective therapy and decreased survival. The therapy-induced changes in SIAH expression are prognostic in quantifying effective/ineffective therapies, differentiating partial responders, identifying resistant tumor clones, and predicting remission/relapse in breast cancer at neoadjuvant settings. The identification of therapy-responsive and prognostic biomarkers is of paramount importance to stratify patients and guide therapies in clinical oncology and personalized medicine. By validating the RAS/SIAH pathway-centered prognostic biomarkers, we hope to guide standard therapies and improve patient survival in the future. Citation Format: Amy H. Tang, Robert E. Van Sciver, Elizaveta Svyatova, Kevin Kanda, Michael P. Lee, Caroline Dasom Lee, Lauren L. Siewertsz Van Reesema, Alex C, Lafever, Amber L. Collier, Apoorva S. Iyer, L.D. Britt, Janet S. Winston, Cynthia A. Allen, David Z. Chang, Gloria M. Petersen, Richard A. Hoefer. Conquering undruggable oncogenic K-RAS-driven incurable metastatic cancer, and delivering precision medicine at neoadjuvant settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 584.