Citations

Abstract Background: Recent studies have demonstrated a benefit of adjuvant capecitabine in early stage breast cancer, particularly in patients with residual disease after neoadjuvant chemotherapy. Subset analyses suggest that patients with triple negative breast cancer (TNBC) may be more likely to benefit with capecitabine in this setting. However, more precise biomarkers to predict which patients are most likely to benefit from capecitabine are needed. Methods: The NanoString Breast Cancer 360TM (BC360) panel was used to quantify mRNA expression in FFPE tissue samples from patients with TNBC in the FinXX trial. Gene signature scores were analyzed using prespecified algorithms developed by NanoString. 30 additional custom genes related to capecitabine metabolism and function were added. Patients in FinXX trial were randomized to receive either 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF) or 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Cox proportional hazard ratio (HR) was used to determine the association of each gene signature with recurrence free survival (RFS). Results: A total of 111 samples from patients with TNBC in the FinXX trial were available for gene expression analysis. 57 patients were treated with T+CEF and 54 patients were treated with TX+CEX. The median age was 52 years and median follow up was 10.2 years. Consistent with the previous analysis of the FinXX trial, patients with TNBC had nonsignificant but favorable RFS with capecitabine (HR 0.60, 95% CI 0.27-1.3, p 0.2). Among 39 individual genes and metagene signatures generated with the BC360 panel, there were 4 gene signatures significantly associated with improved RFS favoring an addition of capecitabine with TX+CEX compared to T+CEF. These were the cytotoxic cell signature (HR 0.37, 95%CI 0.15-0.92, p 0.03), endothelial signature (HR 0.18, 95%CI 0.04-0.83, p 0.03), mast cell signature (HR 0.43, 95%CI 0.21-0.88, p 0.02), and PDL2 gene (HR 0.29, 95%CI 0.09-0.99, p 0.05). PAM50 intrinsic subtype was not predictive of capecitabine benefit within this TNBC subset. Moreover, we identified additional individual 12 genes that were significantly associated with capecitabine benefit (p-FDR<0.05). Among these genes, high expression of CES1, which encodes an enzyme that activates capecitabine, was significantly associated with improved RFS when treated with capecitabine (HR 0.71, 95%CI 0.32-1.61 with p-interaction=0.04). Conclusion: Our analyses demonstrated potential predictive individual genes and metagene signatures that may be used to identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Interestingly, several gene signatures related to immune response and genes related to capecitabine activation were associated with improved outcome in TNBC patients treated with capecitabine in the FinXX trial. While these findings are compatible with basic science reports, future studies are needed to validate the significance of these gene signatures as predictive biomarkers for capecitabine benefit. Citation Format: Chumsri S, Asleh K, Brauer HA, Mashadi-Hossein A, Lauttia LS, Lindman H, Nielsen TO, Joensuu H, Thompson EA. Predictive gene signatures of adjuvant capecitabine benefit in triple negative breast cancer in the FinXX trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-05.

Abstract Objectives To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. Methods Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. Results Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. Conclusion SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.

ObjectiveThe study aims to demonstrate the reproducibility and feasibility of creating a hemilaryngeal model with a medialized vocal fold (VF) using 3‐dimensional (3D) modeling techniques in both healthy larynges and those affected by cancer.Study DesignThree‐dimensional modeling of human larynges.SettingTertiary academic referral center and regenerative medicine laboratory.Subjects and MethodsComputed tomography (CT) scans from 10 healthy control and 10 patients with laryngeal cancer were segmented and imported into 3D modeling software. The larynx was cut sagittally to create a hemilaryngeal model and the vocal fold medialized. Measurements were taken from the CT and 3D model data and compared.ResultsAll control modeling data closely matched the CT data and were not statistically different from each other. There was a significant correlation between subglottic anteroposterior diameter and VF length (r2 = 0.78, P =. 0008), and it may be a valuable tool to infer true VF dimension in cases where disruption has occurred. The modeling data from patients with cancer did not show statistical difference to the control data, showing that accurate modeling can also be achieved in patients with laryngeal cancer.ConclusionCT scan‐based 3D modeling of the larynx and VF is possible and reproducible. The results closely match those previously reported in the literature and can also be replicated in cases with laryngeal cancer. This study paves the way for future de novo fabricated laryngeal scaffolds that can be synthesized using 3D printers and tailored to meet surgical demands.

Background: The AMPLIFY randomized clinical trial showed that apixaban was associated with significantly lower major bleeding (MB) compared to warfarin for patients with venous thromboembolism (VTE). The main objective of this study was to compare the risk of major bleeding (MB), clinically relevant non-major bleeding (CRNM), and recurrent VTE among VTE patients treated with apixaban vs warfarin in the US Medicare population. Methods: Patients (aged ≥65 years) prescribed apixaban or warfarin within 30 days following a VTE event diagnosed in hospital or ambulatory setting were identified from 01SEPT2014-31DEC2016 using 100% CMS Medicare data. The first apixaban or warfarin prescription claim outside of the hospital was defined as the index date. Patients were required to have had continuous health plan enrollment for 6 months and no parenteral or oral anticoagulant use before the index VTE event. Outcomes were assessed from index date to the earliest of discontinuation, switch, health plan disenrollment, death, 6 months post-index date, or 31DEC2016. One-to-one propensity score matching (PSM) was used to balance patient characteristics. Cox proportional hazard models were used to estimate the risk of MB, CRNM bleeding, and recurrent VTE. Results: Among 37,799 patients meeting inclusion criteria, 25,284 patients initiated warfarin (66.9%) and 12,515 patients initiated apixaban (33.1%). Post-PSM, 11,363 matched pairs of apixaban-warfarin patients were identified, with a mean follow-up period of 4.0 and 4.4 months. Mean age was 78 years; nearly 37% of patients were male with a mean Charlson Comorbidity Index score of 2.9 in both groups. Apixaban was associated with a lower risk of MB (HR: 0.76; 95% CI: 0.64-0.91) and CRNM bleeding (HR: 0.77; 95% CI: 0.70-0.84) compared to warfarin. The risk of recurrent VTE was similar among apixaban and warfarin patients (HR: 1.04; 95% CI: 0.75-1.43; Figure). Conclusions: Among US Medicare patients with VTE, apixaban was associated with a lower risk of MB and CRNM bleeding and similar risk of recurrent VTE compared to warfarin. These results may be supportive in evaluating the risk-benefit ratio of apixaban for treatment of elderly VTE patients.