Oleandrin and Its Derivative Odoroside A, Both Cardiac Glycosides, Exhibit Anticancer Effects by Inhibiting Invasion via Suppressing the STAT-3 Signaling Pathway

Ko, Young Shin,Rugira, Trojan,Jin, Hana,Park, Sang Won,Kim, Hye Jung MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.11

<P>The cardiac glycosides oleandrin and odoroside A, polyphenolic monomer compounds extracted from <I>Nerium oleander</I>, have been found to have antitumor effects on various tumors at low doses. However, the mechanisms of anticancer effects of oleandrin and odoroside A are not well known. Therefore, in this study, we aimed to investigate the anticancer effects of oleandrin and odoroside A and their associated mechanisms in highly metastatic MDA-MB-231 breast cancer cells and radiotherapy-resistant (RT-R) MDA-MB-231 cells. Our results showed that oleandrin and odoroside A dose-dependently decreased the colony formation and the invasion of both cell lines at nanomolar ranges. Furthermore, oleandrin (50 nM) and odoroside A (100 nM) reduced octamer-binding transcription factor 3/4 (OCT3/4) and β-catenin levels and matrix metalloproteinase-9 (MMP-9) activity. Finally, we found that phospho-STAT-3 levels were increased in MDA-MB-231 and RT-R-MDA-MB-231, but not in endothelial cells (ECs), and that the levels were significantly decreased by oleandrin (50 nM) and odoroside A (100 nM). Inhibition of phospho-signal transducer and activator of transcription (STAT)-3 significantly reduced OCT3/4 and β-catenin levels and MMP-9 activity, ultimately resulting in reduced invasion. These results suggest that the anticancer effects of oleandrin and odoroside A might be due to the inhibition of invasion through of phospho-STAT-3-mediated pathways that are involved in the regulation of invasion-related molecules.</P>

Cryopreserved fascia lata allograft use in surgical facial reanimation: a retrospective study of seven cases

Silan, Francesco,Consiglio, Fabio,Dell'Antonia, Francesco,Montagner, Giulia,Trojan, Diletta,Berna, Giorgio Korean Association of Maxillofacial Plastic and Re 2020 Maxillofacial Plastic Reconstructive Surgery Vol.42 No.-

Background: Facial palsy treatment comprises static and dynamic techniques. Among dynamic techniques, local temporalis transposition represents a reliable solution to achieve facial reanimation. The present study describes a modification of the temporalis tendon transfer using a cryopreserved fascia allograft. Case presentation: Between March 2015 and September 2018, seven patients with facial palsy underwent facial reanimation with temporalis tendon transfer and fascia lata allograft. Patients with long-term palsy were considered, and both physical and social functions were evaluated. The mean follow-up time was 21.5 months. No immediate complications were observed. Patients reported improvement in facial symmetry both in static and dynamic. Improvement was noticed also in articulation, eating, drinking, and saliva control. The Facial Disability Index revealed an improvement both in physical function subscale and in the social/well-being function subscale. Conclusions: This modified orthodromic technique allows to reduce the operative time and the risk of complications connected to the use of autologous tissues. The use of the cryopreserved fascia allografts from cadaveric donors seems to provide promising and long-standing results in the treatment of facial palsy.

Hepatic Safety and Biomarker Assessments in Sorafenib-Experienced Patients with Advanced Hepatocellular Carcinoma Treated with Nivolumab in the CheckMate-040 Study

( Thomas Yau ),( Tim Meyer ),( Ignacio Melero ),( Chiun Hsu ),( Masa-toshi Kudo ),( Su-pin Choo ),( Jorg Trojan ),( Theodore H. Welling ),( Yoon-koo Kang ),( Winnie Yeo ),( Akhil Chopra ),( Adyb Baaki 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Nivolumab (NIVO) is a fully human anti-PD-1 IgG4 mAb that demonstrated durable responses, manageable safety, and long-term survival in pts with advanced HCC (aHCC) in CheckMate-040 (El-Khoueiry AB et al. Lancet 2017). Here we present updated hepatic safety and biomarker analyses in sorafenib-experienced (sor-exp) pts in CheckMate-040. Methods: Sor-exp pts with or without chronic viral hepatitis received NIVO 3 mg/kg Q2W. Primary endpoint was objective response rate (ORR) reported by blinded independent central review using RECIST v1.1. Secondary endpoints included overall survival (OS), disease control rate (DCR), and safety. Exploratory analyses of on-treatment HCV and HBV viral kinetics and alpha-fetoprotein (AFP) levels were performed. Results: Median duration of follow-up was 14.9 mo. Baseline Child-Pugh scores of 5 or 6 and extrahepatic metastases were observed in 99% and 71% of pts, respectively. The ORR with NIVO was 14%; the DCR was 56%; median OS was 15.6 mo. Any-grade and grade 3-4 hepatic treatment-related AEs (TRAEs) occurred in 12 (8%) and 5 (3%) pts, respectively; 100% of grade 3-4 hepatic TRAEs resolved. Frequencies of grade 3-4 treatment-related ALT/AST elevations were 2%-3%. No drug-related deaths due to hepatic AEs occurred, and no new safety signals were observed. AFP levels at baseline were not associated with response; however, AFP levels in responders appeared to decrease on treatment. Updated data will be presented. Conclusions: NIVO demonstrated long-term survival and objective responses across etiologies and manageable overall and hepatic safety profile in aHCC. Responses occurred irrespective of baseline AFP levels, and AFP declines were associated with response.

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase ½ dose escalation and expansion trial

El-Khoueiry, A.B.,Sangro, B.,Yau, T.,Crocenzi, T.S.,Kudo, M.,Hsu, C.,Kim, T.Y.,Choo, S.P.,Trojan, J.,Welling, T.H.,Meyer, T.,Kang, Y.K.,Yeo, W.,Chopra, A.,Anderson, J.,dela Cruz, C.,Lang, L.,Neely, J. J. Onwhyn ; Elsevier Science Ltd 2017 The Lancet Vol.389 No.10088

Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods: We did a phase ½, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade ¾ treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Funding: Bristol-Myers Squibb.