A008 Presence of tissue factor and other components of atherosclerosis in human aortic valve stenosis

BackgroundIt is now generally accepted that calcific aortic valve disease is an atherosclerotic-like process. Recent studies in an experimental model of aortic valve sclerosis demonstrated the presence of tissue factor (TF), the main contributor to atherosclerotic plaque thrombogenicity, in diseased valve leaflets. We assessed the hypothesis that human aortic valve disease is an atherosclerotic-like process in which TF plays an important role and evaluated the valvular expression and localization of TF and other components of atherosclerosis.MethodsCalcified aortic valves (n=52) were obtained from patients undergoing aortic valve replacement. Leaflet structure, cellular and lipid infiltration and expression of TF, its inhibitors, VEGF and other components of atherosclerosis were evaluated by histological and immunohistochemical staining. TF, TFPI, osteopontin, MMP- 9, TIMP-1 and VEGF antigen were measured by ELISA and TF and alkaline phosphatase activity were determined using chromogenic assays. Finally, we performed semi-quantification of TF transcripts by RT- PCR and further analyzed protein expression by Western blot.ResultsHistological and immunohistochemical staining of the valve leaflets revealed neovascularisation at the centre of the lesions, overall macrophage and myofibroblast infiltration and the abundant presence of MMP-9. On the other hand, TF and TFPI were associated with calcification and extracellular lipid deposits in the fibrosa and the subendothelial layer of the aortic side of the leaflets. Correspondingly, TF antigen and activity were found to be higher in calcified regions of the valve leaflets (733.29±70.49pg/mgvs 429.40±73.17pg/mg and 144.75±14.65pg/mgvs 40.15±6.19pg/mg respectively (p<0.0001)). Similar results were found for osteopontin, MMP-9, TIMP-1 and VEGF. In contrast, TFPI antigen was found to be much lower in these calcified regions (722.54±153.92pg/mgvs 2459.28±285.36pg/mg (p<0.0001)).ConclusionThese results demonstrate that aortic valve lesions display several characteristics of atherosclerosis, including TF expression. In addition, we showed that TF is colocalized with calcification and lipid deposition. Further studies are now set up to evaluate the role of TF in aortic valve disease and its association with other components of the atherosclerotic process

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT0268950

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC

Pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of treatment options from the phase III KEYNOTE-040 trial

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Ankle pressure and ankle brachial index after heavy load incremental exercise

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Long-term response to second-line afatinib in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Analysis of the LUX-Head & Neck 1 (LHN1) trial

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Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G2/M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5′-nucleotidase and DNA polymerase-α. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs