Clinical decision pathway and management of locally advanced head and neck squamous cell carcinoma: A multidisciplinary consensus in Asia-Pacific.

OBJECTIVES: To develop consensus on patient characteristics and disease-related factors considered in deciding treatment approaches for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) based on real-world treatment patterns in 4 territories in Asia-Pacific. METHODS: A three-round modified Delphi involving a multidisciplinary panel of HN surgeons, medical oncologists, and radiation oncologists was used. Of 41 panelists recruited, responses of 26 from Australia, Japan, Singapore, and Taiwan were analyzed. All panelists had ≥five years' experience managing LA-HNSCC patients and treated ≥15 patients with LA-HNSCC annually. RESULTS: All statements on definitions of LA-HNSCC, treatment intolerance and cisplatin dosing reached consensus. 4 of 7 statements on unresectability, 2 of 4 on adjuvant chemoradiotherapy, 7 of 13 on induction chemotherapy, 1 of 8 on absolute contraindications and 7 of 11 on relative contraindications to high-dose cisplatin did not reach consensus. In all territories except Taiwan, high-dose cisplatin was preferred in definitive and adjuvant settings for patients with no contraindications to cisplatin; weekly cisplatin (40 mg/m2) preferred for patients with relative contraindications to high-dose cisplatin. For Taiwan, the main treatment option was weekly cisplatin. For patients with absolute contraindications to cisplatin, carboplatin ± 5-fluorouracil or radiotherapy alone were preferred alternatives in both definitive and adjuvant settings. CONCLUSION: This multidisciplinary consensus provides insights into management of LA-HNSCC in Asia-Pacific based on patient- and disease-related factors that guide selection of treatment modality and systemic treatment. Despite strong consensus on use of cisplatin-based regimens, areas of non-consensus showed that variability in practice exists where there is limited evidence.

Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats.

The anaphylatoxin C5a generated by activation of the innate immunity complement system is a potent inflammatory peptide mediator through the G-protein-coupled receptor C5aR (CD88) present in immune-inflammatory cells, including monocytes, macrophages, neutrophils, T cells, and mast cells. Inflammatory cells infiltrate and initiate the development of fibrosis in the chronically hypertensive heart. In this study, we have investigated whether treatment with a selective C5aR antagonist prevents cardiovascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Control and DOCA-salt rats were treated with PMX53 (AcF-[OPdChaWR], 1 mg·kg·d oral gavage) for 32 days; structural and functional changes in cardiovascular system were determined. DOCA-salt hypertension increased leukocyte extravasation into ventricular tissue, increasing collagen deposition and ventricular stiffness; PMX53 treatment attenuated these changes, thereby improving cardiac function. Further, treatment with PMX53 suppressed an increased expression of C5aR in the left ventricle from DOCA-salt rats, consistent with the reduced infiltration of inflammatory cells. Vascular endothelial dysfunction in thoracic aortic rings was attenuated by PMX53 treatment, but systolic blood pressure was unchanged in DOCA-salt rats. In the heart, PMX53 treatment attenuated inflammatory cell infiltration, fibrosis, and ventricular stiffness, indicating that C5aR is critically involved in ventricular remodeling by regulating inflammatory responses in the hypertensive heart.

EphB/ephrin-B interactions mediate human MSC attachment, migration and osteochondral differentiation.

Bone marrow derived mesenchymal stem/stromal cells (MSC) contribute to skeletal tissue formation and the regulation of haematopoiesis. The Eph/ephrin family of receptor tyrosine kinases is potentially important in the maintenance of the stem cell niche within neural, intestinal and dental tissues and has recently been shown to play a role in regulating bone homeostasis. However, the contribution of EphB/ephrin-B molecules in human MSC function remains to be determined. In the present study, EphB and ephrin-B molecules were expressed by ex vivo expanded human MSC populations and within human bone marrow trephine samples. To elucidate the contribution of EphB/ephrin-B molecules in MSC recruitment, we performed functional spreading and migration assays and showed that reverse ephrin-B signalling inhibited MSC attachment and spreading by activating Src-, PI3Kinase- and JNK-dependent signalling pathways. In contrast, forward EphB2 signalling promoted MSC migration by activating the Src kinase- and Abl-dependent signalling pathways. Furthermore, activation of ephrin-B1 and/or ephrin-B2 molecules expressed by MSC was found to increase osteogenic differentiation, while ephrin-B1 activation promoted chondrogenic differentiation. These observations suggest that EphB/ephrin-B interactions may mediate the recruitment, migration and differentiation of MSC during bone repair.

Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents.

The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact-mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the "low-affinity" ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents.

The role of the Eph-ephrin signalling system in the regulation of developmental patterning.

The Eph and ephrin system, consisting of fourteen Eph receptor tyrosine kinase proteins and nine ephrin membrane proteins in vertebrates, has been implicated in the regulation of many critical events during development. Binding of cell surface Eph and ephrin proteins results in bi-directional signals, which regulate the cytoskeletal, adhesive and motile properties of the interacting cells. Through these signals Eph and ephrin proteins are involved in early embryonic cell movements, which establish the germ layers, cell movements involved in formation of tissue boundaries and the pathfinding of axons. This review focuses on two vertebrate models, the zebrafish and mouse, in which experimental perturbation of Eph and/or ephrin expression in vivo have provided important insights into the role and functioning of the Eph/ephrin system.