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Background: Tigilanol tiglate, a short-chain diterpene ester, is being developed as intratumoral treatment of a broad range of cancers. We conducted the first-in-human study of intratumoral tigilanol tiglate in patients with solid tumors. Methods: Tigilanol tiglate was administered in a multicentre, non randomized, single-arm study, with escalating doses beginning with 0·06 mg/m2 in tumors estimated to be at least twice the volume of injection (dose-escalation cohorts). Patients with smaller tumors were assigned to the local effects cohort and received the appropriate dose for tumor size. Findings: Twenty-two patients were enrolled. The maximum dose was 3·6 mg/m2 and the maximum tolerated dose was not reached. There was one report of dose-limiting toxicity (upper airway obstruction), two serious adverse events (upper airway obstruction and septicemia), 160 treatment-emergent adverse events, and no deaths. Injection site reactions in all tumors and tumor types occurred even at the lowest dose. Six of the 22 patients experienced a treatment response, with four of the six patients achieving complete response. Interpretation: Intratumoral tigilanol tiglate was generally well tolerated, the maximum tolerated dose was not reached, and clinical activity was observed in 9 tumor types including complete response in four patients. These results support the continued development of tigilanol tiglate for intratumoral administration. Funding: QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study. Keywords: Diterpene ester, EBC-46, Intratumoral, Protein kinase C, Tigilanol tiglate

To demonstrate safety of a developed intranasal dexamethasone-infused in situ gelling formulation, quantification of a validated clinical biomarker indicative of cytotoxic potential using a human sinonasal explant model was first confirmed. Systematic cytotoxicity studies using the lactate dehydrogenase (LDH) detection assay revealed no elevation from baseline, in LDH levels, with tissue integrity of explanted human nasal mucosa also maintained; this was further corroborated using tissue histopathological examination. Next, with safety confirmed ex vivo, freshly excised human nasal tissue was utilised to quantify dexamethasone release from the lead sol–gel systems; this being achieved through development and validation of a HPLC-UV analytical method, which reliably quantified controlled therapeutic release and deposition into mucosal tissue. Collectively, these findings indicate promise in the safety of each excipient within the concentrations employed in the functional sol–gel system, complemented by successful and reliable drug release and deposition into human nasal mucosal tissue. These findings pave the way for application of the dexamethasone-based sol–gel system to the extended delivery of corticosteroids to nasal mucosa in the management of localised inflammatory conditions of an acute and chronic nature, such as chronic rhinosinusitis, which can be expected to benefit from controlled and extended drug delivery characteristics imparted by appropriately engineered in situ gelling systems. Keywords: Intranasal soluble gels, Sinusitis, Explant human nasal mucosa, Tissue toxicity, LDH assay, Drug deposition in human nasal mucosa

Objectives To determine whether the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) for HPV associated oropharyngeal carcinoma (HPV + OPC) is a better discriminator of overall survival (OS), compared with the 7th edition (7th Ed) AJCC/UICC TNM staging following curative radiotherapy (RT). Material and methods The 5-year OS for all patients with non-metastatic (M0) p16-confirmed OPC treated between 2005 and 2015 was determined and grouped based on the 7th Ed AJCC/UICC TNM and ICON-S staging. Results A total of 279 patients met the inclusion criteria. The 5-year OS with the 7th Ed TNM classification were Stage I/II 88.9% (95% CI; 70.6–100%), Stage III 93.8% (95% CI; 85.9–100%), Stage IVa 86.4% (95% CI; 81.6–91.5%) and Stage IVb 62.3% (95% CI; 46.8–82.8%). On multivariate Cox regression analysis there was no statistically significant OS difference when comparing Stage I/II with, Stage III (p = 0.98, HR = 0.97, 95% CI; 0.11–8.64), IVa (p = 0.67, HR = 1.56, 95% CI; 0.2–11.94) and IVb (p = 0.11, HR = 5.54, 95% CI; 0.69–44.52), respectively. The 5-year OS with ICON-S staging were Stage I 93.6% (95% CI; 89.4–98.0%), Stage II 81.9% (95% CI; 73.7–91.1%) and Stage III 69.1% (95%; 57.9–82.6%). There was a consistent decrease of OS with increasing stage. On multivariate Cox regression analysis, when compared to Stage I, OS was significantly lower for stage II (p = 0.007, HR = 2.84, 95% CI; 1.33–6.05) and stage III (p Conclusion The ICON-S staging provides better OS stratification for HPV + OPC following RT compared with the 7th Ed TNM staging.

Mucoadhesive in situ gelling systems (soluble gels) have received considerable attention recently as effective stimuli-transforming vectors for a range of drug delivery applications. Considering this fact, the present work involves systematic formulation development, optimization, functional evaluation and ex vivo performance of thermosensitive soluble gels containing dexamethasone 21-phosphate disodium salt (DXN) as the model therapeutic. A series of in situ gel-forming systems comprising the thermoreversible polymer poloxamer-407 (P407), along with hydroxypropyl methyl cellulose (HPMC) and chitosan were first formulated. The optimized soluble gels were evaluated for their potential to promote greater retention at the mucosal surface, for improved therapeutic efficacy, compared to existing solution/suspension-based steroid formulations used clinically. Optimized soluble gels demonstrated a desirable gelation temperature with Newtonian fluid behaviour observed under storage conditions (4-8°C), and pseudoplastic fluid behaviour recorded at nasal cavity/sinus temperature (≈34°C). The in vitro characterization of formulations including rheological evaluation, textural analysis and mucoadhesion studies of the gel form were investigated. Considerable improvement in mechanical properties and mucoadhesion was observed with incorporation of HPMC and chitosan into the gelling systems. The lead poloxamer-based soluble gels, PGHC4 and PGHC7, which were carried through to ex vivo permeation studies displayed extended drug release profiles in conditions mimicking the human nasal cavity, which indicates their suitability for treating a range of conditions affecting the nasal cavity/sinuses.

The temporal bone can be affected by primary or secondary malignancies. The latter are far more common. The complex anatomy of this region requires a thorough understanding in order to manage these lesions safely. Herein we present a brief description of the techniques used to resect malignant temporal bone lesions.

Tumors of the jugular foramen are rare and often benign. The surgical management of these conditions is often associated with considerable post operative morbidity. Complications include injury to the lower cranial nerves causing dysphagia and dysphonia, facial nerve paresis and loss of hearing. The POTS approach takes the vector of dissection from a lateral trajectory to a posterio-lateral trajectory. In the setting of the more posteriorly placed jugular foramen schwannomas this allows for resection and offers the opportunity for preservation of auditory and facial function.

Choosing the optimal approach to a given skull base tumor continues to be a matter of great debate. While endoscopy has revolutionized the management of various cranial base pathologies a thorough understanding of all approaches available to the skull base team is critical in order to properly manage these lesions. Herein, we present an overview of the most relevant approaches used to access the skull base. It is important for the skull base surgeon to be familiar with these approaches and understand what each approach can achieve.

Conclusions: By PET/CT simulation, changes in TNM classification or clinical stages occurred frequently for NPC. Although no significant improvement in overall survival rate and loco-regional control rate was noted by PET/CT simulation compared with a historical control, PET/CT simulation may contribute to reduce marginal recurrences in IMRT. Author Disclosure: T. Matsuura: None. Y. Nishimura: None. K. Ishikawa: None.