Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

The reliability of "Analyze" software in measuring orbital volume utilizing CT-derived data.

INTRODUCTION: Craniomaxillofacial surgeons require to estimate the orbital volume in a variety of clinical situations. This paper evaluates a new method based on software analysis of computerized tomography (CT) scan data. MATERIAL AND METHODS: Five dried skulls with prosthetic globes and periorbita were non-helically scanned in an Elscint 2400 CT scanner. Images obtained were processed using the "Analyze" software package and results compared to the volume of the intraorbital prosthesis as determined by a volume displacement gravimetric method. RESULTS: Estimates of volume produced by the software varied from the gold standard by 0.06-50.44%, with a mean error of 8.8%. CONCLUSION: Despite the use of a variety of scan protocols it was not possible to obtain results with "Analyze" software which were sufficiently accurate for clinical use.

Pharmacologic modalities in the treatment of osteoradionecrosis of the jaw.

Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head and neck surgery. Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic modalities to manage this disorder. These treatment regimens may allow medical management to replace major reconstructive surgery for some patients who have already undergone chemoradiotherapy or combined modality therapy for head and neck cancer.