Abstract Background: We studied the relationship between trismus (maximum interincisor opening [MIO] ≤35 mm) and the dose to the ipsilateral masseter muscle (iMM) and ipsilateral medial pterygoid muscle (iMPM). Methods: Pretreatment and post-treatment measurement of MIO at 13 weeks revealed 17% of trismus cases in 83 patients treated with chemoradiation and intensity-modulated radiation therapy. Logistic regression models were fitted with dose parameters of the iMM and iMPM and baseline MIO (bMIO). A risk classification tree was generated to obtain optimal cut-off values and risk groups. Results: Dose levels of iMM and iMPM were highly correlated due to proximity. Both iMPM and iMM dose parameters were predictive for trismus, especially mean dose and intermediate dose volume parameters. Adding bMIO, significantly improved Normal Tissue Complication Probability (NTCP) models. Optimal cutoffs were 58 Gy (mean dose iMPM), 22 Gy (mean dose iMM) and 46 mm (bMIO). Conclusions: Both iMPM and iMM doses, as well as bMIO, are clinically relevant parameters for trismus prediction.
Purpose / objective: Head and neck cancer patients treated with chemoradiation are at risk for developing trismus (reduced mouth opening). Trismus is often a persisting side-effect and difficult to manage. It impairs eating, speech and oral hygiene, affecting quality of life. Although several studies identified the masseter muscle (MM) as one of the main organs at risk, currently this structure is rarely considered during treatment planning. Prospective studies for chemoradiation are lacking. The aim of our study was to quantify the relationship between radiation dose to the MM and development of radiation-induced trismus in an IMRT-VMAT population. Results: At the first evaluation, 6-12 weeks post-treatment, fourteen patients had developed radiation-induced trismus (15%). On average, mouth opening decreased with 4.1 mm, or 8.2 % relative to baseline. Mean dose to the ipsilateral MM was a stronger predictor for trismus than mean dose to the contralateral MM, as indicated by the lowest -2 log likelihood (Table 1). Figure 1A shows the correlation between the ipsilateral mean masseter dose and the relative decrease in mouth opening, with trismus cases indicated in red. No trismus cases were observed in 33 patients (35%) with a mean dose to the ipsilateral MM < 20 Gy. The risk of trismus in the other 60 patients (65%) increased with higher mean doses to the ipsilateral MM. Figure 1B shows the fitted NTCP curve as a function of the mean dose, with a TD50 of 55 Gy. The actual incidence (with 1 SE) of trismus cases within 5 dose bins is indicated as well, showing a good correspondence with the NTCP fit with a relatively large uncertainty in the dose area > 50 Gy. Patients with tumors located in the oropharynx were at highest risk.
Background: Adverse outcome pathway (AOP) networks are versatile tools in toxicology and risk assessment that capture and visualize mechanisms driving toxicity originating from various data sources. They share a common structure consisting of a set of molecular initiating events and key events, connected by key event relationships, leading to the actual adverse outcome. AOP networks are to be considered living documents that should be frequently updated by feeding in new data. Such iterative optimization exercises are typically done manually, which not only is a time-consuming effort, but also bears the risk of overlooking critical data. The present study introduces a novel approach for AOP network optimization of a previously published AOP network on chemical-induced cholestasis using artificial intelligence to facilitate automated data collection followed by subsequent quantitative confidence assessment of molecular initiating events, key events, and key event relationships. Methods: Artificial intelligence-assisted data collection was performed by means of the free web platform Sysrev. Confidence levels of the tailored Bradford-Hill criteria were quantified for the purpose of weight-of-evidence assessment of the optimized AOP network. Scores were calculated for biological plausibility, empirical evidence, and essentiality, and were integrated into a total key event relationship confidence value. The optimized AOP network was visualized using Cytoscape with the node size representing the incidence of the key event and the edge size indicating the total confidence in the key event relationship. Results: This resulted in the identification of 38 and 135 unique key events and key event relationships, respectively. Transporter changes was the key event with the highest incidence, and formed the most confident key event relationship with the adverse outcome, cholestasis. Other important key events present in the AOP network include: nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation and apoptosis. Conclusions: This process led to the creation of an extensively informative AOP network focused on chemical-induced cholestasis. This optimized AOP network may serve as a mechanistic compass for the development of a battery of in vitro assays to reliably predict chemical-induced cholestatic injury.
