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We investigated the prognostic utility of preoperative neck lymph node-to-primary tumor maximum standardized uptake value ratios (NTRs) in oral cavity squamous cell carcinoma (OSCC). We retrospectively reviewed the medical records of 141 consecutive patients who were diagnosed as having OSCC and had received fluorodeoxyglucose–positron emission tomography within 2 weeks prior to radical surgery between 2009 and 2018. To determine the optimal NTR cutoff, receiver operating characteristic analysis for overall survival (OS) was executed. The NTR's prognostic value for disease-free survival (DFS) and OS were determined through Cox proportional hazards analysis and the Kaplan–Meier method. We determined the median (range) follow-up duration to be 35.2 (2.1–122.4) months. The optimal NTR cutoff was 0.273, and patients with a higher NTR (≥0.273) exhibited significantly worse DFS and OS (p = 0.010 and 0.003, respectively). A higher NTR (≥0.273) predicted poorer DFS (hazard ratio: 2.696, p = 0.008) and OS (hazard ratio: 4.865, p = 0.003) in multivariable analysis. We created a nomogram on the basis of the NTR, and it could accurately predict OS (concordance index: 0.774). Preoperative NTRs may be a useful prognostic biomarker for DFS and OS in patients with OSCC who have undergone surgery. NTR-based nomograms may also be helpful prognostic tools in clinical trials. [ABSTRACT FROM AUTHOR]

The use of predictive models is becoming widespread. However, these models should be developed appropriately (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modeling Studies [CHARMS] and Prediction model Risk Of Bias ASsessment Tool [PROBAST] statements). Concerning mortality/recurrence in oropharyngeal cancer, we are not aware of any systematic reviews of the predictive models. We carried out a systematic review of the MEDLINE/EMBASE databases of those predictive models. In these models, we analyzed the 11 domains of the CHARMS statement and the risk of bias and applicability, using the PROBAST tool. Six papers were finally included in the systematic review and all of them presented high risk of bias and several limitations in the statistical analysis. The applicability was satisfactory in five out of six studies. None of the models could be considered ready for use in clinical practice., (© 2019 Wiley Periodicals, Inc.)

Chemokine receptor CXCR4 is overexpressed in neoplasms and its expression is related to tumour invasion, metastasis and aggressiveness. 68Ga-Pentixafor is used to non-invasively image the expression of CXCR4 in tumours and has been widely used in haematological malignancies. Recent evidence shows that therapies targeting CXCR4 can increase the chemosensitivity of the tumour as well as inhibit tumour metastasis and aggressiveness. 68Ga-Pentixafor has shown promise as an elegant radiotracer to aid in the selection of patients whose tumours demonstrate CXCR4 overexpression and who therefore may benefit from novel therapies targeting CXCR4. In addition, its therapeutic partners 177Lu- and 90Y-Pentixather have been investigated in the treatment of patients with advanced haematological malignancies, and initial studies have shown a good treatment response in metabolically active lesions. 68Ga-Pentixafor in solid tumours complements 18F-FDG by providing prognostic information and selecting patients who may benefit from therapies targeting CXCR4. This review summarises the available literature on the potential applications of 68Ga-Pentixafor in solid tumours. [ABSTRACT FROM AUTHOR]

Purpose: Although metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have shown good prognostic value in head and neck cancer (HNC), there are still many issues to resolve before their potential application in standard clinical practice. The purpose of this study was to compare the discrimination ability of two relevant segmentation methods in HNC and to evaluate the potential benefit of adding lymph nodes' metabolism (LNM) to the measurements. Methods: We retrospectively analyzed a recently published database of 62 patients with HNC treated with chemoradiotherapy. MTV and TLG were measured using an absolute threshold of SUV2.5. Comparison analysis with previously published background-level threshold (BLT) results was done through Concordance index (C-index) in eight prognostic models. Results: BLT obtained better C-index values in five out of the eight models. The addition of LNM improved C-index values in six of the prognostic models. Conclusion: We found a potential benefit in adding LNM to the main tumor measurements, as well as in using a BLT for MTV segmentation compared to the most commonly used SUV2.5 threshold. Despite its limitations, this study suggests a practical and simple manner to use these parameters in standard clinical practice, aiming to help elaborate a general consensus. [ABSTRACT FROM AUTHOR]

Background: The American Joint Committee on Cancer (AJCC) Precision Medicine Core (PMC) has recognized the need for more personalized probabilistic predictions above the "TNM" staging system and has recently released a checklist of inclusion and exclusion criteria for evaluating prognostic models. Methods: A systematic review of articles in which nomograms were created for head and neck cancer (HNC) was carried out according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The AJCC PMC criteria were used to score the individual studies. Results: Forty‐four studies were included in the final qualitative analysis. The mean number of inclusion criteria met was 9.3 out of 13, and the mean number of exclusion criteria met was 2.1 out of 3. Studies were generally of high quality, but no single study fulfilled all of the AJCC PMC criteria. Conclusion: This is the first study to utilize the AJCC checklist to comprehensively evaluate the published prognostic nomograms in HNC. Future studies should attempt to adhere to the AJCC PMC criteria. Recommendations for future research are given. Summary: The AJCC recently released a set of criteria to grade the quality of prognostic cancer models. In this study, we grade all published nomograms for head and neck cancer according to the new guidelines. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this multicentre retrospective study of locally advanced head and neck cancer (LAHNC) treated with definitive radiotherapy were to (1) identify positron emission tomography (PET)-18F-fluorodeoxyglucose (18F-FDG) parameters correlated with overall survival (OS) in a training cohort, (2) compute a prognostic model, and (3) externally validate this model in an independent cohort.Materials and methods: A total of 237 consecutive LAHNC patients divided into training (n = 127) and validation cohorts (n = 110) were retrospectively analysed. The following PET parameters were analysed: SUVMax, metabolic tumour volume (MTV), total lesion glycolysis (TLG), and SUVMean for the primary tumour and lymph nodes using a relative SUVMax threshold or an absolute SUV threshold. Cox analyses were performed on OS in the training cohort. The c-index was used to identify the highly prognostic parameters. A prognostic model was subsequently identified, and a nomogram was generated. The model was externally tested in the validation cohort.Results: In univariate analysis, the significant PET parameters for the primary tumour included MTV (relative thresholds from 6 to 83% and absolute thresholds from 1.5 to 6.5) and TLG (relative thresholds from 1 to 82% and absolute thresholds from 0.5 to 4.5). For the lymph nodes, the significant parameters included MTV and TLG regardless of the threshold value. In multivariate analysis, tumour site, p16 status, MTV35% of the primary tumour, and MTV44% of the lymph nodes were independent predictors of OS. Based on these four parameters, a prognostic model was identified with a c-index of 0.72. The corresponding nomogram was generated. This prognostic model was externally validated, achieving a c-index of 0.66.Conclusions: A prognostic model of OS based on primary tumour and lymph node MTV, tumour site, and p16 status was proposed and validated. The corresponding nomogram may be used to tailor individualized treatment. [ABSTRACT FROM AUTHOR]

Purpose: Evidence is conflicting on the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in head and neck squamous cell carcinoma. The aim of our study was to determine the impact of semiquantitative and qualitative metabolic parameters on the outcome in patients managed with standard treatment for locally advanced disease.Methods: A systematic review of the literature was conducted. A meta-analysis was performed of studies providing estimates of relative risk (RR) for the association between semiquantitative metabolic parameters and efficacy outcome measures.Results: The analysis included 25 studies, for a total of 2,223 subjects. The most frequent primary tumour site was the oropharynx (1,150/2,223 patients, 51.7%). According to the available data, the majority of patients had stage III/IV disease (1,709/1,799, 94.9%; no information available in four studies) and were treated with standard concurrent chemoradiotherapy (1,562/2,009 patients, 77.7%; only one study without available information). A total of 11, 8 and 4 independent studies provided RR estimates for the association between baseline FDG PET metrics and overall survival (OS), progression-free survival (PFS) and locoregional control (LRC), respectively. High pretreatment metabolic tumour volume (MTV) was significantly associated with a worse OS (summary RR 1.86, 95% CI 1.08-3.21), PFS (summary RR 1.81, 95% CI 1.14-2.89) and LRC (summary RR 3.49, 95% CI 1.65-7.35). Given the large heterogeneity (I2 > 50%) affecting the summary measures, no cumulative threshold for an unfavourable prognosis could be defined. No statistically significant association was found between SUVmax and any of the outcome measures.Conclusion: FDG PET has prognostic relevance in the context of locally advanced head and neck squamous cell carcinoma. Pretreatment MTV is the only metabolic variable with a significant impact on patient outcome. Because of the heterogeneity and the lack of standardized methodology, no definitive conclusions on optimal cut-off values can be drawn. [ABSTRACT FROM AUTHOR]

Mast cell stimulation triggers the formation of a Rac GTPase‐activated actin‐rich degranulation zone, and a RhoA‐activated granule capture for exocytosis. Mast cells are tissue‐resident immune cells that produce potent proinflammatory mediators, which are stored in cytoplasmic granules. Stimulation triggers degranulation, a process that mobilizes granules to dock and fuse to the plasma membrane, releasing mediators. Mast cell degranulation has an important role in immunity but can also intensify inflammation and contribute to allergic disorders. Hence, it is important to understand signaling pathways that regulate mast cell degranulation. Here, we examined the role of Rho proteins in regulating mast cell activation leading to degranulation. RBL‐2H3 cells and bone marrow–derived mast cells (BMMCs) were stimulated through aggregation of FcɛRI receptors. Stimulated cells showed a large increase in the levels of activated Rac and, to a lesser extent, RhoA. Drugs were used to acutely inhibit the function of specific Rho proteins. The Rac inhibitor EHT‐1864 and the RhoA inhibitor rhosin inhibited degranulation. Microscopic characterization showed that, upon stimulation, RBL‐2H3 cells formed surface ridges that grew into large protrusions reminiscent of circular dorsal ruffles, which flattened into large lamellipodia. LysoTracker‐labeled cells showed granules stream into peripheral protrusions. EHT‐1864 reduced granule motility, whereas rhosin increased motility; both drugs affected the formation of peripheral protrusions. These results showed that, in response to stimuli, Rho proteins control discrete cytoskeletal remodeling processes that are needed for granule exocytosis. Rac is required to stimulate the remodeling of mast cells, triggering actin‐mediated flattening of the cell periphery to create an active degranulation zone, whereas RhoA controls the streaming of highly motile granules into the active zone. [ABSTRACT FROM AUTHOR]

The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP-binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies. [ABSTRACT FROM AUTHOR]

Background: Overall, 40% of patients with a locally advanced head and neck cancer (LAHNC) treated by chemoradiotherapy (CRT) present local recurrence within 2 years after the treatment. The aims of this study were to characterize voxel-wise the sub-regions where tumor recurrence appear and to predict their location from pre-treatment 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images. Materials and methods: Twenty-six patients with local failure after treatment were included in this study. Local recurrence volume was identified by co-registering pre-treatment and recurrent PET/CT images using a customized rigid registration algorithm. A large set of voxel-wise features were extracted from pre-treatment PET to train a random forest model allowing to predict local recurrence at the voxel level. Results: Out of 26 expert-assessed registrations, 15 provided enough accuracy to identify recurrence volumes and were included for further analysis. Recurrence volume represented on average 23% of the initial tumor volume. The MTV with a threshold of 50% of SUVmax plus a 3D margin of 10 mm covered on average 89.8% of the recurrence and 96.9% of the initial tumor. SUV and MTV alone were not sufficient to identify the area of recurrence. Using a random forest model, 15 parameters, combining radiomics and spatial location, were identified, allowing to predict the recurrence sub-regions with a median area under the receiver operating curve of 0.71 (range 0.14–0.91). Conclusion: As opposed to regional comparisons which do not bring enough evidence for accurate prediction of recurrence volume, a voxel-wise analysis of FDG-uptake features suggested a potential to predict recurrence with enough accuracy to consider tailoring CRT by dose escalation within likely radioresistant regions. [ABSTRACT FROM AUTHOR]

Objectif de l’étude Les objectifs de ce travail étaient d’identifier, pour des cancers non oropharyngé localement évolués pris en charge par chimioradiothérapie, des paramètres de tomographie par émission de positons (TEP) quantitatifs prédictif de la survie sans progression et dans un second temps d’établir un score pronostique. Matériel et méthode Un total de 78 patients, avec un suivi médian de 23 mois, issus de trois centres (Rennes, Lorient et Lausanne), ont été inclus dans cette étude rétrospective. En plus de la standard uptake value maximale (SUVMax), les paramètres de TEP de volume ( metabolic tumor volume [MTV] et total lesion glycolysis [TLG]) ont été calculés en utilisant différentes valeurs de seuillage en valeur absolue (de 0 à 20) ou relative (de 0 à 100 % de la SUVMax). L’ensemble des paramètres cliniques et de TEP a été analysé et une corrélation avec la survie sans récidive a été recherchée. Un modèle pronostique de survie sans progression a été défini. Une validation interne a été réalisée par une méthode de ré-échantillonnage ( bootstrap ). Résultats En analyse multifactorielle, le MTV était le seul facteur pronostique indépendant de la survie sans progression, alors que les facteurs classiques cliniques ([stade T, volume tumoral macroscopique], stade selon l’American Joint Committee on Cancer [AJCC]) étaient peu ou pas significatifs. Après ré-échantillonnage, le c-index ajusté était de 0,69. La calibration interne a retrouvé un bon ajustement entre la survie sans progression prédite et la survie sans progression observée à 24 mois. Un score prédictif a été calculé, permettant d’identifier deux groupes à risque. La durée médiane de la survie sans progression était de 37 mois (intervalle de confiance à 95 % [IC95 %] : 36–55 mois pour le groupe de bas risque et de 8 mois [IC95 % : 5–15 mois] pour le groupe de haut risque, p < 0,01). Conclusion Le MTV est un puissant facteur pronostique de la survie sans progression chez les patients pris en charge par chimioradiothérapie. L’utilisation du MTV pourrait permettre une identification précoce des cancers de pronostic défavorable, candidat potentiel à une intensification thérapeutique. Une validation externe prospective sera nécessaire pour confirmer ces résultats. [ABSTRACT FROM AUTHOR]