Oral and oropharyngeal cancer surgery with free-flap reconstruction in the elderly: Factors associated with long-term quality of life, patient needs and concerns. A GETTEC cross-sectional study

Objectives: To assess the factors associated with long-term quality of life (QoL) and patient concerns in elderly oral or oropharyngeal cancer (OOPC) patients after oncologic surgery and free-flap reconstruction. Methods: Patients aged over 70 years who were still alive and disease-free at least 1 year after surgery were enrolled in this cross-sectional multicentric study. Patients completed the EORTC QLQ-C30, -H&N35 and -ELD14 QoL questionnaires, and the Hospital Anxiety and Depression Scale (HADS). Patient needs were evaluated using the Patient Concerns Inventory (PCI). Factors associated with these clinical outcomes were determined in univariate and multivariate analysis. Results: Sixty-four patients were included in this study. Long-term QoL, functioning scales and patient autonomy were well-preserved. Main persistent symptoms were fatigue, constipation and oral function-related disorders. Salivary and mastication/swallowing problems were the main patient concerns. The mean number of patient concerns increased with the deterioration of their QoL. Psychological distress (HADS score ≥ 15) and patient frailty (G8 score < 15) were significantly associated with poor QoL outcomes. Conclusions: We found a negative correlation between the number of patient concerns and QoL. Dental rehabilitation and psychological and nutritional supportive measures are of critical importance in the multidisciplinary management of elderly OOPC patients

CD44, &gamma;-H2AX, and p-ATM Expressions in Short-Term Ex Vivo Culture of Tumour Slices Predict the Treatment Response in Patients with Oral Squamous Cell Carcinoma

Squamous cell carcinoma is the most common type of head and neck cancer (HNSCC) with a disease-free survival at 3 years that does not exceed 30%. Biomarkers able to predict clinical outcomes are clearly needed. The purpose of this study was to investigate whether a short-term culture of tumour fragments irradiated ex vivo could anticipate patient responses to chemo- and/or radiotherapies. Biopsies were collected prior to treatment from a cohort of 28 patients with non-operable tumours of the oral cavity or oropharynx, and then cultured ex vivo. Short-term biopsy slice culture is a robust method that keeps cells viable for 7 days. Different biomarkers involved in the stemness status (CD44) or the DNA damage response (pATM and &gamma;-H2AX) were investigated for their potential to predict the treatment response. A higher expression of all these markers was predictive of a poor response to treatment. This allowed the stratification of responder or non-responder patients to treatment. Moreover, the ratio for the expression of the three markers 24 h after 4 Gy irradiation versus 0 Gy was higher in responder than in non-responder patients. Finally, combining these biomarkers greatly improved their predictive potential, especially when the &gamma;-H2AX ratio was associated with the CD44 ratio or the pATM ratio. These results encourage further evaluation of these biomarkers in a larger cohort of patients

Biomarkers predictive of treatment response in patients with advanced squamous cell carcinoma of the oropharynx

Les carcinomes épidermoïdes de la tête et du cou (HNSCC) sont des cancers de mauvais pronostic, le plus souvent diagnostiqués à un stade avancé, présentant souvent des récidives locorégionales, une extension métastatique, et un taux de survie à 5 ans des patients qui n’excède pas 40 %. En dehors du statut HPV, il n’existe pas pour les HNSCC au stade curatif, de biomarqueurs de diagnostic précoce, de pronostic, et de choix/suivi thérapeutique, adaptés aux caractéristiques de la tumeur. L’objectif de ce travail était d’identifier des biomarqueurs de la réparation des lésions de l’ADN et de la réponse au stress oxydant, pouvant prédire la réponse à la radiothérapie et/ou la chimiothérapie de patients atteints d’un carcinome épidermoïde de l’oropharynx. Dans le cadre de l’étude clinique ChemRad (NCT02714920), nous nous sommes focalisés sur la détection et la réparation des cassures double brin via l’étude des foci ƴH2AX, la phosphorylation de ATM, et l’expression du marqueur de cellule souche CD44 sur des biopsies tumorales cultivées et irradiées ex vivo. Une surexpression de ƴH2AX, pATM et de CD44 chez les patients non-répondeurs au traitement a été associée à un mauvais pronostic à l’état basal. De plus, le ratio de l’expression de ces trois marqueurs à 24h après irradiation à 4 Gy versus 0 Gy était également prédictif d’une mauvaise réponse au traitement. Enfin la combinaison de ces 3 marqueurs augmentait le potentiel prédictif de la réponse au traitement. Par ailleurs, l’analyse morphologique et phénotypique des cellules tumorales circulantes (CTCs) sur biopsie liquide a permis de mettre en évidence une corrélation entre l’augmentation du nombre de CTCs entre deux cures de chimiothérapie et une diminution de la survie globale. Sur une deuxième cohorte de patients, l’expression de NRF2, facteur de transcription impliqué dans la réponse au stress oxydant, a été analysée ainsi que celle de la peroxiredoxine 6, une protéine régulée par NRF2. Une analyse immunohistochimique sur tissu micro-array (TMA) a montré qu’une expression élevée de NRF2 et de la peroxiredoxine 6 était un facteur de mauvais pronostic sur les survies globale et sans progression. L’association de ces 2 biomarqueurs renforçait la significativité des résultats. A l’issue de ce travail, nous proposons une combinaison de biomarqueurs prédictifs de la réponse à la radio(chimio)thérapie. L’analyse de ces biomarqueurs est réalisée sur biopsie solide, avant tout traitement et leur combinaison renforce le caractère prédictif de la réponse. Dans la suite du parcours du patient, en plus d’un suivi clinique et radiologique, nous montrons qu’une surveillance par biopsie liquide avec identification et quantification des CTCs pourrait être proposée. Ces biomarqueurs doivent maintenant être validés sur des cohortes plus importantes de patients afin de proposer des traitements personnalisés, à partir de leur analyse sur biopsies tumorales initiales, et afin d’améliorer le suivi en identifiant les récidives précoces sur biopsies liquides.Head and neck squamous cell carcinomas (HNSCC) are cancers with a poor prognosis, most often diagnosed at an advanced stage, often with locoregional recurrence, metastatic extension and a 5-year survival rate of patients that does not exceed 40%. Apart from HPV status, there are no biomarkers for early diagnosis, prognosis, and therapeutic choice/follow-up of HNSCC at the curative stage adapted to the characteristics of the tumor. The objective of this work was to identify biomarkers of DNA damage repair and oxidative stress response that could predict the response to radiotherapy and/or chemotherapy in patients with oropharyngeal squamous cell carcinoma. In the ChemRad clinical trial (NCT02714920), we focused on the detection and repair of double-strand breaks through the study of ƴH2AX foci, ATM phosphorylation, and expression of the CD44 stem cell marker in cultured and ex vivo irradiated tumor biopsies. Overexpression of ƴH2AX, pATM, and CD44 in non- responder patients was associated with poor prognosis at the basal state. Moreover, the ratio of the expression of these three markers at 24h after irradiation at 4 Gy versus 0 Gy was also predictive of a poor response to treatment. Finally, the combination of these three markers increased the ability to predict treatment response. Morphological and phenotypic analyses of circulating tumor cells (CTCs) on liquid biopsy showed a correlation between an increase in the number of CTCs between two courses of chemotherapy and a decrease in overall survival. In a second cohort of patients, the expression of NRF2, a transcription factor involved in the response to oxidative stress, was analyzed as well as the expression of peroxiredoxin 6, a protein regulated by NRF2. Immunohistochemical analysis on tissue microarray (TMA) showed that high expression of NRF2 and peroxiredoxin 6 was an unfavorable prognostic factor for overall and progression-free survival. The association of these 2 biomarkers reinforced the significance of the results. In our work, we propose a combination of biomarkers predictive of response to radio(chemo)therapy. The analysis of these biomarkers is carried out on tumor biopsy, before any treatment and their combination reinforces the predictive character of the response. In addition to clinical and radiological follow-up, we show that the monitoring by liquid biopsy with identification and quantification of CTCs could be proposed. The results presented in this work must be validated on larger cohorts of patients in order to propose personalized treatments after biomarkers analysis on tumor biopsies and to improve follow-up by identifying early recurrences thanks to liquid biopsies

Parthénocarpie naturelle chez la tomate. III. - Etude de la parthénocarpie due au gène pat (parthenocarpic fruit) de la lignée « Montfavet 191 »

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Synthesis of an Electrodeficient Dipyridylbenzene-like Terdentate Ligand: Cyclometallating Ligand for Highly Emitting Iridium(III) and Platinum(II) Complexes

Cyclometallated iridium(III) and platinum(II) complexes are intensely used in optoelectronics for their photophysical properties and ability to convert excitons from singlet to triplet state, thus improving the device efficiency. In this contribution, we report the multi-steps synthesis of an electrodeficient dipyridylbenzene-like terdentate ligand [N^C^N], namely 2′,6′-dimethyl-2,3′:5′,2″-terpyridine (6), with 18% overall yield. Compound 6 has been employed to synthesize two phosphorescent complexes of platinum(II) and iridium(III), namely compounds 7 and 8, respectively. Both complexes have been characterized by NMR and high resolution mass spectrometry, and demonstrate high luminescence quantum yields in a deaerated solution at room temperature, with 18% and 61% for 7 and 8, respectively. If the iridium(III) complex displays similar emission properties to [Ir(dpyx)(ppy)Cl] (dpyx = 3,5-dimethyl-2,6-dipyridylbenzene and ppy = 2- phenylpyridine), the platinum(II) derivative, with λem = 470 nm, is a rare example of a fluorine atom-free blue emitting [N^C^N]PtCl complex

A Direct and Versatile Access to a,a-Disubstituted 2-Pyrrolidinyl-methanols by SmI2-Mediated Reductive Coupling

International audienceVarious a,a-disubstituted 2-pyrrolidinyl-methanols are efficiently prepared in a single step from ketones using a SmI2-mediated cross-coupling with 1-pyrroline N-oxide. The N-hydroxy-a,a-diphenylprolinol is also easily prepared and resolved

An unprecedented 7-membered ring enamide cyclization through hypervalent iodine phenolic oxidation

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