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Human papillomavirus (HPV)-driven oropharyngeal cancer incidence in the United States has steadily increased in the past decades and has now become the most frequently diagnosed HPV-associated cancer type, surpassing cervical cancer. Variations in the HPV genome correlate with tumorigenic risk, and the distribution of genetic variants is extensively studied in cervical cancer, but very little is known about new mutations or the distribution of HPV types and variants in oropharyngeal cancer. Here we present an archival tissue cohort study that compares genomic characteristics of HPV associated with cervical versus oropharyngeal tumors using DNA sequence analysis. We found HPV16 to be more prevalent in oropharyngeal samples than in cervical samples (91.2% versus 52.9%), while HPV18 (1.5% versus 18.2%) and HPV45 (0.7% versus 9.9%) were much less prevalent. Differences between cervix and oropharynx in HPV16 variants distribution were more subtle, but the combined European + Asian (EUR+AS) variant group was more prevalent (90.2% versus 71.4%), while the American Asian 1 + American Asian 2 (AA1+AA2) variant group was much less prevalent (4.4% versus 22.5%) in oropharyngeal cancers. HPV prevalence in oropharyngeal cancers showed an increasing trend from 60% in 2003 to 80% in 2016. We also identified over nine times more nonsynonymous mutations in the HPV E6 gene amplified from oropharyngeal samples, but for E7 the difference in mutation rates between the two anatomical locations was not significant. Overall, we showed that HPV genome in oropharyngeal cancer presents important differences when compared to cervical cancer and this may explain the distinct pathomechanisms and susceptibility to treatment of HPV-associated oropharyngeal cancer.

Patient education constitutes a relevant strategy to improve pain management. In the field of therapeutic patient education (TPE), we aimed 1) to assess pain impact in cancer patients, 2) to identify patients' educative needs in pain management, and 3) to refine research criteria for its future evaluation. Pain intensity, relief and interference were assessed in 75 cancer patients with unbalanced background pain. Self-assessment questionnaire evaluated i) patients' pain management and ii) their knowledge and needs in TPE. Most patients experienced pain for more than 6 months and 41.6% reported adequate pain relief. Understanding pain and pain management were major patients' preferences (>58%). Most patients declared they knew their pain treatments, but fewer than half of them were able to name them. However, education concerning pain treatment was considered as essential in <30% of patients. Almost all patients (97.1%) stated pain education as beneficial, with a preference for individualized sessions (41.2%). In addition, the assessment criteria for its future evaluation were refined. Targeted population mainly concerned patients with persistent pain. Only half of patients reported pain relief despite antalgics. Patient education was declared as beneficial for almost all participants. Tailoring a pain TPE on patients' needs has the potential to help them to optimally manage their pain daily.

The first genetic map for Hevea spp. (2n = 36) is presented here. It is based on a [F.sub.1] progeny of 106 individuals allowing the construction of a female, a male, and a synthetic map according to the pseudo-testcross strategy. Progeny were derived from an interspecific cross between PB260, a H. brasiliensis cultivated clone, and RO38, a H. brasiliensisxH. benthamiana interspecific hybrid clone. The disomic inheritance observed for all the codominant markers scattered on the 2n = 36 chromosomes revealed that Hevea behaves as diploids. Homologous linkage groups between the two parental maps were merged using bridge loci. A total of 717 loci constituted the synthetic map, including 301 RFLPs, 388 AFLPs, 18 microsatellites, and 10 isozymes. The markers were assembled into 18 linkage groups, thus reflecting the basic chromosome number, and covered a total distance of 2144 cM. Nine markers were found to be unlinked. Segregation distortion was rare (1.4%). Average marker density was 1 per 3 cM. Comparison of the distance between loci in the parental maps revealed significantly less meiotic recombination in the interspecific hybrid male parent than in the female parent. Hevea origin and genome organisation are discussed.

4-Hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. Y Sauvaire , P Petit , C Broca , M Manteghetti , Y Baissac , J Fernandez-Alvarez , R Gross , M Roye , A Leconte , R Gomis and G Ribes Laboratoire de Recherche sur les Substances Naturelles Végétales, Université Montpellier II, France. Abstract We report the characterization of a new insulinotropic compound, 4-hydroxyisoleucine. This amino acid has been extracted and purified from fenugreek seeds, which are known in traditional medicine for their antidiabetic properties. 4-Hydroxyisoleucine increases glucose-induced insulin release, in the concentration range of 100 micromol/l to 1 mmol/l, through a direct effect on isolated islets of Langerhans from both rats and humans. The stimulating effect of 4-hydroxyisoleucine was strictly glucose dependent; indeed, ineffective at low (3 mmol/l) or basal (5 mmol/l) glucose concentrations, the amino acid potentiated the insulin secretion induced by supranormal (6.6-16.7 mmol/l) concentrations of glucose. In addition, in the isolated perfused rat pancreas, we could show 1) that the pattern of insulin secretion induced by 4-hydroxyisoleucine was biphasic, 2) that this effect occurred in the absence of any change in pancreatic alpha- and delta-cell activity, and 3) that the more glucose concentration was increased, the more insulin response was amplified. Moreover, 4-hydroxyisoleucine did not interact with other agonists of insulin secretion (leucine, arginine, tolbutamide, glyceraldehyde). Therefore, we conclude that 4-hydroxyisoleucine insulinotropic activity might, at least in part, account for fenugreek seeds' antidiabetic properties. This secretagogue may be considered as a novel drug with potential interest for the treatment of NIDDM.

Background Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. Methods The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. Discussion Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. Trial registration NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Background In cases of prevalent lymphadenopathy in the head and neck cancer region, identifying the primary tumor site allows for more precise radiotherapy targeting. This improves treatment by reducing the volumes of mucosal irradiation and potentially lowering morbidity. An extensive diagnostic workup, including FDG PET-CT imaging and bilateral tonsillectomy, has been shown to identify the primary cancer in 60% of cases. Mucosectomy of the tongue base holds promise for detecting additional primary sites. When performed using minimally invasive endoscopic techniques such as transoral robotic surgery (TORS) or transoral laser microsurgery (TLM), mucosectomy results in minimal morbidity. However, the effectiveness of tongue base mucosectomy in detecting primary tumors has yet to be evaluated in a randomized trial involving patients with lymphadenopathy of unknown primary. Methods The RoboCUP trial is a multicentre, open-label, randomized, non-comparative phase 2 trial aiming to evaluate the benefit of bilateral TORS or TLM-assisted tongue base mucosectomy in association to tonsillectomy in the assessment of prevalent cervical lymphadenopathy with a negative exhaustive diagnostic workup. The main endpoint is the proportion of patients with detection of a primary cancer. Surgery will consist in tongue base mucosectomy plus tonsillectomy in the experimental arm, and the standard of care, i.e. tonsillectomy alone in the control arm. Patients will then be treated by intensity modulated radiotherapy, possibly with chemotherapy as radiosensitizer, per current guidelines. Using a single-stage Fleming design, 36 patients will be enrolled in the experimental arm, and 36 patients in the control arm. Discussion This trial aims to improve the diagnostic performances, i.e. detection of primary tumor, in patients with head and neck carcinoma of unknown primary. It is expected that the subsequent therapeutic changes could enhance radiotherapy accuracy, and could improve the prognosis, toxicity profiles and quality-of-life of patients. Trial registration NCT04767048, registered February, 19, 2021.

Background In oncology, the suffering of patients and the burnout of health professionals are key issues. Mindfulness meditation is a holistic approach that can help to improve well-being. While numerous studies have shown the benefits of meditation for both patients and health professionals, the added value of offering shared meditation to groups of patients, health professionals and third persons has not been assessed. Beyond strengthening the relationship between carers and patients, opening up meditation sessions to third parties (neither carers nor patients) enables patients to escape the stigma of their illness. We previously conducted a pilot study that validated the feasibility and the relevance of shared meditation with a specifically designed programme. Methods/Design IMPLIC-2 is a two-arm randomised study designed to assess the added value of this meditation programme (optimised following the pilot study), particularly for cancer patients (our target population). People motivated to follow the programme, without previous regular practice of meditation and able to participate in the sessions are eligible. The study will include 96 participants: 16 health professionals, 16 third persons and 64 patients. The latter will be randomized in two arms: the experimental arm (“Shared” meditation) consisting of 4 mixed groups of 8 patients, 4 health professionals and 4 third parties, and the control arm (“Patient” meditation) consisting of 2 groups of 16 patients. Validated questionnaires will be used to measure the effects of the programme, notably in terms of quality of life, perceived stress, feelings of self-efficacy, qualities of mindfulness and self-compassion, and carers’ burn-out. Participants' perception of a change in their quality of life and satisfaction will be measured at the end of the programme. A complementary qualitative focus-group approach will be used to optimise implementation of the programme beyond the study. Discussion The well-being of oncology patients would be improved. Dealing with overworked carers would have a beneficial impact on the way they interact with patients. In addition, encounters between the three types of population will allow otherness to be viewed differently and alleviate suffering by promoting collective humanity. Trial Registration NCT06041607 , registered: 09/18/2023. Protocol version Version n°1.2 dated from 08/29/2023.

Purpose Acute radiodermatitis (ARD) is a frequent side effect of radiotherapy, a therapeutic option for head and neck squamous cell carcinoma (HNSCC). It is responsible for pain, quality of life (QoL) impairment, and increased risk of treatment discontinuation, which may compromise the prognosis for patients. Local therapies to prevent or alleviate ARD have been proposed without providing any high level of evidence to establish recommendations. Methods We implemented a prospective multicenter randomized study on patients with HNSCC treated with definitive radiotherapy to assess the impact on ear, nose, and throat (ENT) pain of the application of a hydrogel-based skin dressing (HydroTac®) compared with the application of hyaluronic acid (Ialuset®) during radiotherapy. Results Out of 130 enrolled patients, 48 patients per group were assessable for the main endpoint. No difference between groups was found: a worsening of ENT pain of 3 points or more on a visual analog scale from the initiation to 1 month after the end of the radiotherapy was observed for 8 patients (16.7%) who received HydroTac® compared to 13 patients (27%) who received Ialuset® ( p  = 0.342). The proportion of patients who experienced ARD and grades of ARD (CTCAE v4.0 criteria) were similar between groups. Patient compliance with radiodermatitis treatment was poor, with 56.1% of patients in the HydroTac® group having their treatment temporarily stopped. Conclusion The application of a hydrogel dressing to prevent ARD during radiotherapy for HNSCC patients has failed to demonstrate a benefit. These results may be limited by the difficulties of applying the dressing.

Background Cervical cancer is the tenth diagnosed cancer in the world. Early-stage and locally recurrent disease may be cured with radical surgery or chemo-radiotherapy. However, if disease persists or recurs, options are limited and the prognosis is poor. In addition to chemotherapy, bevacizumab, an antiangiogenic agent, has recently demonstrated its efficacy in this setting. Cabozantinib is an oral small molecule tyrosine kinase inhibitor that exhibits potent inhibitory activity against several receptor tyrosine kinases that are known to influence tumor growth, metastasis, and angiogenesis. The main targets of Cabozantinib are VEGFR2, MET and AXL. It is currently approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma and medullary thyroid carcinoma. Given its angiogenic properties associated with growth factor receptors inhibition, Cabozantinib represents a potential active treatment in cervical carcinoma. In this context, we propose to assess the efficacy and safety of cabozantinib monotherapy in advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. Methods This study is a single-arm two-stage multicenter phase II aiming to simultaneously assess efficacy and safety of Cabozantinib among advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. The main criterion will be based on both safety and clinical efficacy by conducting a Bryant-and-Day design. Safety endpoint is the proportion of patients with clinical gastro-intestinal (GI) perforation/fistula, GI-vaginal fistula and genito-urinary (GU) fistula events grade ≥ 2 (NCI CTCAE V.5.0) occurring up to one month after the end of treatment. Efficacy endpoint is the proportion of patients with disease control rate 3 months after Cabozantinib initiation. A patients’ self-reported quality of life evaluation is also planned, as well as the investigation of nutritional outcomes. Cabozantinib will be administered at the daily dose of 60 mg given orally, without interruption until disease progression or discontinuation for any cause. Discussion Cabozantinib is a promising drug for patients with advanced/metastatic cervical cancer where few therapeutics options are available after failure to platinum-based regimen metastatic CC. It appears challenging to assess the interest of Cabozantinib in this indication, taking into account the potential toxicity of the drug. Trial registration NCT04205799 , registered “2019 12 19”. Protocol version Version 3.1 dated from 2020 08 31.

Background Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making. Method The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient’s response to evaluate their predictive value. Discussion This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies. Trial registration The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023.