A mixed method feasibility and acceptability study of a flexible intervention based on acceptance and commitment therapy for patients with cancer.

Propose: This study aimed to propose an innovative, open, and circular program that combines acceptance and commitment therapy (ACT) and mindfulness practices. We assessed its feasibility, acceptability, and first signs of its effect on psychological wellbeing in cancer support treatment. Methods: A single-center, single-arm, uncontrolled study was performed. Forty adult patients with non-metastatic prostate or breast cancer, newly diagnosed or undergoing treatment (chemotherapy, radiotherapy, hormone therapy), were recruited. Three cycles of three MAEva program sessions (MAEva: Mindfulness meditation, Acceptance, and Commitment to values program) over nine consecutive weeks were proposed. During the total of 12 weeks of follow-up, after attending the first session, patients were free to attend subsequent sessions. Results: Adherence to the study was high, with participation in an average of 6.8 out of nine sessions. A total of eight patients attended all sessions over the three cycles, and 90% participated in at least one cycle. Furthermore, attendance was associated with a statistically significant improvement in Quality of Life (QoL). Each additional session was associated with a mean increase in overall QoL score of more than one point (ß = 1.09 [0.13; 2.04], p = 0.02). The fatigue dimensions decreased with session attendance: physical (ß = -2.24 [-3.63; -0.85]), emotional (ß = -2.60 [-4.11; -1.09]), and interference with daily life (ß = -2.33 [-3.95; -0.72]). The qualitative section demonstrated that patients learned skills and shared their ability to "let go". Patients rated the degree of importance of the program at 8.36/10 (SD ± 1.64). Conclusion: This study highlights the feasibility and acceptability of an original program that combines ACT and mindfulness practices in cancer patients. Future studies are required to demonstrate the efficacy of the MAEVA program. The MAEva pilot study is registered with ClinicalTrials.gov under the identifier NCT04751201. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04751201, identifier [NCT04751201].

Personalized follow-up of circulating DNA in resected stage III/IV melanoma: PERCIMEL multicentric prospective study protocol.

BACKGROUND: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. METHODS: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.

Conversational hypnosis versus standard of care to reduce anxiety in patients undergoing marker placement under radiographic control prior to breast cancer surgery: A randomized, multicenter trial.

Background: Surgery is a cornerstone of breast cancer management. Prior to surgery, a wire marker is placed at the site of the tumor, to enable the surgeon to accurately localize the lesion during later surgery. This procedure can generate considerable anxiety for many patients. We investigated the value of conversational hypnosis (CH) in reducing anxiety in patients undergoing preoperative wire placement under radiographic control. Methods: Randomized, multicentre study in 7 centers in France. Inclusion criteria were patients aged >18 years with an Eastern Cooperative Oncology Group performance status ≤2, scheduled to undergo preoperative wire placement in one or several breast lesions. Patients were randomized in a 1:1 ratio, stratified by center to undergo preoperative wire placement with or without the use of CH by a radiological technician trained in the CH technique. The primary endpoint was the percentage of patients with an anxiety score ≥ 6 on a visual analog scale ranging from 0 (absence of anxiety) to 10 (maximal anxiety). Secondary endpoints were pain score, perceived duration reported by the patient, technician satisfaction with their relationship with the patient, and ease of marker insertion reported by the radiologist. Semi-structured interviews were performed with patients to assess their perception of the marker placement procedure. Results: The trial was prematurely interrupted for futility after a planned interim analysis after accrual of 167 patients, i.e., half the planned sample size. Prior to marker placement, 29.3% (n = 24) of patients in the control group had an anxiety score ≥ 6, versus 42.3% (n = 33) in the CH group (p = 0.08). After marker placement, the change of anxiety score was not significantly different between groups (11.0% (n = 9) versus 14.3% (n = 11), p = 0.615). There was no significant difference in any of the secondary endpoints. In the interviews, patients from both groups frequently spoke of a feeling of trust. Conclusion: This study failed to show a benefit of conversational hypnosis on anxiety in patients undergoing marker placement prior to surgery for breast cancer. The fact that some caregivers had learned this personalized therapeutic communication technique may have had a positive impact on the whole caregiving team. Trial registration: The study was registered with ClinicalTrials.gov (NCT02867644).

Clinical evaluation of a device providing simultaneous white-light and fluorescence video streams as well as panoramic imaging during fluorescence assisted-transurethral resection of bladder cancer.

The current clinical study is aimed at evaluating the clinical relevance of an innovative device (called CyPaM2 device) that for the first time provides urologists with (i) a panoramic image of the bladder inner wall within the surgery time, and with (ii) a simultaneous (bimodal) display of fluorescence and white-light video streams during the fluorescence assisted-transurethral resection of bladder cancers procedure. The clinical relevance of this CyPaM2 device was evaluated on 10 patients according to three criteria (image quality, fluorescent lesions detection relevance, and ergonomics) compared with a reference medical device. Innovative features displayed by the CyPaM2 device were evaluated without any possible comparison: (i) simultaneous bimodal display of white-light and fluorescence video streams, (ii) remote light control, and (iii) time delay for the panoramic image building. The results highlight the progress to achieve in order to obtain a fully mature device ready for commercialization and the relevance of the innovative features proposed by the CyPaM2 device confirming their interest.

Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE).

BACKGROUND: Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity - including second malignancies - reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively. METHODS/DESIGN: ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (γH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease...) will be reported. DISCUSSION: ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology. TRIAL REGISTRATION: ID-RCB number: 2015-A00975-44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016.

Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses.

C3 is a component of the complement system that plays a central role in immunity, development and tissue regeneration. In this study, we isolated the C3 cDNA of the Iberian ribbed newt Pleurodeles waltl. This cDNA encodes a 1637 amino acid protein with an estimated molecular mass of 212.5 kDa. The deduced amino acid sequence showed that P. waltl C3 contains all the conserved domains known to be critical for C3 function. Quantitative real-time PCR (qRT-PCR) demonstrated that under normal physiological conditions, P. waltl C3 mRNA is expressed early during development because it is likely required for neurulation. Then, its expression increased as the immune system developed. In adults, the liver is the richest source of C3, though other tissues can also contribute. Further analysis of C3 expression demonstrated that C3 transcription increased when P. waltl larvae were exposed to pH or temperature stress, suggesting that environmental modifications might affect this animal's defenses against pathogens.

Gravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis.

Our previous research demonstrated that spaceflight conditions affect antibody production in response to an antigenic stimulation in adult amphibians. Here, we investigated whether antibody synthesis is affected when animal development occurs onboard a space station. To answer this question, embryos of the Iberian ribbed newt, Pleurodeles waltl, were sent to the International Space Station (ISS) before the initiation of immunoglobulin heavy-chain expression. Thus, antibody synthesis began in space. On landing, we determined the effects of spaceflight on P. waltl development and IgM heavy-chain transcription. Results were compared with those obtained using embryos that developed on Earth. We find that IgM heavy-chain transcription is doubled at landing and that spaceflight does not affect P. waltl development and does not induce inflammation. We also recreated the environmental modifications encountered by the embryos during their development onboard the ISS. This strategy allowed us to demonstrate that gravity change is the factor responsible for antibody heavy-chain transcription modifications that are associated with NF-κB mRNA level variations. Taken together, and given that the larvae were not immunized, these data suggest a modification of lymphopoiesis when gravity changes occur during ontogeny.

Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit?

This year, we celebrate the 40th birthday of the first landing of humans on the moon. By 2020, astronauts should return to the lunar surface and establish an outpost there that will provide a technical basis for future manned missions to Mars. This paper summarizes major constraints associated with a trip to Mars, presents immunological hazards associated with this type of mission, and shows that our current understanding of the immunosuppressive effects of spaceflight is limited. Weakening of the immune system associated with spaceflight is therefore an area that should be considered more thoroughly before we undertake prolonged space voyages.

Spaceflight-associated changes in immunoglobulin VH gene expression in the amphibian Pleurodeles waltl.

Understanding why the immune system is depressed during spaceflight is of obvious importance for future human deep-space missions, such as the foreseen missions to Mars. However, little is known about the effects of these flights on humoral immunity. We previously immunized adult Pleurodeles waltl (urodele amphibian) onboard the Mir space station and showed that heavy-chain variable (VH) domains of specific IgM antibodies are encoded by genes belonging to the VHII and VHVI families. We have now determined how these animals use their individual VHII and VHVI genes by screening IgM heavy-chain cDNA libraries and by quantifying IgM heavy-chain transcripts encoded by these genes. Results were compared with those obtained using control animals immunized on Earth under the same conditions as onboard Mir. Our experiments revealed an increase in the expression of IgM heavy-chain mRNAs encoded by the VHII and VHVI.C genes and a strong decrease in the expression of IgM heavy-chain mRNAs encoded by the VHVI.A and VHVI.B genes in spaceflight animals. Consequently, different heavy-chain mRNAs are expressed by spaceflight animals, demonstrating that this environment affects the humoral response. These observations may be due to a change in B-cell selection under spaceflight conditions.

[PPARs and cell-cell or cell-extracellular matrix interactions]. / PPAR et interactions des cellules entre elles ou avec la matrice extracellulaire.

The peroxisome proliferator-activated receptors (PPARs) are transcription factors and belong to the superfamily of nuclear receptors. They are encoded by three genes located on different chromosomes: PPARalpha, PPARbeta/delta and PPARgamma. PPARalpha plays a key role in the control of lipid metabolism and homeostasis. PPARbeta/delta is expressed ubiquitously and participates in skeletal muscle physiology. PPARbeta/delta and PPARgamma are important factors for placental development and function as well as for embryo implantation. In addition, PPARgamma is mainly involved in adipogenesis. PPARs also participate more or less to cell proliferation, differentiation and apoptosis. Surprisingly, the involvement of these transcription factors in cell-cell and/or cell-matrix interactions has not yet been reviewed except for their role as therapeutic agents in inflammation. Nevertheless, several pioneer reports have recently provided some new insights in this research field, by suggesting that PPARs are involved, directly or indirectly, in these interactions and that their activation by specific ligands may lead to potential therapeutic approaches.

Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells.

This study tests the hypothesis that the activators of peroxisome proliferator-activated receptors (PPARs) and 9-cis-retinoic acid receptor (RXR) regulate human semaphorin 6B (Sema6B) gene expression. The human MCF-7 breast adenocarcinoma cell line was chosen because it expresses Sema6B at a high level. The Sema6B mRNA level was analyzed by RT-PCR and the semaphorin 6B protein content was determined using a polyclonal antibody that we have produced and characterized. Treatments with fenofibrate (a PPARalpha activator) and troglitazone (a PPARgamma ligand) strongly decreased the Sema6B mRNA. The drop in Sema6B mRNA level and in protein content was more important when the treatment combined the action of fenofibrate or troglitazone and 9-cis-retinoic acid. On the other hand, no significant change was observed in the Sema6B mRNA and protein levels when the cells were exposed to the combined action of GW610742 (a PPARbeta activator) and 9-cis-retinoic acid. These data suggest that PPARalpha/RXR and PPARgamma/RXR heterodimers are involved in the regulation of Sema6B gene expression and open new perspectives concerning the participation of these nuclear receptors in cell recognition and migration.

Induction of the expression of the peroxisome proliferator-activated receptor alpha (PPARalpha) by clofibrate in jerboa tissues.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear hormone receptor superfamily that can be activated by natural fatty acids and various xenobiotics, including clofibrate. This transcription factor primarily regulates genes involved in lipid metabolism and homeostasis. We present the expression pattern of the PPARalpha subtype in the adult jerboa Jaculus orientalis, determined by RT-PCR and Western blotting using specific probes and a polyclonal antibody for PPARalpha, respectively. PPARalpha is highly expressed in liver and kidney, and to a lesser extent in duodenum and colon. PPARalpha expression is increased at the mRNA and protein levels in liver and duodenum of jerboa treated for 2 weeks with the peroxisome proliferator (PP) clofibrate. The induction is tissue-specific as no significant changes are observed in kidney and colon. The present data indicate that the PP-induced PPARalpha gene expression is not dependent on the PPARalpha content in target cells.