Cost-effectiveness of weekly adaptive radiotherapy versus standard IMRT in head and neck cancer alongside the ARTIX trial.

BACKGROUND AND PURPOSE: We performed a cost-effectiveness analysis (CEA) comparing an adaptive radiotherapy (ART) strategy, based on weekly replanning, aiming to correct the parotid gland overdose during treatment and expecting therefore to decrease xerostomia, when compared to a standard IMRT. MATERIALS AND METHODS: We conducted the ARTIX trial, a randomized, parallel-group, multicentric study comparing a systematic weekly replanning ART to a standard IMRT. The primary endpoint was the frequency of xerostomia at 12 months, measured by stimulating salivary flow with paraffin. The CEA was designed alongside the ARTIX trial which was linked to the French national health data system (SNDS). For each patient, healthcare consumptions and costs were provided by the SNDS. The reference case analysis was based on the primary endpoint of the trial. Sensitivity and scenario analyses were performed. RESULTS: Of the 129 patients randomly assigned between 2013 and 2018, only 2 records were not linked to the SNDS, which provides a linkage proportion of 98.4%. All of the other 127 records were linked with good to very good robustness. On the intent-to-treat population at 12 months, mean total costs per patient were €41,564 (SD 23,624) and €33,063 (SD 16,886) for ART and standard IMRT arms, respectively (p = 0.033). Incremental cost effectiveness ratio (ICER) was €162,444 per xerostomia avoided. At 24 months, ICER was €194,521 per xerostomia avoided. For both progression-free and overall survival, ART was dominated by standard IMRT. CONCLUSION: The ART strategy was deemed to be not cost-effective compared with standard IMRT for patients with locally advanced oropharyngeal cancer.

Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer: A Phase 3 Randomized Clinical Trial.

Importance: Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers. Objective: To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer. Design, Setting, and Participants: This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022. Interventions: The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning). Main Outcomes and Measures: The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival. Results: A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms. Conclusions and Relevance: This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates. Trial Registration: ClinicalTrials.gov Identifier: NCT01874587.

Effectiveness of a Mobile App (PIMPmyHospital) in Reducing Therapeutic Turnaround Times in an Emergency Department: Protocol for a Pre- and Posttest Study.

BACKGROUND: Delays in reviewing issued laboratory results in emergency departments (EDs) can adversely affect efficiency and quality of care. One opportunity to improve therapeutic turnaround time could be to provide real-time access to laboratory results on mobile devices available to every caregiver. We developed a mobile app named "Patients In My Pocket in my Hospital" (PIMPmyHospital) to help ED caregivers automatically obtain and share relevant information about the patients they care for including laboratory results. OBJECTIVE: This pre- and posttest study aims to explore whether the implementation of the PIMPmyHospital app impacts the timeliness with which ED physicians and nurses remotely access laboratory results while actively working in their real-world environment, including ED length of stay, technology acceptance and usability among users, and how specific in-app alerts impact on its effectiveness. METHODS: This single-center study of nonequivalent pre- and posttest comparison group design will be conducted before and after the implementation of the app in a tertiary pediatric ED in Switzerland. The retrospective period will cover the previous 12 months, and the prospective period will cover the following 6 months. Participants will be postgraduate residents pursuing a ≤6-year residency in pediatrics, pediatric emergency medicine fellows, and registered nurses from the pediatric ED. The primary outcome will be the mean elapsed time in minutes from delivery of laboratory results to caregivers' consideration by accessing them either through the hospital's electronic medical records or through the app before and after the implementation of the app, respectively. As secondary outcomes, participants will be queried about the acceptance and usability of the app using the Unified Theory of Acceptance and Use of Technology model and the System Usability Scale. ED length of stay will be compared before and after the implementation of the app for patients with laboratory results. The impact of specific alerts on the app, such as a flashing icon or sound for reported pathological values, will be reported. RESULTS: Retrospective data collection gathered from the institutional data set will span a 12-month period from October 2021 to October 2022, while the 6-month prospective collection will begin with the implementation of the app in November 2022 and is expected to cease at the end of April 2023. We expect the results of the study to be published in a peer-reviewed journal in late 2023. CONCLUSIONS: This study will show the potential reach, effectiveness, acceptance, and use of the PIMPmyHospital app among ED caregivers. The findings of this study will serve as the basis for future research on the app and any further development to improve its effectiveness. Trial Registration: ClinicalTrials.gov NCT05557331; https://clinicaltrials.gov/ct2/show/NCT05557331. TRIAL REGISTRATION: ClinicalTrials.gov NCT05557331; https://clinicaltrials.gov/ct2/show/NCT05557331. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/43695.

Group VII ethylene response factors, MtERF74 and MtERF75, sustain nitrogen fixation in Medicago truncatula microoxic nodules.

Group VII ethylene response factors (ERF-VII) are plant-specific transcription factors (TFs) known for their role in the activation of hypoxia-responsive genes under low oxygen stress but also in plant endogenous hypoxic niches. However, their function in the microaerophilic nitrogen-fixing nodules of legumes has not yet been investigated. We investigated regulation and the function of the two Medicago truncatula ERF-VII TFs (MtERF74 and MtERF75) in roots and nodules, MtERF74 and MtERF75 in response to hypoxia stress and during the nodulation process using an RNA interference strategy and targeted proteolysis of MtERF75. Knockdown of MtERF74 and MtERF75 partially blocked the induction of hypoxia-responsive genes in roots exposed to hypoxia stress. In addition, a significant reduction in nodulation capacity and nitrogen fixation activity was observed in mature nodules of double knockdown transgenic roots. Overall, the results indicate that MtERF74 and MtERF75 are involved in the induction of MtNR1 and Pgb1.1 expression for efficient Phytogb-nitric oxide respiration in the nodule.

A Mobile App for Advance Care Planning and Advance Directives (Accordons-nous): Development and Usability Study.

BACKGROUND: Advance care planning, including advance directives, is an important tool that allows patients to express their preferences for care if they are no longer able to express themselves. We developed Accordons-nous, a smartphone app that informs patients about advance care planning and advance directives, facilitates communication on these sensitive topics, and helps patients express their values and preferences for care. OBJECTIVE: The first objective of this study is to conduct a usability test of this app. The second objective is to collect users' critical opinions on the usability and relevance of the tool. METHODS: We conducted a usability test by means of a think-aloud method, asking 10 representative patients to complete 7 browsing tasks. We double coded the filmed sessions to obtain descriptive data on task completion (with or without help), time spent, number of clicks, and the types of problems encountered. We assessed the severity of the problems encountered and identified the modifications needed to address these problems. We evaluated the readability of the app using Scolarius, a French equivalent of the Flesch Reading Ease test. By means of a posttest questionnaire, we asked participants to assess the app's usability (System Usability Scale), relevance (Mobile App Rating Scale, section F), and whether they would recommend the app to the target groups: patients, health professionals, and patients' caring relatives. RESULTS: Participants completed the 7 think-aloud tasks in 80% (56/70) of the cases without any help from the experimenter, in 16% (11/70) of the cases with some help, and failed in 4% (3/70) of the cases. The analysis of failures and difficulties encountered revealed a series of major usability problems that could be addressed with minor modifications to the app. Accordons-nous obtained high scores on readability (overall score of 87.4 on Scolarius test, corresponding to elementary school level), usability (85.3/100 on System Usability Scale test), relevance (4.3/5 on the Mobile App Rating Scale, section F), and overall subjective endorsement on 3 I would recommend questions (4.7/5). CONCLUSIONS: This usability test helped us make the final changes to our app before its official launch.

Effectiveness of a Mobile App in Reducing Therapeutic Turnaround Time and Facilitating Communication between Caregivers in a Pediatric Emergency Department: A Randomized Controlled Pilot Trial.

For maintaining collaboration and coordination among emergency department (ED) caregivers, it is essential to effectively share patient-centered information. Indirect activities on patients, such as searching for laboratory results and sharing information with scattered colleagues, waste resources to the detriment of patients and staff. Therefore, we conducted a pilot study to evaluate the initial efficacy of a mobile app to facilitate rapid mobile access to central laboratory results and remote interprofessional communication. A total of 10 ED residents and registered nurses were randomized regarding the use of the app versus conventional methods during semi-simulated scenarios in a pediatric ED (PED). The primary outcome was the elapsed time in minutes in each group from the availability of laboratory results to their consideration by participants. The secondary outcome was the elapsed time to find a colleague upon request. Time to consider laboratory results was significantly reduced from 23 min (IQR 10.5-49.0) to 1 min (IQR 0-5.0) with the use of the app compared to conventional methods (92.2% reduction in mean times, p = 0.0079). Time to find a colleague was reduced from 24 min to 1 min (i.e., 93.0% reduction). Dedicated mobile apps have the potential to improve information sharing and remote communication in emergency care.

Kaempferol as a precursor for ubiquinone (coenzyme Q) biosynthesis: An atypical node between specialized metabolism and primary metabolism.

Ubiquinone (coenzyme Q) is a vital respiratory cofactor and liposoluble antioxidant. Studies have shown that plants derive approximately a quarter of 4-hydroxybenzoate, which serves as the direct ring precursor of ubiquinone, from the catabolism of kaempferol. Biochemical and genetic evidence suggests that the release of 4-hydroxybenzoate from kaempferol is catalyzed by heme-dependent peroxidases and that 3-O-glycosylations of kaempferol act as a negative regulator of this process. These findings not only represent an atypical instance of primary metabolite being derived from specialized metabolism but also raise the question as to whether ubiquinone contributes to the ROS scavenging and signaling functions already established for flavonols.

A dedicated flavin-dependent monooxygenase catalyzes the hydroxylation of demethoxyubiquinone into ubiquinone (coenzyme Q) in Arabidopsis.

Ubiquinone (Coenzyme Q) is a vital respiratory cofactor and liposoluble antioxidant. In plants, it is not known how the C-6 hydroxylation of demethoxyubiquinone, the penultimate step in ubiquinone biosynthesis, is catalyzed. The combination of cross-species gene network modeling along with mining of embryo-defective mutant databases of Arabidopsis thaliana identified the embryo lethal locus EMB2421 (At1g24340) as a top candidate for the missing plant demethoxyubiquinone hydroxylase. In marked contrast with prototypical eukaryotic demethoxyubiquinone hydroxylases, the catalytic mechanism of which depends on a carboxylate-bridged di-iron domain, At1g24340 is homologous to FAD-dependent oxidoreductases that instead use NAD(P)H as an electron donor. Complementation assays in Saccharomyces cerevisiae and Escherichia coli demonstrated that At1g24340 encodes a functional demethoxyubiquinone hydroxylase and that the enzyme displays strict specificity for the C-6 position of the benzoquinone ring. Laser-scanning confocal microscopy also showed that GFP-tagged At1g24340 is targeted to mitochondria. Silencing of At1g24340 resulted in 40 to 74% decrease in ubiquinone content and de novo ubiquinone biosynthesis. Consistent with the role of At1g24340 as a benzenoid ring modification enzyme, this metabolic blockage could not be bypassed by supplementation with 4-hydroxybenzoate, the immediate precursor of ubiquinone's ring. Unlike in yeast, in Arabidopsis overexpression of demethoxyubiquinone hydroxylase did not boost ubiquinone content. Phylogenetic reconstructions indicated that plant demethoxyubiquinone hydroxylase is most closely related to prokaryotic monooxygenases that act on halogenated aromatics and likely descends from an event of horizontal gene transfer between a green alga and a bacterium.

Prognostic factors of colorectal cancer patients with brain metastases.

INTRODUCTION: Brain metastases (BMs) from colorectal cancer (CRC) are rare (≈2%) but are increasing with the improvement of CRC prognosis. The main objective of this study was to evaluate the prognostic factors of BM from CRC. MATERIALS AND METHODS: This multicenter retrospective study included all consecutive patients with BM from CRC diagnosed between 2000 and 2017. THEORY/CALCULATION: Prognostic factors of OS were evaluated in univariate (log-rank test) and multivariate analyses (Cox regression model). These prognostic factors could help the management of patients with BM from CRC. RESULTS: A total of 358 patients were included with a median age of 65.5 years. Primary tumors were mostly located in the rectum (42.4%) or left colon (37.2%) and frequently KRAS-mutated (56.9%). The median time from metastatic CRC diagnosis to BM diagnosis was 18.5 ± 2.5 months. BMs were predominantly single (56.9%) and only supratentorial (54.4%). BM resection was performed in 33.0% of the cases and 73.2% of patients had brain radiotherapy alone or after surgery. Median OS was 5.1 ± 0.3 months. In multivariate analysis, age under 65 years, ECOG performance status 0-1, single BM and less than 3 chemotherapy lines before BM diagnosis were associated with better OS. Prognostic scores, i.e. recursive partitioning analysis (RPA), Graded Prognostic Assessment (GPA), Disease Specific-Graded Prognostic Assessment (DS-GPA), Gastro-Intestinal-Graded Prognostic Assessment (GI-GPA) and the nomogram were statistically significantly associated with OS but the most relevant prognosis criteria seemed the ECOG performance status 0-1. CONCLUSIONS: ECOG performance status, number of BM and number of chemotherapy lines are the most relevant factors in the management of patients with BM from CRC.

Nitrate reductases and hemoglobins control nitrogen-fixing symbiosis by regulating nitric oxide accumulation.

The interaction between legumes and rhizobia leads to the establishment of a symbiotic relationship between plant and bacteria. This is characterized by the formation of a new organ, the nodule, which facilitates the fixation of atmospheric nitrogen (N2) by nitrogenase through the creation of a hypoxic environment. Nitric oxide (NO) accumulates at each stage of the symbiotic process. NO is involved in defense responses, nodule organogenesis and development, nitrogen fixation metabolism, and senescence induction. During symbiosis, either successively or simultaneously, NO regulates gene expression, modulates enzyme activities, and acts as a metabolic intermediate in energy regeneration processes via phytoglobin-NO respiration and the bacterial denitrification pathway. Due to the transition from normoxia to hypoxia during nodule formation, and the progressive presence of the bacterial partner in the growing nodules, NO production and degradation pathways change during the symbiotic process. This review analyzes the different source and degradation pathways of NO, and highlights the role of nitrate reductases and hemoproteins of both the plant and bacterial partners in the control of NO accumulation.

Plant Nitrate Reductases Regulate Nitric Oxide Production and Nitrogen-Fixing Metabolism During the Medicago truncatula-Sinorhizobium meliloti Symbiosis.

Nitrate reductase (NR) is the first enzyme of the nitrogen reduction pathway in plants, leading to the production of ammonia. However, in the nitrogen-fixing symbiosis between legumes and rhizobia, atmospheric nitrogen (N2) is directly reduced to ammonia by the bacterial nitrogenase, which questions the role of NR in symbiosis. Next to that, NR is the best-characterized source of nitric oxide (NO) in plants, and NO is known to be produced during the symbiosis. In the present study, we first surveyed the three NR genes (MtNR1, MtNR2, and MtNR3) present in the Medicago truncatula genome and addressed their expression, activity, and potential involvement in NO production during the symbiosis between M. truncatula and Sinorhizobium meliloti. Our results show that MtNR1 and MtNR2 gene expression and activity are correlated with NO production throughout the symbiotic process and that MtNR1 is particularly involved in NO production in mature nodules. Moreover, NRs are involved together with the mitochondrial electron transfer chain in NO production throughout the symbiotic process and energy regeneration in N2-fixing nodules. Using an in vivo NMR spectrometric approach, we show that, in mature nodules, NRs participate also in the regulation of energy state, cytosolic pH, carbon and nitrogen metabolism under both normoxia and hypoxia. These data point to the importance of NR activity for the N2-fixing symbiosis and provide a first explanation of its role in this process.

Medicago truncatula Phytoglobin 1.1 controls symbiotic nodulation and nitrogen fixation via the regulation of nitric oxide concentration.

In legumes, phytoglobins (Phytogbs) are known to regulate nitric oxide (NO) during early phase of the nitrogen-fixing symbiosis and to buffer oxygen in functioning nodules. However, their expression profile and respective role in NO control at each stage of the symbiosis remain little-known. We first surveyed the Phytogb genes occurring in Medicago truncatula genome. We analyzed their expression pattern and NO production from inoculation with Sinorhizobium meliloti up to 8 wk post-inoculation. Finally, using overexpression and silencing strategy, we addressed the role of the Phytogb1.1-NO couple in the symbiosis. Three peaks of Phytogb expression and NO production were detected during the symbiotic process. NO upregulates Phytogbs1 expression and downregulates Lbs and Phytogbs3 ones. Phytogb1.1 silencing and overexpression experiments reveal that Phytogb1.1-NO couple controls the progression of the symbiosis: high NO concentration promotes defense responses and nodular organogenesis, whereas low NO promotes the infection process and nodular development. Both NO excess and deficiency provoke a 30% inhibition of nodule establishment. In mature nodules, Phytogb1.1 regulates NO to limit its toxic effects while allowing the functioning of Phytogb-NO respiration to maintain the energetic state. This work highlights the regulatory role played by Phytogb1.1-NO couple in the successive stages of symbiosis.

Examining the Inter Hemispheric Transfer Time Test: A new computerized cognitive test to incorporate into therapeutic strategy for patients with brain metastases? A pilot study.

OBJECTIVE: To evaluate the computerized Inter Hemispheric Transfer Time Test (IHTTT), a cognitive test designed for the detection of information processing speed impairment in patients undergoing stereotactic radiation therapy for brain metastases. METHODS: Inclusion criteria: age ≥18 years, brain metastases treated by stereotactic radiotherapy (SRT) with dose schedule: 33 Gy in 3 fractions, solid tumour, ≥70 Karnofsky Performance Status, Mini-Mental State Evaluation (MMSE) ≥ 24, no history of stroke brain injury. Twenty-nine patients were recruited from June 2014 to April 2015. All recruited patients were administered Frontal Assessment Battery at Bedside (FAB), IHTTT and QLQ-C30 quality of life questionnaire before SRT, at one-month, six-month and one-year follow-up. The primary endpoint was Interhemispheric Transfer Index (IHTI). Secondary endpoints included Interhemispheric Transfer Time (IHTT), MMSE, FAB, and quality of life. RESULTS: A significant evolution of cognitive function over time was assessed by the IHTTT: IHTT = 720 ±â€¯27 ms at baseline, 728 ±â€¯20 at one month, 736 ±â€¯36 at 6 months, 799 ±â€¯111 at one-year follow-up (p = 0.0010); IHTI = 13.1 ±â€¯31.4, 11.5 ±â€¯24.3, 50.6 ±â€¯57.9, 91.0 ±â€¯59.4 (p < 0.0001). There was also a significant evolution over time for MMSE (p = 0.014) but neither for FAB score nor the quality of life scores. IHTI was strongly related to progression-free survival (p = 0.0091). CONCLUSION: Our results suggest that IHTTT is able to detect the evolution of cognitive function over time. IHTTT could be an interesting sensitive cognitive test to include in evaluation of patients with brain metastases irradiated by SRT.

Nitric oxide signaling, metabolism and toxicity in nitrogen-fixing symbiosis.

Interactions between legumes and rhizobia lead to the establishment of a symbiotic relationship characterized by the formation of a new organ, the nodule, which facilitates the fixation of atmospheric nitrogen (N2) by nitrogenase through the creation of a hypoxic environment. Significant amounts of nitric oxide (NO) accumulate at different stages of nodule development, suggesting that NO performs specific signaling and/or metabolic functions during symbiosis. NO, which regulates nodule gene expression, accumulates to high levels in hypoxic nodules. NO accumulation is considered to assist energy metabolism within the hypoxic environment of the nodule via a phytoglobin-NO-mediated respiration process. NO is a potent inhibitor of the activity of nitrogenase and other plant and bacterial enzymes, acting as a developmental signal in the induction of nodule senescence. Hence, key questions concern the relative importance of the signaling and metabolic functions of NO versus its toxic action and how NO levels are regulated to be compatible with nitrogen fixation functions. This review analyses these paradoxical roles of NO at various stages of symbiosis, and highlights the role of plant phytoglobins and bacterial hemoproteins in the control of NO accumulation.

Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases.

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.

Cell Cycle Changes after Glioblastoma Stem Cell Irradiation: The Major Role of RAD51.

"Glioma Stem Cells" (GSCs) are known to play a role in glioblastoma (GBM) recurrence. Homologous recombination (HR) defects and cell cycle checkpoint abnormalities can contribute concurrently to the radioresistance of GSCs. DNA repair protein RAD51 homolog 1 (RAD51) is a crucial protein for HR and its inhibition has been shown to sensitize GSCs to irradiation. The aim of this study was to examine the consequences of ionizing radiation (IR) for cell cycle progression in GSCs. In addition, we intended to assess the potential effect of RAD51 inhibition on cell cycle progression. Five radiosensitive GSC lines and five GSC lines that were previously characterized as radioresistant were exposed to 4Gy IR, and cell cycle analysis was done by fluorescence-activated cell sorting (FACS) at 24, 48, 72, and 96 h with or without RAD51 inhibitor. Following 4Gy IR, all GSC lines presented a significant increase in G2 phase at 24 h, which was maintained over 72 h. In the presence of RAD51 inhibitor, radioresistant GSCs showed delayed G2 arrest post-irradiation for up to 48 h. This study demonstrates that all GSCs can promote G2 arrest in response to radiation-induced DNA damage. However, following RAD51 inhibition, the cell cycle checkpoint response differed. This study contributes to the characterization of the radioresistance mechanisms of GSCs, thereby supporting the rationale of targeting RAD51-dependent repair pathways in view of radiosensitizing GSCs.

Interest of Supportive and Barrier Protective Skin Care Products in the Daily Prevention and Treatment of Cutaneous Toxicity During Radiotherapy for Breast Cancer.

PURPOSE: As many as 50% of patients with cancer develop acute skin reactions to some degree with radiotherapy. Proactive skin care is often recommended to minimise these skin reactions and maintain the integrity of the epidermal barrier; nevertheless, no consensual guidelines are systematically used. This multicentre, observational, prospective study evaluated the tolerability and benefit of supportive and barrier protective skin care products in preventing radiotherapy-induced skin reactions in 253 women initiating radiotherapy (exclusive or adjuvant) for breast cancer. METHODS: Patients received a kit of 5 commercially available skin care products before the first radiotherapy treatment. The following variables were assessed: cutaneous adverse events, investigator-assessed skin reactions (oedema, erythema, dryness, desquamation) before and after radiotherapy course, investigator, and patient opinion on products benefit. Results were analysed by frequency of product use (heavy versus low). RESULTS: Average age was 60 years (range: 34-85). Over 92% of patients reported good to excellent tolerance on irradiated skin for each product. During the 6-week radiotherapy period, we observed that heavy product users had less skin reactions than the low users, particularly within 10 days of radiotherapy initiation (8% versus 18%; p = .031). Positive physician's opinion on product use was more frequent for high (66.6%) versus low (32%) users. Patient-assessed patient benefit index was generally >1, indicating relevant treatment benefit, with a tendency for better benefit in high versus low users. CONCLUSIONS: These results support recommendations to use skin care products to minimise the impact of secondary cutaneous reactions with radiotherapy cancer treatment.

Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome.

Glioblastoma (GBM) represents the most common and lethal primary malignant brain tumor. The standard treatment for glioblastoma patients involves surgical resection with concomitant radio and chemotherapy. Despite today's clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months. Tumor resistance and recurrence is strongly correlated with a subpopulation of highly radioresistant and invasive cells termed Glioblastoma Stem Cells (GSCs). The transcription factor STAT3 has been found to be constitutively activated in different tumors including GBM and enhanced tumor radioresistance. In this study, we assessed radiosensitization of GSC lines isolated from patients by inhibition of STAT3 activation using Stattic or WP1066. We showed that inhibitor treatment before cell irradiation decreased the surviving fraction of GSCs suggesting that STAT3 inhibition could potentiate radiation effects. Finally, we investigated STAT3 activation status on 61 GBM clinical samples and found a preferential phosphorylation of STAT3 on Serine727 (pS727). Moreover, we found that pS727 was associated with a significant lower overall patient survival and progression-free survival but not pY705. Taken together, our results suggest that pS727-STAT3 could be a potential prognostic marker and could constitute a therapeutic target to sensitize highly radioresistant GSCs.

Pathways of nitric oxide metabolism and operation of phytoglobins in legume nodules: missing links and future directions.

The interaction between legumes and rhizobia leads to the establishment of a beneficial symbiotic relationship. Recent advances in legume - rhizobium symbiosis revealed that various reactive oxygen and nitrogen species including nitric oxide (NO) play important roles during this process. Nodule development occurs with a transition from a normoxic environment during the establishment of symbiosis to a microoxic environment in functional nodules. Such oxygen dynamics are required for activation and repression of various NO production and scavenging pathways. Both the plant and bacterial partners participate in the synthesis and degradation of NO. However, the pathways of NO production and degradation as well as their cross-talk and involvement in the metabolism are still a matter of debate. The plant-originated reductive pathways are known to contribute to the NO production in nodules under hypoxic conditions. Non-symbiotic hemoglobin (phytoglobin) (Pgb) possesses high NO oxygenation capacity, buffers and scavenges NO. Its operation, through a respiratory cycle called Pgb-NO cycle, leads to the maintenance of redox and energy balance in nodules. The role of Pgb/NO cycle under fluctuating NO production from soil needs further investigation for complete understanding of NO regulatory mechanism governing nodule development to attain optimal food security under changing environment.

[Brain metastases: Focal treatment (surgery and radiation therapy) and cognitive consequences]. / Métastases cérébrales : rôle des traitements focaux (chirurgie et radiothérapie) et leur impact cognitif.

Brain metastases represent the first cause of malignant brain tumor. Without radiation therapy, prognosis was poor with fast neurological deterioration, and a median overall survival of one month. Nowadays, therapeutic options depend on brain metastases presentation, extra brain disease, performance status and estimated prognostic (DS GPA). Therefore, for oligometastatic brain patients with a better prognosis, this therapeutic modality is controversial. In fact, whole-brain radiation therapy improves neurological outcomes, but it can also induce late neuro-cognitive sequelae for long-term survivors of brain metastases. Thus, in this strategy for preserving good cognitive functions, stereotactic radiation therapy is a promising treatment. Delivering precisely targeted radiation in few high-doses in one to four brain metastases, allows to reduce radiation damage to normal tissues and it should allow to decrease radiation-induced cognitive decline. In this paper, we will discuss about therapeutic strategies (radiation therapy and surgery) with their neuro-cognitive consequences for brain metastases patients and future concerning preservation of cognitive functions.