Summary Background How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more ...aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. Methods This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional 3D conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00423475. Findings Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% 95% CI 75–84 vs 62% 57–67; hazard ratio HR 0·50, 95% CI 0·38–0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 8% of 366 patients had a grade 2 or worse event; 30 patients 8% had hot flushes and five patients 1% had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 8% in the radiotherapy alone group vs 26 7% in the radiotherapy plus goserelin group) and sexual disorders (20 5% vs 30 8%). No treatment-related deaths occurred. Interpretation Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. Funding French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.
High rate outdoor production units of microalgae can undergo temperature fluctuations. Seasonal temperature variations as well as more rapid daily fluctuations are liable to modify the growth ...conditions of microalgae and hence affect production efficiency. The effect of elevated temperatures, above optimal growth temperatures, on growth is seldom reported in literature, but often described as more deleterious than low temperatures. Depending on the species, different strategies are deployed to counteract the effect of above optimal temperatures such as energy re-balancing and cell shrinking. Moreover, long term adaptation of certain species over generation cycles has also been proven efficient to increase optimal temperatures. Physical models coupled to biological kinetics are able to predict the evolution of temperature in the growth media and its effect on the growth rate, highlighting the downstream drastic economic and environmental impacts. Regarding the relative elasticity of microalgae towards temperature issues, cell mortality can depend on species or adapted species and in certain cases can be attenuated. These elements can complement existing models and help visualize the effective impacts of temperature on outdoor cultures.
Radiotherapy is the standard salvage treatment after radical prostatectomy. To date, the role of androgen deprivation therapy has not been formally shown. In this follow-up study, we aimed to update ...the results of the GETUG-AFU 16 trial, which assessed the efficacy of radiotherapy plus androgen suppression versus radiotherapy alone.
GETUG-AFU 16 was an open-label, multicentre, phase 3, randomised, controlled trial that enrolled men (aged ≥18 years) with Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed adenocarcinoma of the prostate (but no previous androgen suppression or pelvic radiotherapy), stage pT2, T3, or T4a (bladder neck involvement only) and pN0 or pNx according to the tumour, node, metastasis (TNM) staging system, whose prostate-specific antigen (PSA) concentration increased from 0·1 ng/mL to between 0·2 ng/mL and 2·0 ng/mL after radical prostatectomy, without evidence of clinical disease. Patients were assigned through central randomisation (1:1) to short-term androgen suppression (subcutaneous injection of 10·8 mg goserelin on the first day of irradiation and 3 months later) plus radiotherapy (3D conformal radiotherapy or intensity modulated radiotherapy of 66 Gy in 33 fractions, 5 days a week for 7 weeks) or radiotherapy alone. Randomisation was stratified using a permuted block method (block sizes of two and four) according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival in the intention-to-treat population. This post-hoc one-shot data collection done 4 years after last data cutoff included patients who were alive at the time of the primary analysis and updated long-term patient status by including dates for first local progression, metastatic disease diagnosis, or death (if any of these had occurred) or the date of the last tumour evaluation or last PSA measurement. Survival at 120 months was reported. Late serious adverse effects were assessed. This trial is registered on ClinicalTrials.gov, NCT00423475.
Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. At the time of data cutoff (March 12, 2019), the median follow-up was 112 months (IQR 102–123). The 120-month progression-free survival was 64% (95% CI 58–69) for patients treated with radiotherapy plus goserelin and 49% (43–54) for patients treated with radiotherapy alone (hazard ratio 0·54, 0·43–0·68; stratified log-rank test p<0·0001). Two cases of secondary cancer occurred since the primary analysis, but were not considered to be treatment related. No treatment-related deaths occurred.
The 120-month progression-free survival confirmed the results from the primary analysis. Salvage radiotherapy combined with short-term androgen suppression significantly reduced risk of biochemical or clinical progression and death compared with salvage radiotherapy alone. The results of the GETUG-AFU 16 trial confirm the efficacy of androgen suppression plus radiotherapy as salvage treatment in patients with increasing PSA concentration after radical prostatectomy for prostate cancer.
The French Health ministry, AstraZeneca, la Ligue Contre le Cancer, and La Ligue de Haute-Savoie.
This paper provides an analysis of the potential environmental impacts of biodiesel production from microalgae. High production yields of microalgae have called forth interest of economic and ...scientific actors but it is still unclear whether the production of biodiesel is environmentally interesting and which transformation steps need further adjustment and optimization. A comparative LCA study of a virtual facility has been undertaken to assess the energetic balance and the potential environmental impacts of the whole process chain, from the biomass production to the biodiesel combustion. Two different culture conditions, nominal fertilizing or nitrogen starvation, as well as two different extraction options, dry or wet extraction, have been tested. The best scenario has been compared to first generation biodiesel and oil diesel. The outcome confirms the potential of microalgae as an energy source but highlights the imperative necessity of decreasing the energy and fertilizer consumption. Therefore control of nitrogen stress during the culture and optimization of wet extraction seem to be valuable options. This study also emphasizes the potential of anaerobic digestion of oilcakes as a way to reduce external energy demand and to recycle a part of the mineral fertilizers.
To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy.
This multicenter phase 3 study enrolled patients with ...positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes.
T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 only for medial/central or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival.
In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.
OBJECTIVESUsing French transcatheter aortic valve replacement (TAVR) registries linked with the nationwide administrative databases, the study compared the rates of long-term mortality, bleeding, and ...ischemic events after TAVR in patients requiring oral anticoagulation with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). BACKGROUNDThe choice of optimal drug for anticoagulation after TAVR remains debated. METHODSData from the France-TAVI and FRANCE-2 registries were linked to the French national health single-payer claims database, from 2010 to 2017. Propensity score matching was used to reduce treatment-selection bias. Two primary endpoints were death from any cause (efficacy) and major bleeding (safety). RESULTSA total of 24,581 patients who underwent TAVR were included and 8,962 (36.4%) were treated with OAC. Among anticoagulated patients, 2,180 (24.3%) were on DOACs. After propensity matching, at 3 years, mortality (hazard ratio HR: 1.37; 95% confidence interval CI: 1.12-1.67; P < 0.005) and major bleeding including hemorrhagic stroke (HR: 1.64; 95% CI: 1.17-2.29; P < 0.005) were lower in patients on DOACs compared with those on VKAs. The rates of ischemic stroke (HR: 1.32; 95% CI: 0.81-2.15; P = 0.27) and acute coronary syndrome (HR: 1.17; 95% CI: 0.68-1.99; P = 0.57) did not differ among groups. CONCLUSIONSIn these large multicenter French TAVR registries with an exhaustive clinical follow-up, the long-term mortality and major bleeding were lower with DOACs than VKAs at discharge. The present study supports preferential use of DOACs rather than VKAs in patients requiring oral anticoagulation therapy after TAVR.
•A comprehensive growth model for high rate algae-bacteria ponds was implemented.•The ALBA model was calibrated and validated on 443 days of outdoor experimentation.•The minimum-law was used as ...ground principle to describe multi-limitation kinetics.•Sensitivity functions were studied under periodic regime and seasonal variability.•Carbon and Nitrogen fate were quantified at different oxygen transfer conditions.
This paper proposes a new model describing the algae-bacteria ecosystem evolution in an outdoor raceway for wastewater treatment. The ALBA model is based on mass balances of COD, C, N and P, but also H and O. It describes growth and interactions among algae, heterotrophic and nitrifying bacteria, while local climate drives light and temperature. Relevant chemical/physical processes are also included. The minimum-law was used as ground principle to describe the multi-limitation kinetics. The model was set-up and calibrated with an original data set recorded on a 56 m2 raceway located in the South of France, continuously treating synthetic wastewater. The main process variables were daily measured along 443 days of operations and dissolved O2 and pH were on-line recorded. A sub-dataset was used for calibration and the model was successfully validated, along the different seasons over a period of 414 days. The model proved to be effective in reproducing both the short term nycthemeral dynamics and the long-term seasonal ones. The analysis of different scenarios reveals the fate of nitrogen and the key role played by oxygen and CO2 in the interactions between the different players of the ecosystem. On average, the process turns out to be CO2 neutral, as compared to a standard activated sludge where approximately half of the influent carbon will end up in the atmosphere. The ALBA model revealed that a suboptimal regulation of the paddle wheel can bring to several detrimental impacts. At high velocity, the strong aeration will reduce the available oxygen provided by photo-oxygenation, while very low aeration can rapidly lead to oxygen inhibition of the photosynthetic process. On the other hand, during night, the paddle wheel is fundamental to ensure enough oxygen in the system to support algal-bacteria respiration. The model can be used to support advanced control strategies, including smart regulation of the paddle wheel velocity to more efficiently balance the mixing, aeration and degassing effects.
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The day-to-day variations of sleep and physical activity are associated with various health outcomes in adults, and previous studies suggested a bidirectional association between these behaviors. The ...daily associations between sleep and physical activity have been examined in observational or interventional contexts. The primary goal of the current systematic review and meta-analysis was to summarize existing evidence about daily associations between sleep and physical activity outcomes at inter- and intra-individual level in adults. A systematic search of records in eight databases from inception to July 2019 identified 33 peer-reviewed empirical publications that examined daily sleep–physical activity association in adults. The qualitative and quantitative analyses of included studies did not support a bidirectional daily association between sleep outcomes and physical activity. Multilevel meta-analyses showed that three sleep parameters were associated with physical activity the following day: sleep quality, sleep efficiency, and wake after sleep onset. However, the associations were small, and varied in terms of direction and level of variability (e.g., inter- or intra-individual). Daytime physical activity was associated with lower total sleep time the following night at an inter-person level with a small effect size. From a clinical perspective, care providers should monitor the effects of better sleep promotion on physical activity behaviors in their patients. Future studies should examine sleep and physical activity during a longer period and perform additional sophisticated statistical analyses.
https://osf.io/w6uy5/.
To determine whether the mutational profile of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is unique by comparison with other diffuse large B-cell lymphoma subtypes, we ...analyzed a total cohort of 20 PCLBCL-LT patients by using next-generation sequencing with a lymphoma panel designed for diffuse large B-cell lymphoma. We also analyzed 12 pairs of tumor and control DNA samples by whole-exome sequencing, which led us to perform resequencing of three selected genes not included in the lymphoma panel: TBL1XR1, KLHL6, and IKZF3. Our study clearly identifies an original mutational landscape of PCLBCL-LT with a very restricted set of highly recurrent mutations (>40%) involving MYD88 (p.L265P variant), PIM1, and CD79B. Other genes involved in B-cell signaling, NF-κB activation, or DNA modeling were found altered, notably TBL1XR1 (33%), MYC (26%) CREBBP (26%), and IRF4 (21%) or HIST1H1E (41%). MYD88L265P variant was associated with copy number variations or copy neutral loss of heterozygosity in 60% of patients. The most frequent genetic losses involved CDKN2A/2B, TNFAIP3/A20, PRDM1, TCF3, and CIITA. Together, these results show that PCLBCL-LT exhibits a unique mutational landscape, combining highly recurrent hotspot mutations in genes involved in NF-kB and B-cell signaling pathways, which provides a rationale for using selective inhibitors of the B-cell receptor.
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