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Reports demonstrate the role of M-CSF (CSF1) in tumor progression in mouse models as well as the prognostic value of macrophage numbers in breast cancer patients. Recently, a subset of CD14+ monocytes expressing the Tie2 receptor, once thought to be predominantly expressed on endothelial cells, has been characterized. We hypothesized that increased levels of CSF1 in breast tumors can regulate differentiation of Tie2- monocytes to a Tie2+ phenotype. We treated CD14+ human monocytes with CSF1 and found a significant increase in CD14+/Tie2+ positivity. To understand if CSF1-induced Tie2 expression on these cells improved their migratory ability, we pre-treated CD14+ monocytes with CSF1 and used Boyden chemotaxis chambers to observe enhanced response to angiopoietin-2 (ANG2), the chemotactic ligand for the Tie2 receptor. We found that CSF1 pre-treatment significantly augmented chemotaxis and that Tie2 receptor upregulation was responsible as siRNA targeting Tie2 receptor abrogated this effect. To understand any augmented angiogenic effect produced by treating these cells with CSF1, we cultured human umbilical vein endothelial cells (HUVECs) with conditioned supernatants from CSF1-pre-treated CD14+ monocytes for a tube formation assay. While supernatants from CSF1-pre-treated TEMs increased HUVEC branching, a neutralizing antibody against the CSF1R abrogated this activity, as did siRNA against the Tie2 receptor. To test our hypothesis in vivo, we treated PyMT tumor-bearing mice with CSF1 and observed an expansion in the TEM population relative to total F4/80+ cells, which resulted in increased angiogenesis. Investigation into the mechanism of Tie2 receptor upregulation on CD14+ monocytes by CSF1 revealed a synergistic contribution from the PI3 kinase and HIF pathways as the PI3 kinase inhibitor LY294002, as well as HIF-1α-deficient macrophages differentiated from the bone marrow of HIF-1αfl/fl/LysMcre mice, diminished CSF1-stimulated Tie2 receptor expression.

Changes in reflex spinal pathways after stroke have been shown to affect motor activity in agonist and antagonist muscles acting at the same joint. However, only a few studies have evaluated the heteronymous reflex pathways modulating motoneuronal activity at different joints. This study investigates whether there are changes in the spinal facilitatory and inhibitory pathways linking knee to ankle extensors and if such changes may be related to motor deficits after stroke. The early facilitation and later inhibition of soleus H reflex evoked by the stimulation of femoral nerve at 2 times the motor threshold of the quadriceps were assessed in 15 healthy participants and on the paretic and the non-paretic sides of 15 stroke participants. The relationships between this reflex modulation and the levels of motor recovery, coordination and spasticity were then studied. Results show a significant (Mann-Whitney U; P

PurposeConcerns gradually arose about misuse of gabapentinoids (gabapentin and pregabalin), especially when used in combination with opioids. Because it can be a driver of usage, trends in prescribing habits may be interesting to analyse. The aim of this study is to examine the evolution of prescriptions of opioids and gabapentinoids in England from 2015 to 2020 at a regional level.MethodsThis study included data from April 2015 to February 2020, focusing on prescribing data, extracted the OpenPrescribing database. We described the evolution of the prescriptions of opioids and gabapentinoids and calculated their ratios for each month. We used Analyses of Variance (ANOVAs) to compare data between and within regions (over time).ResultsDuring this period, opioid prescriptions remained stable (from -3.3% to +2.2%/year) and increased for gabapentinoids generally (from +1.5% to +2.2%). The ratio between gabapentinoid to opioid prescriptions increased by more than 20% in 2020 compared to 2015, variably between regions (F(6,406) = [120.2]; PConclusionsGabapentinoids are increasingly prescribed in England. The ratio of gabapentinoid to opioid prescriptions in England increased from 2015 to 2020. The reclassification of gabapentinoids as controlled drugs, in 2019, may have been associated with a significant reduction, although larger prescribers may have been less influenced.

There is an increasing need for rapid, reliable, non-invasive, and inexpensive mass testing methods as the global COVID-19 pandemic continues. Detection dogs could be a possible solution to identify individuals infected with SARS-CoV-2. Previous studies have shown that dogs can detect SARS-CoV-2 on sweat samples. This study aims to establish the dogs’ sensitivity (true positive rate) which measures the proportion of people with COVID-19 that are correctly identified, and specificity (true negative rate) which measures the proportion of people without COVID-19 that are correctly identified. Seven search and rescue dogs were tested using a total of 218 axillary sweat samples (62 positive and 156 negative) in olfaction cones following a randomised and double-blind protocol. Sensitivity ranged from 87% to 94%, and specificity ranged from 78% to 92%, with four dogs over 90%. These results were used to calculate the positive predictive value and negative predictive value for each dog for different infection probabilities (how likely it is for an individual to be SARS-CoV-2 positive), ranging from 10–50%. These results were compared with a reference diagnostic tool which has 95% specificity and sensitivity. Negative predictive values for six dogs ranged from ≥98% at 10% infection probability to ≥88% at 50% infection probability compared with the reference tool which ranged from 99% to 95%. Positive predictive values ranged from ≥40% at 10% infection probability to ≥80% at 50% infection probability compared with the reference tool which ranged from 68% to 95%. This study confirms previous results, suggesting that dogs could play an important role in mass-testing situations. Future challenges include optimal training methods and standardisation for large numbers of detection dogs and infrastructure supporting their deployment.

The Maldives tuna fishery landings in 2018 were 148, 000 t and accounted for nearly a quarter of the global pole-and-line tuna catch. This fishery partially relies on a network of 55 anchored fish aggregating devices (AFADs) deployed around the archipelago. About one-third of the total pole-and-line tuna catch is harvested at AFADs. Although the AFAD fishery has existed for 35 years, knowledge on the behaviour of tuna in the AFAD array is still limited, precluding the development of science-based fishery management. In this study, local ecological knowledge (LEK) of fishers was used to improve our understanding of tuna behaviour, through personal interviews of 54 pole-and-line fishers from different parts of the archipelago. Interview results suggest that during the northeast monsoon tuna are more abundant on the eastern side of the Maldives, while during the southwest monsoon they are more abundant on the western side of the Maldives. Most fishers believed that tuna tend to stay at the AFADs for 3 to 6 days and remain within 2 miles from the AFADs when they are associated. Fishers believe that strong currents is the main factor for tuna departure from AFADs, though high sea surface temperatures and stormy conditions were also thought to contribute to departures. Moderate currents are believed to be a favourable condition to form aggregations at the AFADs while other factors such as suitable temperature, prey and attractants enhance this aggregation. Fishers also believe that there are multiple schools segregated according to size and species at AFADs and that catchability is higher at dawn and in the late afternoon when the tuna occur shallower in the water column. This study is an important step towards engaging the Maldivian tuna fishers into a science-based fishery management.

BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years. At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65-2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34-3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.Trial registrationClinicalTrials.gov NCT01806259.

Study objectiveTo investigate the performance of a rapid RT-PCR assay to detect influenza A/B at emergency department admission.MethodsThis single-center prospective study recruited adult patients attending the emergency department for influenza-like illness. Triage nurses performed nasopharyngeal swab samples and ran rapid RT-PCR assays using a dedicated device (cobas Liat, Roche Diagnostics, Meylan, France) located at triage. The same swab sample was also analyzed in the department of virology using conventional RT-PCR techniques. Patients were included 24 hours-a-day, 7 days-a-week. The primary outcome was the diagnostic accuracy of the rapid RT-PCR assay performed at triage.ResultsA total of 187 patients were included over 11 days in January 2018. Median age was 70 years (interquartile range 44 to 84) and 95 (51%) were male. Nine (5%) assays had to be repeated due to failure of the first assay. The sensitivity of the rapid RT-PCR assay performed at triage was 0.98 (95% confidence interval (CI): 0.91-1.00) and the specificity was 0.99 (95% CI: 0.94-1.00). A total of 92 (49%) assays were performed at night-time or during the weekend. The median time from patient entry to rapid RT-PCR assay results was 46 [interquartile range 36-55] minutes.ConclusionRapid RT-PCR assay performed by nurses at triage to detect influenza A/B is feasible and highly accurate.

BACKGROUND:Public health programs to prevent invasive meningococcal disease (IMD) with monovalent serogroup C meningococcal conjugate vaccine (MCV-C) and quadrivalent meningococcal conjugate vaccines (MCV-4) in infancy and adolescence vary across Canadian provinces. This study evaluated the cost-effectiveness of various vaccination strategies against IMD using current and anticipated future pricing and recent epidemiology. METHODS:A cohort model was developed to estimate the clinical burden and costs (CAN$2014) of IMD in the Canadian population over a 100-year time horizon for three strategies: (1) MCV-C in infants and adolescents (MCV-C/C); (2) MCV-C in infants and MCV-4 in adolescents (MCV-C/4); and (3) MCV-4 in infants (2 doses) and adolescents (MCV-4/4). The source for IMD incidence was Canadian surveillance data. The effectiveness of MCV-C was based on published literature. The effectiveness of MCV-4 against all vaccination regimens was assumed to be the same as for MCV-C regimens against serogroup C. Herd effects were estimated by calibration to estimates reported in prior analyses. Costs were from published sources. Vaccines prices were projected to decline over time reflecting historical procurement trends. RESULTS:Over the modeling horizon there are a projected 11,438 IMD cases and 1,195 IMD deaths with MCV-C/C; expected total costs are $597.5 million. MCV-C/4 is projected to reduce cases of IMD by 1,826 (16%) and IMD deaths by 161 (13%). Vaccination costs are increased by $32 million but direct and indirect IMD costs are projected to be reduced by $46 million. MCV-C/4 is therefore dominant vs. MCV-C/C in the base case. Cost-effectiveness of MCV-4/4 was $111,286 per QALY gained versus MCV-C/4 (2575/206 IMD cases/deaths prevented; incremental costs $68 million). CONCLUSIONS:If historical trends in Canadian vaccines prices continue, use of MCV-4 instead of MCV-C in adolescents may be cost-effective. From an economic perspective, switching to MCV-4 as the adolescent booster should be considered.

OBJECTIVES: Smoking during pregnancy may cause many health problems for pregnant women and their newborns. However, there is a paucity of research that has examined the predictors of smoking during pregnancy in Canada. This study used data from the 2009-2010 Canadian Community Health Survey (CCHS) to estimate the prevalence of smoking during pregnancy and examine the demographic, socioeconomic, health-related and behavioral determinants of this behavior. METHODS AND FINDINGS: The data were obtained from the 2009-2010 CCHS master data file. Weighted estimates of the prevalence were calculated. Multivariable logistic regression was used to determine demographic, socioeconomic, health related and behavioral characteristics associated with smoking behavior during pregnancy. Women living in the Northern Territories had a high rate of smoking during pregnancy (59.3%). The prevalence of smoking during pregnancy was also high among women under 25 years old, of low socioeconomic status, who reported not having a regular medical doctor, being fair to poor in self-perceived health, having at least one chronic disease, having at least one mental illness, being heavy smokers, and being regular alcohol drinkers. Results from multivariable logistic regression revealed that the odds of smoking during pregnancy were decreased with increasing age (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99), having a regular family doctor [OR, 0.24; 95% CI, 0.11-0.52], having highest level of family income [OR, 0.09; 95% CI, 0.03-0.29]. Mothers who reported poor or fair self-perceived health [OR, 2.13; 95% CI, 0.96-4.71] and those who had at least one mental illness [OR, 1.81; 95% CI, 1.00-3.28] had greater odds of smoking during pregnancy. CONCLUSIONS: There are a number of demographic, socio-economic, health-related and behavioral characteristics that should be considered in developing and implementing effective population health promotional strategies to prevent smoking during pregnancy, promoting health and well-being of pregnant women and their newborns.

White-nose syndrome (WNS) has claimed the lives of millions of hibernating insectivorous bats in North America. Its etiologic agent, the psychrophilic fungus Geomyces destructans, causes skin lesions that are the hallmark of the disease. The fungal infection is characterized by a white powdery growth on muzzle, ears and wing membranes. While WNS may threaten some species of North American bats with regional extinction, infection in hibernating bats in Europe seems not to be associated with significant mortality. We performed histopathological investigations on biopsy samples of 11 hibernating European bats, originating from 4 different countries, colonized by G. destructans. One additional bat was euthanized to allow thorough examination of multiple strips of its wing membranes. Molecular analyses of touch imprints, swabs and skin samples confirmed that fungal structures were G. destructans. Additionally, archived field notes on hibernacula monitoring data in the Harz Mountains, Germany, over an 11-year period (2000-2011) revealed multiple capture-recapture events of 8 banded bats repeatedly displaying characteristic fungal colonization. Skin lesions of G. destructans-affected hibernating European bats are intriguingly similar to the epidermal lesions described in North American bats. Nevertheless, deep invasion of fungal hyphae into the dermal connective tissue with resulting ulceration like in North American bats was not observed in the biopsy samples of European bats; all lesions found were restricted to the layers of the epidermis and its adnexae. Two bats had mild epidermal cupping erosions as described for North American bats. The possible mechanisms for any difference in outcomes of G. destructans infection in European and North American bats still need to be elucidated.

Redox sensing is of primary importance for fungi to cope with oxidant compounds found in their environment. Plant pathogens are particularly subject to the oxidative burst during the primary steps of infection. In the budding yeast Saccharomyces cerevisiae, it is the transcription factor Yap1 that mediates the response to oxidative stress via activation of genes coding for detoxification enzymes. In the cereal pathogen Fusarium graminearum, Fgap1 a homologue of Yap1 was identified and its role was investigated. During infection, this pathogen produces mycotoxins belonging to the trichothecenes family that accumulate in the grains. The global regulation of toxin biosynthesis is not completely understood. However, it is now clearly established that an oxidative stress activates the production of toxins by F. graminearum. The involvement of Fgap1 in this activation was investigated. A deleted mutant and a strain expressing a truncated constitutive form of Fgap1 were constructed. None of the mutants was affected in pathogenicity. The deleted mutant showed higher level of trichothecenes production associated with overexpression of Tri genes. Moreover activation of toxin accumulation in response to oxidative stress was no longer observed. Regarding the mutant with the truncated constitutive form of Fgap1, toxin production was strongly reduced. Expression of oxidative stress response genes was not activated in the deleted mutant and expression of the gene encoding the mitochondrial superoxide dismutase MnSOD1 was up-regulated in the mutant with the truncated constitutive form of Fgap1. Our results demonstrate that Fgap1 plays a key role in the link between oxidative stress response and F. graminearum secondary metabolism.

Prion diseases are unique pathologies in which the infectious particles are prions, a protein aggregate. The prion protein has many particular features, such as spontaneous aggregation, conformation transmission to other native PrP proteins and transmission from an individual to another. Protein aggregation is now frequently associated to many human diseases, for example Alzheimer's disease, Parkinson's disease or type 2 diabetes. A few proteins associated to these conformational diseases are part of a new category of proteins, called prionoids: proteins that share some, but not all, of the characteristics associated with prions. The p53 protein, a transcription factor that plays a major role in cancer, has recently been suggested to be a possible prionoid. The protein has been shown to accumulate in multiple cancer cell types, and its aggregation has also been reproduced in vitro by many independent groups. These observations suggest a role for p53 aggregates in cancer development. This study aims to test the «prion-like» features of p53. Our results show in vitro aggregation of the full length and N-terminally truncated protein (p53C), and penetration of these aggregates into cells. According to our findings, the aggregates enter cells using macropinocytosis, a non-specific pathway of entry. Lastly, we also show that once internalized by the cell, p53C aggregates can co-aggregate with endogenous p53 protein. Together, these findings suggest prion-like characteristics for p53 protein, based on the fact that p53 can spontaneously aggregate, these aggregates can penetrate cells and co-aggregate with cellular p53.

Marine phytoplankton account for about 50% of all global net primary productivity (NPP). Active fluorometry, mainly Fast Repetition Rate fluorometry (FRRf), has been advocated as means of providing high resolution estimates of NPP. However, not measuring CO2-fixation directly, FRRf instead provides photosynthetic quantum efficiency estimates from which electron transfer rates (ETR) and ultimately CO2-fixation rates can be derived. Consequently, conversions of ETRs to CO2-fixation requires knowledge of the electron requirement for carbon fixation (Φe,C, ETR/CO2 uptake rate) and its dependence on environmental gradients. Such knowledge is critical for large scale implementation of active fluorescence to better characterise CO2-uptake. Here we examine the variability of experimentally determined Φe,C values in relation to key environmental variables with the aim of developing new working algorithms for the calculation of Φe,C from environmental variables. Coincident FRRf and (14)C-uptake and environmental data from 14 studies covering 12 marine regions were analysed via a meta-analytical, non-parametric, multivariate approach. Combining all studies, Φe,C varied between 1.15 and 54.2 mol e(-) (mol C)(-1) with a mean of 10.9 ± 6.91 mol e(-) mol C)(-1). Although variability of Φe,C was related to environmental gradients at global scales, region-specific analyses provided far improved predictive capability. However, use of regional Φ e,C algorithms requires objective means of defining regions of interest, which remains challenging. Considering individual studies and specific small-scale regions, temperature, nutrient and light availability were correlated with Φ e,C albeit to varying degrees and depending on the study/region and the composition of the extant phytoplankton community. At the level of large biogeographic regions and distinct water masses, Φ e,C was related to nutrient availability, chlorophyll, as well as temperature and/or salinity in most regions, while light availability was also important in Baltic Sea and shelf waters. The novel Φ e,C algorithms provide a major step forward for widespread fluorometry-based NPP estimates and highlight the need for further studying the natural variability of Φe,C to verify and develop algorithms with improved accuracy.

Cancer can be treated by adoptive cell transfer (ACT) of T lymphocytes. However, how to optimally raise human T cells to a differentiation state allowing the best persistence in ACT is a challenge. It is possible to differentiate mouse CD8(+) T cells towards stem cell-like memory (T(SCM)) phenotype upon TCR stimulation with Wnt/ß-catenin pathway activation. Here, we evaluated if T(SCM) can be obtained from human mature CD8(+) T cells following TCR and Wnt/ß-catenin activation through treatment with the chemical agent 4,6-disubstituted pyrrolopyrimidine (TWS119), which inhibits the glycogen synthase kinase-3β (GSK-3β), key inhibitor of the Wnt pathway. Human CD8(+) T cells isolated from peripheral blood or tumor-infiltrating lymphocytes (TIL), and treated with TWS119 gave rise to CD62L(+)CD45RA(+) cells, indicative of early differentiated stage, also expressing CD127 which is normally found on memory cells, and CD133, an hematopoietic stem cell marker. T(SCM) cells raised from either TIL or blood secreted numerous inflammatory mediators, but in lower amounts than those measured without TWS119. Finally, generated T(SCM) CD8(+) T cells expressed elevated Bcl-2 and no detectable caspase-3 activity, suggesting increased persistence. Our data support a role for Wnt/ß-catenin pathway in promoting the T(SCM) subset in human CD8(+) T cells from TIL and the periphery, which are relevant for ACT.

BackgroundThe dramatic mass mortalities amongst hibernating bats in Northeastern America caused by "white nose-syndrome" (WNS) continue to threaten populations of different bat species. The cold-loving fungus, Geomyces destructans, is the most likely causative agent leading to extensive destruction of the skin, particularly the wing membranes. Recent investigations in Europe confirmed the presence of the fungus G. destructans without associated mass mortality in hibernating bats in six countries but its distribution remains poorly known.Methodology/principal findingsWe collected data on the presence of bats with white fungal growth in 12 countries in Europe between 2003 and 2010 and conducted morphological and genetic analysis to confirm the identity of the fungus as Geomyces destructans. Our results demonstrate the presence of the fungus in eight countries spanning over 2000 km from West to East and provide compelling photographic evidence for its presence in another four countries including Romania, and Turkey. Furthermore, matching prevalence data of a hibernaculum monitored over two consecutive years with data from across Europe show that the temporal occurrence of the fungus, which first becomes visible around February, peaks in March but can still be seen in some torpid bats in May or June, is strikingly similar throughout Europe. Finally, we isolated and cultured G. destructans from a cave wall adjacent to a bat with fungal growth.Conclusions/significanceG. destructans is widely found over large areas of the European continent without associated mass mortalities in bats, suggesting that the fungus is native to Europe. The characterisation of the temporal variation in G. destructans growth on bats provides reference data for studying the spatio-temporal dynamic of the fungus. Finally, the presence of G. destructans spores on cave walls suggests that hibernacula could act as passive vectors and/or reservoirs for G. destructans and therefore, might play an important role in the transmission process.

BACKGROUND: RT amplification reaction has revealed that various single viruses or viral co-infections caused acute bronchiolitis in infants, and RV appeared to have a growing involvement in early respiratory diseases. Because remaining controversial, the objective was to determine prospectively the respective role of RSV, RV, hMPV and co-infections on the severity of acute bronchiolitis in very young infants. METHODS AND PRINCIPAL FINDINGS: 209 infants (median age: 2.4 months) were enrolled in a prospective study of infants

BACKGROUND: It is thought that mast seeding is a rare reproductive strategy in the tropics, since tropical climates are less variable, and fruit consumers tend to be more generalist in these regions. However, previous tests of this hypothesis were based on only few tropical datasets, and none from tropical South America. Moreover, reproductive strategies have been quantified based on the coefficient of variation of interannual seed production, an index that potentially confounds masting and high interannual variability in seed production. METHODOLOGY/PRINCIPAL FINDINGS: We developed a new approach to model the monthly variability in seed production for 28 tree species, and 20 liana species monitored during 5 years in a tropical forest of Central French Guiana. We found that 23% of the species showed a masting pattern, 54% an annual fruiting pattern, and 23% an irregular fruiting pattern. The majority of masting species were trees (8 out of 11), most of them animal-dispersed. The classification into reproductive strategies based on the coefficient of variation was inconsistent with our results in nearly half of the cases. CONCLUSIONS/SIGNIFICANCE: Our study is the first to clearly evidence the frequency of the masting strategy in a tropical forest community of Eastern South America. The commonness of the masting strategy in tropical plants may promote species coexistence through storage dynamics.

Purpose: Concerns gradually arose about misuse of gabapentinoids (gabapentin and pregabalin), especially when used in combination with opioids. Because it can be a driver of usage, trends in prescribing habits may be interesting to analyse. The aim of this study is to examine the evolution of prescriptions of opioids and gabapentinoids in England from 2015 to 2020 at a regional level., Methods: This study included data from April 2015 to February 2020, focusing on prescribing data, extracted the OpenPrescribing database. We described the evolution of the prescriptions of opioids and gabapentinoids and calculated their ratios for each month. We used Analyses of Variance (ANOVAs) to compare data between and within regions (over time)., Results: During this period, opioid prescriptions remained stable (from -3.3% to +2.2%/year) and increased for gabapentinoids generally (from +1.5% to +2.2%). The ratio between gabapentinoid to opioid prescriptions increased by more than 20% in 2020 compared to 2015, variably between regions (F(6,406) = [120.2]; P<0.001; LSD Test: P<0.001; ANOVA for repeated measures: P<0.05). In 2019, a decline in the ratio occurred in all regions, but only persisting in the London commissioning region in 2020 (-14.4% in comparison with 2018, 95%CI: -12.8 to -16.3)., Conclusions: Gabapentinoids are increasingly prescribed in England. The ratio of gabapentinoid to opioid prescriptions in England increased from 2015 to 2020. The reclassification of gabapentinoids as controlled drugs, in 2019, may have been associated with a significant reduction, although larger prescribers may have been less influenced., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Xia, Forget. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Ketorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival., Methods: The KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival., Findings: Between February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years. At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65-2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34-3.51)., Conclusions: A single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed., Trial Registration: ClinicalTrials.gov NCT01806259., Competing Interests: The authors have declared that no competing interests exist.