Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The ...establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments.
Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated.
The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred− (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred−: 91.3 months 95% confidence interval (CI): 61.2-not reached versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value.
The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
•An RNA signature of gemcitabine-sensitivity is developed from in vitro and in vivo models of pancreatic cancer.•The resulting GemPred signature identifies a subgroup of patients who are sensitive to adjuvant gemcitabine.•The predictive value of GemPred is validated in two cohorts on both OS and disease-free survival.
Summary
The incidence of vertebral fractures (VF) by vertebral fracture assessment (VFA) was 6.6% in postmenopausal women (FRODOS cohort) after 4 years of follow-up, increasing with prevalent VF and ...minor vertebral deformities, age, lower bone mass, glucocorticoid use, and rheumatoid arthritis. This study supports the usefulness of VFA to identify VF.
Purpose
Vertebral fracture assessment (VFA) is increasingly used to identify spine fractures, but few cohort studies have used this method in prevalence and incidence assessment. We previously reported the prevalence of vertebral fractures (VF) and minor vertebral deformities (MVD) by morphometric VFA in a population-based cohort of postmenopausal women (FRODOS study). Therefore, the aim of this study was to analyze the incidence of VF, the associated risk factors, and particularly the role of MVD in this cohort of subjects.
Methods
We performed a longitudinal analysis of 2510 women aged 59–70 years participating in the FRODOS prevalence study (2006–2009) with evaluable VFA 4 years later. VFA at baseline and in the present study was assessed by quantitative vertebral morphometry and by visual semiquantitative measurement. The multivariate Poisson regression model was performed, and relative risks with confidence interval of 95% were calculated for the incidence of VF. Bone mineral density (BMD) and an osteoporosis questionnaire were collected.
Results
Overall, the incidence of VF was 6.6%, increasing with prevalent VF (24.5%) and in women with prevalent MVD (17.7%). Age and low BMD were also associated risk factors as were the presence of rheumatoid arthritis and exposure to glucocorticoids and bisphosphonates.
Conclusions
The presence of prevalent VF assessed by VFA is associated with further incident spinal fractures in postmenopausal women. In addition, having MVD confers an increased risk of new VF.
The windings concentrated around the teeth offer obvious advantages for the electrical machines with radial air-gap, because the volume of copper used in the end-windings can be reduced. The Joule ...losses are decreased, and the efficiency is improved. These machines are still limited to applications of sub-fractional power and they generally present a reduced number of phases. In the three-phase machines, the concentrated winding is too often restricted to a winding with a short pitch of 120 electrical degrees, i.e., to a winding with performances reduced compared to the traditional structures. But there is a significant number of three-phase structures which can support a concentrated winding if the number of poles is increased. In this article, the authors present a synthesis of the structures of three-phase machines with concentrated windings. (1) In the first part, the structures with a regular distribution of the slots are presented. A systematic method is proposed to determine the windings and the performances are discussed. (2) In the second part, the authors present original structures of three-phase machines with concentrated windings which use an irregular distribution of the slots. A specific method to identify these structures is described, and a comparative analysis of the performances of the original and traditional structures is performed by using a field calculation software.
Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O6-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter ...methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0–300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27–84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15–0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29–1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50–100) seems to be associated with prolonged stable disease.
•Pancreatic neuroendocrine carcinomas are larger and more necrotic than G3-neuroendocrine tumors.•Neuroendocrine carcinomas show lower attenuation than G3- neuroendocrinetumors.•On MRI, ...neuroendocrine carcinomas may contain hemorrhagic content and havelower ADC values than G3- neuroendocrine tumors.•With CT histogram analysis, neuroendocrine carcinomas are more heterogeneous than G3- neuroendocrine tumors.
To compare morphological imaging features and CT texture histogram parameters between grade 3 pancreatic neuroendocrine tumors (G3-NET) and neuroendocrine carcinomas (NEC).
Patients with pathologically proven G3-NET and NEC, according to the 2017 World Health Organization classification who had CT and MRI examinations between 2006-2017 were retrospectively included. CT and MRI examinations were reviewed by two radiologists in consensus and analyzed with respect to tumor size, enhancement patterns, hemorrhagic content, liver metastases and lymphadenopathies. Texture histogram analysis of tumors was performed on arterial and portal phase CT images. images. Morphological imaging features and CT texture histogram parameters of G3-NETs and NECs were compared.
Thirty-seven patients (21 men, 16 women; mean age, 56±13 SD years range: 28-82 years) with 37 tumors (mean diameter, 60±46 SD mm) were included (CT available for all, MRI for 16/37, 43%). Twenty-three patients (23/37; 62%) had NEC and 14 patients (14/37; 38%) had G3-NET. NECs were larger than G3-NETs (mean, 70±51 SD mm range: 18 - 196mm vs. 42±24 SD mm range: 8 - 94mm, respectively; P=0.039), with more tumor necrosis (75% vs. 33%, respectively; P=0.030) and lower attenuation on precontrast (30±4 SD HU range: 25-39 HU vs. 37±6 SD range: 25-45 HU, respectively; P=0.002) and on portal venous phase CT images (75±18 SD HU range: 43 - 108 HU vs. 92±19 SD HU range: 46 - 117 HU, respectively; P=0.014). Hemorrhagic content on MRI was only observed in NEC (P=0.007). The mean ADC value was lower in NEC (1.1±0.1 (SD)×10−3 mm2/s range: (0.91 - 1.3)×10−3 mm2/s vs. 1.4±0.2 (SD)×10−3 mm2/s range: (1.1 - 1.6)×10−3 mm2/s; P=0.005). CT histogram analysis showed that NEC were more heterogeneous on portal venous phase images (Entropy-0: 4.7±0.2 SD range: 4.2-5.1 vs. 4.5±0.4 SD range: 3.7-4.9; P=0.023).
Pancreatic NECs are larger, more frequently hypoattenuating and more heterogeneous with hemorrhagic content than G3-NET on CT and MRI.
After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures that integrate predictors from preclinical models and machine learning offer a rationalized treatment strategy.
Agricultural landscapes are often constituted by a patchwork of crop fields whose seasonal evolution is dependent on specific crop rotation patterns and phenologies. This temporal and spatial ...heterogeneity affects surface hydrometeorological processes and must be taken into account in simulations of land surface and distributed hydrological models. The Sentinel-2 mission allows for the monitoring of land cover and vegetation dynamics at unprecedented spatial resolutions and revisit frequencies (20 m and 5 days, respectively) that are fully compatible with such heterogeneous agricultural landscapes. Here, we evaluate the impact of Sentinel-2-like remote sensing data on the simulation of surface water and energy fluxes via the Interactions between the Surface Biosphere Atmosphere (ISBA) land surface model included in the EXternalized SURface (SURFEX) modeling platform. The study focuses on the effect of the leaf area index (LAI) spatial and temporal variability on these fluxes. We compare the use of the LAI climatology from ECOCLIMAP-II, used by default in SURFEX-ISBA, and time series of LAI derived from the high-resolution Formosat-2 satellite data (8 m). The study area is an agricultural zone in southwestern France covering 576 km2 (24 km × 24 km). An innovative plot-scale approach is used, in which each computational unit has a homogeneous vegetation type. Evaluation of the simulations quality is done by comparing model outputs with in situ eddy covariance measurements of latent heat flux (LE). Our results show that the use of LAI derived from high-resolution remote sensing significantly improves simulated evapotranspiration with respect to ECOCLIMAP-II, especially when the surface is covered with summer crops. The comparison with in situ measurements shows an improvement of roughly 0.3 in the correlation coefficient and a decrease of around 30 % of the root mean square error (RMSE) in the simulated evapotranspiration. This finding is attributable to a better description of LAI evolution processes with Formosat-2 data, which further modify soil water content and drainage of soil reservoirs. Effects on annual drainage patterns remain small but significant, i.e., an increase roughly equivalent to 4 % of annual precipitation levels with simulations using Formosat-2 data in comparison to the reference simulation values. This study illustrates the potential for the Sentinel-2 mission to better represent effects of crop management on water budgeting for large, anthropized river basins.
•Most patient with pancreatic cancer are treated by chemotherapy.•Treatments selection are not personalized on the tumor characteristics.•Signatures predicting chemotherapy efficiency are essential ...for personalizing treatments.•An RNA signature of gemcitabine-sensitivity is developed leveraged on the dissimilarities between 2D and 3D in vitro models.•Combining different in vitro models can help in defining clinically efficient transcriptomic signatures.
Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.
Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in ...patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy.
We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS).
Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10–3 and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS.
iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.
•ChallengES tumor mutation burden (TMB) and MSIsensor for predicting response to immunotherapy in MSI mCRC.•Demonstration that MSI misdiagnoses lead to a false ability of TMB and MSIsensor to predict ICI resistance in MSI mCRC.•Identification and validation of DNA and RNA signatures predictive of response to ICI in these patients with mCRC MSI.•Evidence for a fibrosis signature associated with functional ICI resistance in MSI mCRC.
Different regulations require the monitoring of radioactivity in the environment (e.g., 2013/51/Euratom, Real Decreto 314/2016) to protect the environment and the population from abnormal ...radioactivity presence caused by natural reasons or discharges or accidents in nuclear installations. Nowadays, the monitoring of α- and β-emitting radionuclides is performed discontinuously in laboratories due to the difficulties in applying classical techniques to continuous measurements. This limits the number of samples that can be measured per day, produces high costs per analysis, and introduces a significant delay between the moment of contamination and when it is detected. Plastic scintillation microspheres (PSm) represent a new possibility for continuous measurements because water samples can flow through a bed of PSm connected to a pair of photomultipliers (PMTs), allowing continuous monitoring of the activity. This idea is the basis of the Waterrad detector, which can monitor radioactivity at environmental levels in river water. This paper describes the optimization of a detection cell containing PSm, a detection chamber as well as active and passive shielding. In its final set-up, the Waterrad detector presents a background signal of 0.23 (1) cps and detection efficiencies of 1.86(7)·10−5 cps·L·Bq−1 for 3H, 7.4(8)·10−3 cps·L·Bq−1 for 90Sr/90Y and 5.5(5)·10−3 cps·L·Bq−1 for 241Am. The detection limits in the optimum window for a counting time of 5 h were 490 Bq/L for 3H, 2.3 Bq/L for 90Sr/90Y and 3.0 Bq/L for 241Am. These values indicate that Waterrad can be used as an alarm detector for monitoring radioactivity in water at activity levels similar to those of environmental samples, making it suitable for water or waste surveillance involving a high frequency of measurements.
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•The development of a detector for the continuous monitoring of alpha and beta emitters in water samples is described.•The detector is capable to detect 3H, 241Am and 90Sr/90Y with detection efficiencies of 0.6%, 61% and 159% respectively.•The Waterrad detector was able to provide detection limits in the order of magnitude of the European directive for drinking water for 3H (490 Bq/L) and gross beta (2.3 Bq/L) for 5h counting.•Waterrad detector is capable to perform automated analysis (including sample measurement, calibration and cell cleaning).•The detector is specially designed to provide a fast alarm response since the minimum time of analysis is of 5 min.
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