Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Prevalent vertebral fractures and minor vertebral deformities analyzed by vertebral fracture assessment (VFA) increases the risk of incident fractures in postmenopausal women: the FRODOS study.

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.

Correction to: Prevalent vertebral fractures and minor vertebral deformities analyzed by vertebral fracture assessment (VFA) increases the risk of incident fractures in postmenopausal women: the FRODOS study.

Figure 1 as published in the original version of this article was unfortunately incomplete.

[Simulation training for urinary drainage improves skill retention]. / Simulation et rétention des acquisitions : application au drainage vésical.

INTRODUCTION: Urethral and suprapubic catheterizations are the two methods for urinary drainage. Systematic simulation training could improve the performance and reduce iatrogenic complications. The aim of the study was to evaluate the skills retention using simulation training. MATERIALS AND METHODS: It was an experimental study of the effect of urinary drainage simulation based skills on medical students in order to compare active and passive training methods. On the first session, randomization was proceeded. Then, the participant performed one of the two workshops (urethral or suprapubic catheterization) on a male mannequin. The maximal performance was 40 points on the assessment form. Both workshops were performed on the second (one month) and third sessions (six months). RESULTS: Eighteen participants were included. Main performance was 28.7/40 (23-34.2) at the first session. All the participants improved the performance on the second session with a significant difference (P<0.01) between passive 32.5 (26-36.5) and active participants 36.1/40 (34.5-39). On the third session, a similar difference was observed between passive and active participants (32.5 versus 30.4, P non significant). CONCLUSION: Simulation training seems to improve long-term skill retention of urinary drainage for inexperienced medical students. This preliminary study suggests to incorporate urinary drainage simulation training into all medical school curricula. LEVEL OF EVIDENCE: 4.

Chemometrics quality assessment of wastewater treatment plant effluents using physicochemical parameters and UV absorption measurements.

Chemometric techniques like Principal Component Analysis (PCA) and Partial Least Squares Regression (PLS) are used to explore, analyze and model relationships among different water quality parameters in wastewater treatment plants (WWTP). Different data sets generated by laboratory analysis and by an automatic multi-parametric monitoring system with a new designed optical device have been investigated for temporal variations on water quality parameters measured in the water influent and effluent of a WWTP over different time scales. The obtained results allowed the discovery of the more important relationships among the monitored parameters and of their cyclic dependence on time (daily, monthly and annual cycles) and on different plant management procedures. This study intended also the modeling and prediction of concentrations of several water components and parameters, especially relevant for water quality assessment, such as Dissolved Organic Matter (DOM), Total Organic Carbon (TOC) nitrate, detergent, and phenol concentrations. PLS models were built to correlate target concentrations of these constituents with UV spectra measured in samples collected at (1) laboratory conditions (in synthetic water mixtures); and at (2) WWTP conditions (in real water samples from the plant). Using synthetic water mixtures, specific wavelengths were selected with the aim to establish simple and reliable prediction models, which gave good relative predictions with errors of around 3-4% for nitrates, detergent and phenols concentrations and of around 15% for the DOM in external validation. In the case of nitrate and TOC concentrations modeling in real water samples from the effluent of the WWTP using the reduced spectral data set, results were also promising with low prediction errors (less than 20%).

Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours.

BACKGROUND: Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified. DESIGN: Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology. RESULTS: Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations. CONCLUSION: Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.

Trop-2 is a ubiquitous and promising target in pancreatic adenocarcinoma.

BACKGROUND: Trop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients' outcomes in a large cohort of PDAC. METHODS: We included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. RESULTS: 495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. CONCLUSIONS: Our results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.

Development of an equipment for real-time continuous monitoring of alpha and beta radioactivity in river water.

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 ß-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.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

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.

Morphological imaging and CT histogram analysis to differentiate pancreatic neuroendocrine tumor grade 3 from neuroendocrine carcinoma.

PURPOSE: To compare morphological imaging features and CT texture histogram parameters between grade 3 pancreatic neuroendocrine tumors (G3-NET) and neuroendocrine carcinomas (NEC). MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: Pancreatic NECs are larger, more frequently hypoattenuating and more heterogeneous with hemorrhagic content than G3-NET on CT and MRI.

Disability measured by the modified health assessment questionnaire in early rheumatoid arthritis: prognostic factors after two years of follow-up.

OBJECTIVE: To analyze the rate and baseline prognostic factors of disability measured by the modified HAQ (MHAQ), in a series of patients with early rheumatoid arthritis (RA) after two years of therapy with a structured algorithm using disease-modifying anti-rheumatic drugs (DMARDs). METHODS: One hundred and five patients (81% female) with early RA (disease duration <2 years) treated with the same therapeutic protocol using gold salts and methotrexate in a step-up strategy, together with methylprednisolone (4 mg/day), were followed up for two years. The outcome was the absence of disability (MHAQ=0) after two years of DMARD therapy. Clinical, biological, immunogenetic and radiographic data (Larsen score) were analyzed at study entry and at 12 and 24 months of follow-up. RESULTS: The MHAQ decreased significantly at 6 months after initiation of DMARD therapy and the reduction was maintained at 24 months (mean+/-SD: 0.97+/-0.56 at baseline, 0.51+/- 0.57 at month 6 and 0.45+/-0.5 at month 24). No disability (MHAQ=0) was observed in 26.6% of patients after two years of follow-up. Age, MHAQ>0.5, DAS28>5.1, VAS pain, positive rheumatoid factor and ESR at baseline were associated with disability in the univariate analysis. In the logistic regression analysis, only age (OR: 1.058, 95%CI 1.017; 1.101 p<0.006), rheumatoid factor status (OR: 3.772 95%CI 1.204; 11.813, p<0.02) and MHAQ>0.5 (OR:4.023, 95%CI 1.373; 11.783, p<0.02) were associated with disability (MHAQ>0) at two years. CONCLUSION: In a series of early RA patients treated with a structured algorithm using DMARDs and very low doses of glucocorticoids, no disability was observed in a quarter of patients after two years. Age, rheumatoid factor positivity and MHAQ>0.5 were independent predictors of disability at two years.

A false postoperative recurrence of intraductal and papillary mucinous neoplasm of the pancreas.

Stenosis of pancreatico-digestive anastomoses following pancreaticoduodenectomy is frequently observed. In a patient operated on for intraductal papillary and mucinous neoplasm, it can induce a massive dilatation of the main pancreatic duct leading to the misdiagnosis of tumor recurrence with main duct involvement.

Preoperative imaging and pathologic classification for pancreatic neuroendocrine tumors.

The management of patients with pancreatic neuroendocrine tumor (PNET), whether hormonally secretory or not, is multidisciplinary and often multimodal. Surgical treatment plays a central role because complete resection is the only potentially curative treatment. The choice of the therapeutic plan for a PNET requires precise localization of the primary tumor (which may sometimes be multiple in case of genetic predisposition), confirmation of the diagnosis of PNET, a search for metastases (mainly hepatic), and identification of the main histoprognostic factors. This update focuses on the WHO 2017 histological classification and recent innovations in the preoperative assessment of PNET using conventional and isotopic imaging. The aim is to not only allow the mapping of primary and metastatic lesions but also to predict tumor aggressiveness.

Sporadic pancreatic neuroendocrine tumor: Surgery of the primary tumor.

The management of patients with sporadic pancreatic neuroendocrine tumors (PNET) is multi-disciplinary and often, multimodal. Surgery has a large part in treatment because it is the only potentially curative therapeutic modality if resection can be complete. The update reviews the operative indications and the different surgical techniques available (including parenchymal-sparing surgery) to treat the primary lesion according to patient status, preoperative work-up and whether the tumor is functioning or not. The place of observation for "small" non-functional sporadic PNET is also discussed.

Prognostic markers of clinical remission in early rheumatoid arthritis after two years of DMARDs in a clinical setting.

OBJECTIVE: To analyze the rate and baseline prognostic factors of clinical remission in a series of patients with early rheumatoid arthritis (RA) after 2 years of therapy based on a structured algorithm using disease-modifying anti-rheumatic drugs (DMARDs) in a clinical setting. To determine whether a good therapeutic response at 6 months of therapy is associated with remission at 2 years. METHODS: One hundred and five patients (81% female) with early RA (disease duration < 2 years) treated with the same therapeutic protocol using gold salts and methotrexate in a step-up strategy, together with methylprednisolone (4 mg/day), were followed up for 2 years. The outcome variable was clinical remission after 2 years of DMARD therapy using the 28-joint disease activity score (DAS28 < 2.6). Clinical, biological, immunogenetic and radiographic data (Larsen score) were analyzed at study entry and after 6, 12, 18 and 24 months of follow-up. Therapeutic response was analyzed using the ACR and EULAR criteria. RESULTS: Remission was observed in 34 patients (32.4%) after 2 years of follow-up. A baseline DAS28 score < 5.1 (p = 0.004), hemoglobin (p = 0.04) and male gender (p = 0.02) were associated with remission in the univariate analysis. In the multivariate logistic regression analysis, only a DAS28 < 5.1 was associated with remission at 2 years (OR 4.1, 95% CI: 1.56;10.77, p = 0.004). The percentage of ACR50 responses after 6 months was significantly higher in patients with remission at 2 years than in those without (66.7% vs 43.3%; p = 0.04). Similar results were obtained when analyzing the good EULAR response (50% vs 20.9%; p = 0.003). Furthermore, when the therapeutic response at 6 months was included in the logistic regression model, only an ACR50 response (OR 3.9, 95% CI 1.14;13.38, p = 0.03) and a good EULAR response (OR 6.23, 95% CI 1.61; 24.04, p = 0.008), but not an ACR20 response or a whole EULAR response were significantly associated with remission. CONCLUSION: In a series of early RA patients treated using a structured algorithm with DMARDs and very low doses of glucocorticoids, clinical remission was observed in one-third of patients after 2 years. Low or moderate disease activity (DAS28 < 5.1) at baseline and a good therapeutic response during the first months of therapy predicts clinical remission at 2 years.

Robustness of plastic scintillation microspheres in the continuous measurement of different river waters.

Plastic scintillation microspheres (PSm) represent one of the most promising options for monitoring alpha and beta radioactivity in river water. For that reason, a study of the stability of PSm packed into a cell against the continuous flow of river water with different degrees of turbidity was performed over a period of 100h. The results showed that the volume of the cell became stable after 15h of pumping and continued to be stable throughout the 100h of the experiment. During this period of time, the detection efficiency of the PSm, in terms of efficiency*volume, presented mean values of 0.75(3)% for (3)H and 272(11)% for (90)Sr/(90)Y. No dependence on flow time or river water type was observed. The background was also constant for 100h and for the different water types, although (222)Rn should be removed from the water beforehand to prevent its accumulation in the PSm. Since PSm did not present any degradation throughout the whole experiment, PSm can undoubtedly be used for monitoring radioactivity with low reagent consumption, low waste generation and low maintenance costs.

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-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.

Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized, controlled trial.

BACKGROUND: The mechanism of action of acetaminophen remains unclear. One hypothesis involves an interaction with the serotoninergic system. Antagonists to serotonin (5-HT)3 receptors (setrons) have antiemetic properties. Therefore, co-administration of acetaminophen and a setron could lead to a decrease or a loss of acetaminophen analgesic effects. The aim of this study was to demonstrate such an interaction. METHODS: Paratron is a prospective, randomized, controlled, double-blind, parallel group trial. All children aged 2-7 years (n = 69) scheduled for a tonsillectomy ± adenoidectomy received intraoperative acetaminophen with ondansetron or droperidol. Pain scores [Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)], morphine consumption and the incidence of post-operative nausea and vomiting (PONV) were measured for 24 h following surgery. RESULTS: Pain scores were not different at all times between the groups but median morphine consumption (µg) in recovery was 322.5 [interquartile range (IQR) 0.0-500.0] and 0 (IQR 0-0) in the ondansetron (n = 35) and droperidol (n = 34) groups, respectively (p = 0.004). The percentages of patients who received morphine titration were 57.1% and 20.6% in the ondansetron and droperidol groups, respectively (p = 0.008). No significant difference was found for PONV. CONCLUSIONS: An interaction between acetaminophen and ondansetron is suggested, with children receiving three times more morphine during pain titration in the recovery room. More studies are necessary to evaluate whether this finding is clinically relevant enough to preclude the simultaneous perioperative administration of both drugs in the future.