The clinicopathological features and Epstein-Barr virus (EBV) infection status of lymphoma in children and adolescents in South China is under-researched. South China is a well-known high-incidence area of EBV...
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Δευτέρα 26 Φεβρουαρίου 2018
Clinicopathological features and EBV infection status of lymphoma in children and adolescents in South China: a retrospective study of 662 cases
Low baseline and subsequent higher aortic abdominal aneurysm FDG uptake are associated with poor sac shrinkage post endovascular repair
Abstract
Purpose
The growth phases of medically treated abdominal aortic aneurysms (AAA) are frequently associated with an 18F–fluorodesoxyglucose positron emission tomography (FDG-PET) pattern involving low baseline and subsequent higher FDG uptake. However, the FDG-PET patterns associated with the endovascular aneurysm repair (EVAR) of larger AAA are presently unknown. This study aimed to investigate the relationship between serial AAA FDG uptake measurements, obtained before EVAR and 1 and 6 months post-intervention and subsequent sac shrinkage at 6 months, a well-recognized indicator of successful repair.
Methods
Thirty-three AAA patients referred for EVAR (maximal diameter: 55.4 ± 6.0 mm, total volume: 205.7 ± 63.0 mL) underwent FDG-PET/computed tomography (CT) before EVAR and at 1 and 6 months thereafter, with the monitoring of AAA volume and of a maximal standardized FDG uptake [SUVmax] averaged between the axial slices encompassing the AAA.
Results
Sac shrinkage was highly variable and could be stratified into three terciles: a first tercile in which shrinkage was absent or very limited (0–29 mL) and a third tercile with pronounced shrinkage (56–165 mL). SUVmax values were relatively low at baseline in the 1st tercile (SUVmax: 1.69 ± 0.33), but markedly increased at 6 months (2.42 ± 0.69, p = 0.02 vs. baseline). These SUV max values were by contrast much higher at baseline in the 3rd tercile (SUVmax: 2.53 ± 0.83 p = 0.009 vs. 1st tercile) and stable at 6 months (2.49 ± 0.80), while intermediate results were documented in the 2nd tercile. Lastly, the amount of sac shrinkage, expressed in absolute values or in percentages of baseline AAA volumes, was positively correlated with baseline SUVmax (p = 0.001 for both).
Conclusion
A low pre-EVAR FDG uptake and increased AAA FDG uptake at 6 months are associated with reduced sac shrinkage. This sequential FDG-PET pattern is similar to that already shown to accompany growth phases of medically treated AAA.
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[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques
Abstract
Purpose
The expression of chemokine receptor type 4 (CXCR4) was found co-localized with macrophages on the atherosclerotic vessel wall and participated in the initial emigration of leukocytes. Gallium-68 [68Ga]Pentixafor has recently been introduced for the imaging of atherosclerosis by targeting CXCR4. We sought to evaluate human atherosclerotic lesions using [68Ga]Pentixafor PET/MRI.
Methods
Thirty-eight oncology patients underwent [68Ga]Pentixafor PET/MR imaging at baseline. Maximum standardized uptake values (SUVmax) were derived from hot lesions in seven arterial segments and target-to-blood ratios (TBR) were calculated. ANOVA post-hoc and paired t test were performed for statistical comparison, Spearman's correlation coefficient between uptake ratios and cardiovascular risk factors were assessed. The reproducibility of [68Ga]Pentixafor PET/MRI was assessed in seven patients with a follow-up exanimation by Pearson's regression and Bland–Altman plots analysis.
Results
Thirty-four of 38 patients showed 611 focal [68Ga]Pentixafor uptake that followed the contours of the large arteries. Both prevalence and mean TBRmax were highest in the descending aorta. There were significantly higher TBR values found in men (1.9 ± 0.3) as compared to women (1.7 ± 0.2; p < 0.05). Patients with mean TBRmax > 1.7 showed a significantly higher incidence of diabetes, hypertension hypercholesterolemia and history of cardiovascular disease than patients with mean TBRmax ≤ 1.7. [68Ga]Pentixafor uptake showed a good reproducibility (r = 0.6, p < 0.01), and there was no difference between the mean TBRmax values of plaque lesions (TBRbaseline1.8 ± 0.3 vs TBRfollow-up1.8 ± 0.3) (p = 0.9).
Conclusion
Patients with high arterial uptake showed increased incidence of cardiovascular risk factors, suggesting a potential role of [68Ga]Pentixafor in characterization of atherosclerosis.
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Correction to: Diagnostic and prognostic value of baseline FDG PET/CT skeletal textural features in diffuse large B cell lymphoma
Abstract
The formulae for Dice and Jaccard indices used to assess volumes concordance should read as follows:
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11 C–MET PET/MRI for detection of recurrent glioma
Abstract
Introduction
Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid 11C–MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma.
Methods
Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid 11C–MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid 11C–MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis.
Results
Hybrid 11C–MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for 11C–MET PET (96.77% and 73.68%), and for hybrid 11C–MET-PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid 11C–MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C–MET PET (88%). Furthermore, by rating on a five-point Likert scale significantly higher scores were found for diagnostic confidence when comparing 11C–MET PET/MRI (4.26 ± 0,777) to either PET alone (3.44 ± 0.705) or MRI alone (3.56 ± 0.733).
Conclusion
This feasibility study showed that hybrid PET/MRI might strengthen RANO classification by adding metabolic information to conventional MRI information. Future studies should evaluate the clinical utility of the combined use of 11C–MET PET/MRI in larger patient cohorts.
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Prediction of functional recovery after primary PCI using the estimate of myocardial salvage in gated SPECT early after acute myocardial infarction
Abstract
Purpose
Primary percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) aims to achieve myocardial salvage (MS). Because the reference method for measuring MS requires myocardial perfusion imaging (MPI) after tracer injection before PCI, alternative approaches have been proposed, but none has gained wide acceptance. Gated SPECT MPI can assess infarct size (IS), but can also show myocardial stunning. Thus, we compared functional and perfusion abnormalities early after AMI to estimate MS, and to predict left ventricular ejection fraction (LVEF) recovery at follow-up.
Methods
We studied 120 patients with AMI. Gated SPECT MPI was performed early (before hospital discharge) and at 6 months after AMI to measure IS, MS and functional outcome. MS was defined as the difference between the number of segments with abnormal thickening (i.e. the stunned area or area at risk) and the number of segments with abnormal perfusion (i.e. the final IS), expressed as a percentage of the total number of segments in the AHA model. LVEF was calculated using quantitative gated SPECT.
Results
The area at risk was 40 ± 25%, IS was 17.3 ± 16% and MS was 22 ± 19%. Early LVEF was 46.6 ± 11.6% and late LVEF was 51.4 ± 11.6%, with 54 patients showing at least an increase in LVEF of more than 5 units. ROC analysis showed that MS was able to predict LVEF recovery with an area under the curve (AUC) of 0.79 (p < 0.0001), and using a cut off >23% detected LVEF recovery with 74% sensitivity and 71% specificity. Conversely, IS was associated with an AUC 0.53 (not significant).
Conclusion
MS assessed by a single early gated SPECT MPI study can accurately predict LVEF evolution after primary PCI for AMI.
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Correction to: Dosimetry in clinical radionuclide therapy: the devil is in the detail
Abstract
The above article which was published in Volume 44/ Issue 12 has incorrect page numbers. Instead of 1-3, it should have been 2137-2139.
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Preclinical evaluation of an 18 F-trifluoroborate methionine derivative for glioma imaging
Abstract
Purpose
11C–methionine (MET) is one of the most commonly used amino acid tracers for PET imaging of brain tumors. In this study, we report an 18F-labeled boron-derived methionine analogue, denoted as 18F-B-MET, as a potential substitute of 11C–MET for glioma PET imaging.
Methods
19F-B-MET was synthesized from readily available chemicals according to our previous publication. For kit development, 19F-B-MET was aliquoted in quantities of 10 nmol for on-demand one-step labeling. The 18F-labeling was performed by 18F-19F isotope exchange, and quality control was performed by both HPLC and radio-TLC. Uptake of the tracer was determined in GL26, C6 and U87 tumor cells. PET imaging and the biodistribution assay were performed on mice bearing subcutaneous or orthotopic C6 and U87 tumor xenografts.
Results
Starting with 740–1110 MBq 18F-fluoride, >370 MBq of 18F-B-MET was obtained in 25 min (n = 5) with >99% purity and high specific activity (>37 GBq/μmol). 18F-B-MET demonstrated excellent in vitro stability with <1% decomposition after incubation with plasma for 2 h. In vitro cell uptake assay showed that 18F-B-MET accumulated in tumor cells in a time dependent manner and could be competitively inhibited by natural methionine and other L-type transporter transported amino acids. In vivo biodistribution and imaging studies showed high tumor accumulation (2.99 ± 0.23 %ID/g, n = 6) compared with low uptake of brain (0.262 ± 0.05 %ID/g, n = 6) at 60 min after injection in a subcutaneous C6 tumor model. Orthotropic C6 and U87 tumors were clearly visualized with high tumor to brain ratios at 60 min post-injection, corroborating with tumor L-type amino acid transporter 1 (LAT-1) expression levels.
Conclusion
18F-B-MET was radiolabeled with high yield in a one-step labeling process, showed excellent pharmacokinetic properties in vivo, with high tumor-to-brain contrast.
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Comparison of 18 F–FDG PET/MRI and MRI alone for whole-body staging and potential impact on therapeutic management of women with suspected recurrent pelvic cancer: a follow-up study
Abstract
Purpose
To evaluate the diagnostic performance of 18F–FDG PET/MRI for whole-body staging and potential changes in therapeutic management of women with suspected recurrent pelvic cancer in comparison with MRI alone.
Methods
Seventy-one consecutive women (54 ± 13 years, range: 25–80 years) with suspected recurrence of cervical (32), ovarian (26), endometrial (7), vulvar (4), and vaginal (2) cancer underwent PET/MRI including a diagnostic contrast-enhanced MRI protocol. PET/MRI and MRI datasets were separately evaluated regarding lesion count, localization, categorization (benign/malignant), and diagnostic confidence (3-point scale; 1–3) by two physicians. The reference standard was based on histopathology results and follow-up imaging. Diagnostic accuracy and proportions of malignant and benign lesions rated correctly were retrospectively compared using McNemar's chi2 test. Differences in diagnostic confidence were assessed by Wilcoxon test.
Results
Fifty-five patients showed cancer recurrence. PET/MRI correctly identified more patients with cancer recurrence than MRI alone (100% vs. 83.6%, p < 0.01). In contrast to PET/MRI, MRI alone missed 4/15 patients with pelvic recurrence and miscategorized 8/40 patients with distant metastases as having local recurrence only. Based on the reference standard, 241 lesions were detected in the study cohort (181 malignant, 60 benign). While PET/MRI provided correct identification of 181/181 (100%) malignant lesions, MRI alone correctly identified 135/181 (74.6%) malignant lesions, which was significantly less compared to PET/MRI (p < 0.001). PET/MRI offered superior diagnostic accuracy (99.2% vs. 79.3%, p < 0.001) and diagnostic confidence in the categorization of malignant lesions compared with MRI alone (2.7 ± 0.5 vs. 2.4 ± 0.7, p < 0.001).
Conclusion
PET/MRI demonstrates excellent diagnostic performance and outperforms MRI alone for whole-body staging of women with suspected recurrent pelvic cancer, indicating potential changes in therapy management based on evaluation of local recurrence and distant metastatic spread.
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Up-front PET/CT changes treatment intent in patients with head and neck squamous cell carcinoma
Abstract
Purpose
In patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), we wanted to examine the differences in overall treatment decisions, i.e. curative versus palliative treatment intent, reached by a multidisciplinary team conference (MDTC) based on 18F–fluoro-deoxy-glucose-positron emission tomography/computed tomography (PET/CT) or chest X-ray + MRI of the head and neck (CXR/MRI).
Patients and methods
This was a prospective blinded cohort study based on paired data. Consecutive patients with histologically verified primary HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging was conducted as per standard practice. After at least 3 months (to eliminate recall bias in the team), the first project MDTC was conducted, based on either CXR/MRI or PET/CT, and the tumor board drew conclusions regarding treatment. After an additional 3 months, a second project MDTC was conducted using the complementary imaging modality.
Results
A total of 307 patients were included. Based on CXR/MRI, 303 patients (99%) were recommended for curative treatment and only four patients (1%) for palliative treatment. Based on PET/CT, the MDTC concluded that 278 (91%) patients were suitable for curative treatment and 29 (9%) patients for palliative treatment. The absolute difference of 8% was statistically significant (95% CI: 4.8%–11.5%, p < 0.001).
Conclusions
A PET/CT-based imaging strategy significantly changed the decisions regarding treatment intent made by a MDTC for patients diagnosed with HNSCC, when compared with the standard imaging strategy of CXR/MRI.
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Impact of initial myocardial perfusion imaging versus invasive coronary angiography on outcomes in coronary artery disease: a nationwide cohort study
Abstract
Purpose
In patients with stable coronary artery disease (CAD), two main options exist to guide management: initial invasive coronary angiography (CAG), or selective CAG after risk stratification using myocardial perfusion imaging (MPI). This study compared clinical outcomes between these two strategies in a large, real-world population.
Methods
The initial cohort comprised 1,000,000 randomly selected patients who had been entered in the National Health Insurance Research Database of Taiwan between 2000 and 2011. Patients with acute coronary syndromes, prior myocardial infarction (MI) or coronary revascularization, and prior treadmill testing or stress echocardiography were excluded. The remaining patients with suspected or known CAD were divided into those in whom initial CAG had been performed and those in whom initial MPI had been performed, and were followed until the end of 2011 for all-cause mortality, MI, and revascularization. A Cox proportional hazards model was used to estimate the risk of events after adjusting for covariates.
Results
The MPI and CAG groups each comprised 4,495 patients after frequency matching, with a similar Charlson comorbidity index (CCI). The MPI group had a significantly and dramatically lower incidence of revascularization (729 vs. 2,380, p < 0.001), MI (268 vs. 1,044, p < 0.001), and all-cause mortality (522 vs. 784, p < 0.001) than the CAG group. Multivariable analysis adjusting for age, gender, CCI, and comorbidities showed that in the MPI group fewer patients had revascularization (HR 0.24, 95% CI 0.22–0.26) and MI (HR 0.23, 95% CI 0.20–0.26), and the rate of all-cause mortality was lower (HR 0.58, 95% CI 0.52–0.64).
Conclusions
In patients with suspected stable CAD, compared with initial invasive CAG, a selective strategy guided by MPI was associated with lower rates of revascularization and MI and improved survival.
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Combined evaluation of regional coronary artery calcium and myocardial perfusion by 82 Rb PET/CT in the identification of obstructive coronary artery disease
Abstract
Purpose
Cardiac imaging with PET/CT allows measurement of coronary artery calcium (CAC), myocardial perfusion and coronary vascular function. We investigated whether the combined assessment of regional CAC score, ischemic total perfusion deficit (ITPD) and quantitative coronary vascular function would further improve the diagnostic accuracy of PET/CT in predicting obstructive coronary artery disease (CAD).
Methods
We analyzed 113 patients with suspected CAD referred to 82Rb PET/CT myocardial perfusion imaging with available coronary angiographic data. Obstructive CAD was defined as ≥75% stenosis. The receiver operating characteristic area under curve (AUC) was applied to evaluate the ability of CAC score, ITPD, hyperemic myocardial blood flow (MBF) and coronary flow reserve (CFR) to identify CAD.
Results
Vessels with obstructive CAD (71 vessels) had higher ITPD (4.6 ± 6.2 vs. 0.6 ± 1.3) and lower hyperemic MBF (1.01 ± 0.5 vs. 1.75 ± 0.6 ml/min/g) and CFR (1.56 ± 0.6 vs. 2.38 ± 0.7; all p < 0.001) than those without. In prediction of per-vessel CAD, the AUCs for the models including CAC/ITPD/hyperemic MBF (0.869) and CAC/ITPD/CFR (0.875) were higher (both p < 0.01) than for the model including CAC/ITPD (0.790). Compared with CAC/ITPD, continuous net reclassification improvement was 0.69 (95% bootstrap confidence interval, CI, 0.365–1.088) for the CAC/ITPD/hyperemic MBF model and 0.99 (95% bootstrap CI 0.64–1.26) for the CAC/ITPD/CFR model.
Conclusion
Hyperemic MBF and CFR provide incremental information about the presence of CAD over CAC score and perfusion imaging parameters. The combined use of CAC, myocardial perfusion imaging and quantitative coronary vascular function in may help predict more accurately the presence of obstructive CAD.
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F18-choline PET/CT guided surgery in primary hyperparathyroidism when ultrasound and MIBI SPECT/CT are negative or inconclusive: the APACH1 study
Abstract
Purpose
To evaluate the sensitivity of F18-choline (FCH) PET/CT for parathyroid adenoma detection prior to surgery in patients with primary hyperparathyroidism and negative or inconclusive cervical ultrasound and Tc99m-sestaMIBI SPECT/CT.
Methods
We conducted a prospective bicentric study (NCT02432599). All patients underwent FCH PET/CT. The result was scored positive, inconclusive or negative. The number of uptakes and their sites were recorded. The FCH PET/CT result guided the surgical procedure (minimally invasive parathyroidectomy, bilateral cervical exploration, or other in case of multiple or ectopic foci). FCH PET/CT results were compared to the surgical and pathological findings and the follow-up.
Results
Twenty-five patients were included. Mean calcium and PTH levels prior to surgery were 2.76 ± 0.17 mmol/l and 94.8 ± 37.4 ng/l. Nineteen (76%) FCH PET/CTs were scored positive, 3 (12%) inconclusive and 3 (12%) negative, showing 21 cases of uniglandular disease, including 1 ectopic localization and 1 case of multiglandular (3 foci) disease. Mean lesion size was 13.1 ± 8.6 mm. Twenty-four patients underwent surgery. FCH PET/CT guided surgery in 22 (88%) patients, allowing for 17 minimally invasive parathyroidectomies, 1 bilateral cervical exploration for multifocality and 4 other surgical procedures. Two patients with negative FCH-PET/CT underwent bilateral cervical exploration. When dichotomizing the FCH PET/CT results, thereby classifying the inconclusive FCH PET/CT results as positive, the per lesion and per patient sensitivities were 91.3% (95%CI: 72.0–98.9) and 90.5% (95%CI: 69.6–98.8) and the corresponding positive predictive values were 87.5% (95%CI: 67.6–97.3) and 86.4% (95%CI: 65.1–97.1), respectively.
Twenty-one (88%) patients were considered cured after surgery. Their mean calcium level after surgery was 2.36 ± 0.17 mmol/l.
Conclusions
Preoperative FCH PET/CT has a high sensitivity and positive predictive value for parathyroid adenoma detection in patients with primary hyperparathyroidism and negative or inconclusive conventional imaging results. Bilateral cervical exploration could be avoided in the majority (75%) of patients.
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Effect of CRP value on 18 F–FDG PET vascular positivity in Takayasu arteritis: a systematic review and per-patient based meta-analysis
Abstract
Purpose
The aim of this study was to quantify the association between the CRP value and 18F–FDG PET vascular positivity in Takayasu arteritis (TAK) through a structured dedicated systematic review and meta-analysis.
Methods
From January 2000 to December 2016, the PubMed/MEDLINE database was searched for articles specifically dealing with the assessment of vascular inflammation using 18F–FDG PET and CRP biomarkers in TAK. Inclusion criteria for the qualitative analysis were (1) 18F–FDG PET used to assess the disease activity, (2) The use of the ACR criteria for the diagnosis of TAK, (3) No case mixed vasculitis (i.e., no giant cell arteritis), and (4) CRP concentration and clinical disease activity available. For the meta-analysis, PET-positive and PET-negative subgroups with the corresponding CRP concentrations were generated based on per patient data. The standard mean difference, which represents the effect of the CRP concentrations on the 18F–FDG PET vascular uptake, was computed for all studies, and then the results were pooled together.
Results
Among the 33 initial citations, nine complete articles including 210 patients fulfilled the inclusion criteria. Five studies found a significant correlation between the 18F–FDG PET and CRP concentration, one provided a trend towards association and three did not find any association between the two biomarkers. Six studies found a significant association between 18F–FDG PET and clinical disease activity, one found a trend towards association and the last two studies did not evaluate this correlation. The meta-analysis (121 patients) provided the following results: Standard Mean Deviation = 0.54 [0.15;0.92]; Chi2 = 3.35; I2 = 0%; Test for overall effect: Z = 2.70 (P = 0.007).
Conclusion
The CRP concentration only moderately reflects the 18F–FDG PET vascular positivity in TAK, suggesting dissociated information. Standardized longitudinal prospective studies are necessary to assess the value of 18F–FDG PET as an independent biomarker for subtle vascular wall inflammation detection.
http://ift.tt/2sWKDA9
One-step synthesis of an 18 F-labeled boron-derived methionine analog: a substitute for 11 C-methionine?
Abstract
Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and 11C-methionine (11C-MET) is one of the most extensively investigated. However, widespread clinical use of 11C-MET is challenging due to the short half-life of 11C and low radiolabeling yield. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Yang and colleagues report an 18F-labeled boron-derived methionine analog, 18F-B-MET, as a potential substitute for 11C-MET in PET imaging of glioma. The push-button synthesis, highly efficient radiolabeling, and good imaging performance in glioma models make this tracer a promising candidate for future clinical translation.
http://ift.tt/2FbhBBX
Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer
Opinion statement
Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well-designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice.
http://ift.tt/2GMYKu5
Value-Based Care in Hematopoietic Cell Transplantation and Cellular Therapy: Challenges and Opportunities
Abstract
Purpose of Review
Improved tolerability and outcomes after hematopoietic cell transplantation (HCT), along with the availability of alternative donors, have expanded its use. With this growth, and the development of additional cellular therapies, we also aim to increase effectiveness, efficiency, and the quality of the care provided. Fundamentally, the goal of value-based care is to have better health outcomes with streamlined processes, improved patient experience, and lower costs for both the patients and the health care system. HCT and cellular therapy treatments are multiphase treatments which allow for interventions at each juncture.
Recent Findings
We present a summary of the current literature with focus on program structure and overall system capacity, coordination of therapy across providers, standardization across institutions, diversity and disparities in care, patient quality of life, and cost implications.
Summary
Each of these topics provides challenges and opportunities to improve value-based care for HCT and cellular therapy patients.
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Can doctors and patients correctly estimate cardiovascular risk? A cross-sectional study in primary care
Objective
Accurate cardiovascular risk estimations by patients and doctors are important as these affect health behaviour and medical decision making. We aimed to determine if doctors and patients were accurately estimating the absolute cardiovascular risk of patients in primary care.
MethodsA cross-sectional study was carried out in primary care clinics in Malaysia in 2014. Patients aged 35 years and above without known cardiovascular disease (CVDs) were included. Face-to-face interviews with a structured questionnaire were used to collect sociodemographic and clinical data as well as patients' perception and doctors' estimate of the patients' CVD risk. Associations were tested using 2, correlation and independent t-tests.
ResultsWe recruited 1094 patients and 57 doctors. Using the Framingham Risk Score (FRS) alone, 508 patients (46.4%) were in the high-risk group. When diabetes was included as high risk, the number increased to 776 (70.9%). Only 34.4% of patients and 55.7% of doctors correctly estimated the patient's CVD risk in comparison with the reference FRS.
Of the high-risk patients, 664 (85.6%) underestimated their CV risk. Factors associated with underestimation by patients included not having family history of CVD (adjusted OR (AOR): 2.705, 95% CI 1.538 to 4.757), smaller waist circumference (AOR: 0.979,95% CI 0.960 to 0.999) and ethnicity in comparison with the Malay as reference group (indigenous/others: AOR: 0.129, 95% CI 0.071 to 0.235). Doctors underestimated risk in 59.8% of the high-risk group. Factors associated with underestimation by doctors were patients factors such as being female (AOR: 2.232, 95% CI 1.460 to 3.410), younger age (AOR: 0.908, 95% CI 0.886 to 0.930), non-hypertensive (AOR: 1.731, 95% CI 1.067 to 2.808), non-diabetic (AOR: 1.931, 95% CI 1.114 to 3.348), higher high-density lipoprotein levels (AOR: 3.546, 95% CI 2.025 to 6.209), lower systolic blood pressure (AOR: 0.970, 95% CI 0.957 to 0.982), non-smoker (AOR: 2.246, 95% CI 1.354 to 3.726) and ethnicity in comparison with the Malay as reference group (Indian: AOR: 0.430, 95% CI 0.257 to 0.720; indigenous/others: AOR: 2.498, 95% CI 1.346 to 4.636).
ConclusionsThe majority of consultations occurring between doctors and patients are being informed by inaccurate cardiovascular risk estimation.
http://ift.tt/2BTuFtx
Predictive risk modelling under different data access scenarios: who is identified as high risk and for how long?
Objective
This observational study critically explored the performance of different predictive risk models simulating three data access scenarios, comparing: (1) sociodemographic and clinical profiles; (2) consistency in high-risk designation across models; and (3) persistence of high-risk status over time.
MethodsCross-sectional health survey data (2006–2009) for more than 260 000 Australian adults 45+ years were linked to longitudinal individual hospital, primary care, pharmacy and mortality data. Three risk models predicting acute emergency hospitalisations were explored, simulating conditions where data are accessed through primary care practice management systems, or through hospital-based electronic records, or through a hypothetical 'full' model using a wider array of linked data. High-risk patients were identified using different risk score thresholds. Models were reapplied monthly for 24 months to assess persistence in high-risk categorisation.
ResultsThe three models displayed similar statistical performance. Three-quarters of patients in the high-risk quintile from the 'full' model were also identified using the primary care or hospital-based models, with the remaining patients differing according to age, frailty, multimorbidity, self-rated health, polypharmacy, prior hospitalisations and imminent mortality. The use of higher risk prediction thresholds resulted in lower levels of agreement in high-risk designation across models and greater morbidity and mortality in identified patient populations. Persistence of high-risk status varied across approaches according to updated information on utilisation history, with up to 25% of patients reassessed as lower risk within 1 year.
Conclusion/implicationsSmall differences in risk predictors or risk thresholds resulted in comparatively large differences in who was classified as high risk and for how long. Pragmatic predictive risk modelling design decisions based on data availability or projected high-risk patient numbers may therefore influence individuals identified as high-risk, overall case mix and risk persistence. Routine data linkage would enable greater flexibility in developing and optimising predictive risk models appropriate to both case-finding and performance measurement applications.
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Improving Conduct and Reporting of Narrative Synthesis of Quantitative Data (ICONS-Quant): protocol for a mixed methods study to develop a reporting guideline
Introduction
Reliable evidence syntheses, based on rigorous systematic reviews, provide essential support for evidence-informed clinical practice and health policy. Systematic reviews should use reproducible and transparent methods to draw conclusions from the available body of evidence. Narrative synthesis of quantitative data (NS) is a method commonly used in systematic reviews where it may not be appropriate, or possible, to meta-analyse estimates of intervention effects. A common criticism of NS is that it is opaque and subject to author interpretation, casting doubt on the trustworthiness of a review's conclusions. Despite published guidance funded by the UK's Economic and Social Research Council on the conduct of NS, recent work suggests that this guidance is rarely used and many review authors appear to be unclear about best practice. To improve the way that NS is conducted and reported, we are developing a reporting guideline for NS of quantitative data.
MethodsWe will assess how NS is implemented and reported in Cochrane systematic reviews and the findings will inform the creation of a Delphi consensus exercise by an expert panel. We will use this Delphi survey to develop a checklist for reporting standards for NS. This will be accompanied by supplementary guidance on the conduct and reporting of NS, as well as an online training resource.
Ethics and disseminationEthical approval for the Delphi survey was obtained from the University of Glasgow in December 2017 (reference 400170060). Dissemination of the results of this study will be through peer-reviewed publications, and national and international conferences.
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Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy
Human Gene Therapy , Vol. 0, No. 0.
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Intraoperative Evaluation of Prophylactic Hysterectomy and Salpingo-oophorectomy Specimens in Hereditary Gynecologic Cancer Syndromes
Abstract
Aims
Prophylactic total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) have become routine procedures in women at genetic risk for gynecologic malignancies. Intraoperative pathology diagnosis of an occult malignancy provides the opportunity for immediate surgical staging and helps avoiding a second surgery. However, no standard guidelines exist for optimal intraoperative evaluation (IOE) of these specimens. We performed a retrospective analysis of prophylactic TH and BSO cases to assess the presence of gross findings, frozen and permanent section sampling practices, frozen section diagnoses and diagnostic discrepancies.
Methods and results
All prophylactic TH and BSO cases between 1990-2017 were retrieved from our departmental archives. A total of 413 cases were included in the study: 27 with Lynch syndrome (LS), 222 with germline BRCA 1 or 2 mutations, and 164 cases with strong family or personal history (non-Lynch/ non-BRCA). Only less than half of all cases (159 of 413; 38.5%) were sent for IOE: fifteen of 27 (56%) LS cases, 93 of 222 (42%) BRCA cases and 51 of 164 (31%) non-Lynch/ non-BRCA cases. A total of 19 patients (4.6% of patients combining all 3 groups) had a final diagnosis of malignancy or pre-malignancy on permanent sections. Of these 19 cases, 8 had a corresponding gross lesion (42%) and could have been diagnosed on frozen section; however, only one of them underwent IOE.
Conclusions
Our results highlight the potential benefits and challenges of IOE in this setting and may provide a basis for future practice recommendations.
This article is protected by copyright. All rights reserved.
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A novel anterior decompression technique (vertebral body sliding osteotomy) for ossification of posterior longitudinal ligament of the cervical spine
Publication date: Available online 26 February 2018
Source:The Spine Journal
Author(s): Dong-Ho Lee, Jae Hwan Cho, Choon Sung Lee, Chang Ju Hwang, Sung Hoon Choi, Chul Gie Hong
Background ContextConventional anterior decompression surgery for cervical myelopathy, including anterior corpectomy and fusion, is technically demanding and known to be associated with a higher incidence of surgery-related complications, including cerebrospinal fluid (CSF) leakage, neurologic deterioration, and graft failure compared with posterior surgery.PurposeWe introduce a novel anterior decompression technique (vertebral body sliding osteotomy; VBSO) for cervical myelopathy caused by ossification of posterior longitudinal ligament (OPLL) and evaluate the efficacy and safety of this procedure.Study DesignThis is a case series for novel surgical technique.Patient SampleFourteen patients (M:F=11:3, mean age 56.9±10) with cervical myelopathy caused by OPLL who underwent VBSO by a single surgeon were included.Outcome MeasuresThe surgical outcome was evaluated according to the Japanese Orthopaedic Association score for cervical myelopathy (C-JOA score), and the recovery rate of the C-JOA score. Patients were also evaluated radiographically with plain and dynamic cervical spine radiographs and pre- and postoperative CT images.MethodsFourteen patients were followed for more than 24 months and operation time, estimated blood loss (EBL), neurologic outcomes, and surgery-related complications were investigated. Radiological measurements were also performed to analyze following parameters: (1) canal occupying ratio and postoperative canal widening, (2) Pre- and postoperative sagittal alignment.ResultsThe mean recovery rate of C-JOA score at the final follow-up was 68.65 ± 17.8%. There were no perioperative complications, including neurologic deterioration, vertebral artery injury, esophageal injury, graft dislodgement, and CSF leaks, after surgery except for pseudarthrosis in 1 case. An average spinal canal compromised ratio by OPLL decreased from 61.5 ± 8.1% preoperatively to 16.5 ± 11.2% postoperatively. An average postoperative canal widening was 5.15 ± 1.39 mm, and improvement of cervical alignment was observed in all patients with average recovery angle of 7.3 ± 6.1° postoperatively.ConclusionsThe VBSO allows sufficient decompression of spinal cord and provides excellent neurologic outcomes. Because surgeons do not need to manipulate the OPLL mass directly, this technique could significantly decrease surgery-related complications. Furthermore, as it is based on the multi-level discectomy and fusion technique, it would be more helpful to restore a physiologic lordosis.
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Bony ingrowth potential of 3D printed porous titanium alloy: a direct comparison of interbody cage materials in an in vivo ovine lumbar fusion model
Publication date: Available online 26 February 2018
Source:The Spine Journal
Author(s): Kirk McGilvray, Jeremiah Easley, Howard B. Seim, Daniel Regan, Sigurd H. Berven, Wellington K. Hsu, Thomas E. Mroz, Christian M. Puttlitz
Background ContextThere is significant variability in the materials commonly used for interbody cages in spine surgery. It is theorized that 3-D printed interbody cages utilizing porous titanium material can provide more consistent bone ingrowth and biological fixation.PurposeThe purpose of this study was to provide an evidence-based approach to decision making regarding interbody materials for spinal fusion.Study DesignComparative animal study.MethodsA skeletally mature ovine lumbar fusion model was utilized for this study. Interbody fusions were performed at (L2-L3 and L4-L5) in 27 mature sheep using three different interbody cages (i.e., polyetheretherketone [PEEK], plasma sprayed porous titanium coated PEEK [PSP], and 3-D printed porous titanium alloy cage [PTA]). Non-destructive kinematic testing was performed in the three primary directions of motion. The specimens were then analyzed using micro-computed tomography (µCT); quantitative measures of the bony fusion were performed. Histomorphometric analyses were also performed in the sagittal plane through the interbody device. Outcome parameters were compared between cage designs and time-points.ResultsFlexion-extension range of motion (ROM) was statistically reduced for the PTA group as compared to the PEEK cages at 16 weeks (p-value = 0.02). Only the PTA cages demonstrated a statistically significant decrease in ROM and increase in stiffness across all three loading directions between the 8-week and 16-week sacrifice time-points (p-value ≤ 0.01). Micro-CT data demonstrated significantly greater total bone volume within the graft window for the PTA cages at both 8-weeks and 16-weeks compared to the PEEK cages (p-value < 0.01).ConclusionsA direct comparison of interbody implants demonstrates significant and measurable differences in biomechanical, µCT, and histologic performance in an ovine model. The 3-D printed porous titanium interbody cage resulted in statistically significant reductions in ROM, increases in the bone ingrowth profile, as well as average construct stiffness compared to PEEK and PSP.
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Clinical outcomes of percutaneous suction aspiration and drainage for the treatment of infective spondylodiscitis with paravertebral and/or epidural abscess
Publication date: Available online 26 February 2018
Source:The Spine Journal
Author(s): Tsunemasa Matsubara, Kei Yamada, Kimiaki Sato, Masafumi Gotoh, Kensei Nagata, Naoto Shiba
Background contextPatients with infective spondylodiscitis who failed conservative treatment are generally indicated for open surgery. However, some patients are poor candidates for standard surgery, hence the need to evaluate less invasive approaches. Good outcomes were previously reported for percutaneous suction aspiration and drainage (PSAD) in the treatment of infective spondylodiscitis resistant to conservative therapy. We recently extended the surgical approach of PSAD to allow drainage of paravertebral or epidural abscesses in patients with progressive infective spondylodiscitis.PurposeTo evaluate the clinical outcomes of PSAD for infective spondylodiscitis with paravertebral and/or epidural abscess.DesignRetrospective case series.Patient samplePatients with infective spondylodiscitis and associated epidural and/or paravertebral abscess treated using PSAD at our institution, between 1998 and 2014.Outcome measuresSerum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and imaging data obtained via plain radiography, computed tomography, and magnetic resonance imaging were analyzed. Serum measurements were taken preoperatively and at several time points postoperatively. Clinical outcomes were evaluated using the modified MacNab criteria for overall functional mobility.MethodsData were obtained from the patients' case notes, radiological images, and medical records. Student's t-test was used to assess the relevance of changes in serum levels of CRP and ESR at each evaluated time point, as well as the change in sagittal Cobb angle between the preoperative state and the state at final follow-up.ResultsFifty-two patients (31 men and 21 women; average age, 70.6 years) were included in our analysis. The median (range) CRP levels and ESR values at the time of diagnosis were 6.86 (0.04–20.15) mg/dL and 78.8 (26–120) mm/h, respectively. At one year postoperatively, these values had decreased to 0.18 (0.0–1.2) mg/dL and 13.8 (4–28) mm/h for CRP and ESR, respectively. At final follow-up, bone union was observed in 80.8% (42/52) of patients, with instability identified in five patients. Regarding functional mobility, excellent outcomes were obtained in 26.9% (14/52) of patients, whereas good, fair, and poor outcomes were noted in 42.3% (22/52), 3.9% (2/52), and 26.9% (14/52) of patients, respectively. Overall, treatment was considered effective in 69.2% (36/52) of patients.ConclusionsPSAD can serve as an effective alternative to open surgery for the treatment of patients with progressive infective spondylodiscitis and associated paravertebral and/or epidural abscess.
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The in vivo response to a novel ti coating compared to PEEK: evaluation of the periphery and inner surfaces of an implant
Publication date: Available online 26 February 2018
Source:The Spine Journal
Author(s): W.R. Walsh, M. Pelletier, C. Christou, J. He, F. Vizesi, S.D. Boden
BackgroundContext: Increasing bone ongrowth and ingrowth of PEEK interbody fusion devices has the potential to improve clinical outcomes.PurposeThis study evaluated the in vivo response of promoting new bone growth and bone apposition with NM compared to PEEK alone in a cancellous implantation site with an empty aperture.Study DesignThis is a randomized control animal studyMethodsImplants and funding for this study were provided by SeaSpine (60,000 USD).Cylindrical dowels with two apertures were prepared as PEEK with a sub-micron layer of the titanium (NanoMetalene, NM). The titanium coating was applied over the entire implant (Group 1) or just the apertures (Group 2). PEEK implants with no coating served as controls (Group 3). Implants were placed in the cancellous bone of the distal femur or proximal tibia with no graft material placed in the apertures in eight adult sheep. Bone ongrowth to the surface of the implant and ingrowth into the apertures was assessed at 4 and 8 week after surgery with micro-computed tomography and undecalcified histology.ResultsThe apertures in the implants were notably empty in the PEEK group at 4 and 8 weeks. In contrast, new bone formation into the apertures was found in samples coated with NM even though no graft material was placed into the defect. The bone growing into the aperture tracked along the titanium layer. Apertures with the titanium coating demonstrated significantly more bone by micro-CT qualitative grading compared to PEEK with average bone coverage scores of Group 1 (NM) 1.62±0.89, Group 2 (NM apertures only) 1.62±0.77 and Group 3 (PEEK) 0.43±0.51 respectively at 4 weeks (p<0.01) and Group 1 (NM) 1.79±1.19, Group 2 (NM apertures only) 1.98±1.18 and Group 3 (PEEK) 0.69±0.87 respectively at 8 weeks (p<0.05). The amount of bone in the apertures (ingrowth) quantified using the volumetric data from the micro computed tomography supported an overall increase in bone volume inside the apertures with the titanium coating compared to PEEK. Histology showed newly formed woven bone tracked along the surface of the titanium in the apertures. The PEEK interface presented the typical non-reactive fibrous tissue inside the apertures at 4 weeks and some focal contact with bone on the outside at 4 weeks and 8 weeksConclusionsMicro-computed tomography and histology demonstrated bone ongrowth to the surfaces coated with NM where the newly formed bone tracked along the thin titanium coated surfaces. PEEK surfaces presented the non-reactive fibrous tissue at the interface as previously reported in pre-clinical scenarios.
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Treatment of Clostridium difficile infection with a small molecule inhibitor of toxin UDP-glucose hydrolysis activity [PublishAheadOfPrint]
Clostridium difficile infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality and associated healthcare costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows C. difficile to flourish. Treatment of CDI with antimicrobials is generally effective in the short-term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective non-antimicrobial therapy. Here we report a highly potent small molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intra-rectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated similar efficacy to vancomycin in a hamster disease model. Overall, these results demonstrate that small molecule inhibition of C. difficile toxin UDP-glucose hydrolysis activity is a promising non-antimicrobial approach to the treatment of CDI.
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An Antibiotic stewardship program (ASP) blueprint for optimizing Verigene BC-GN within an institution: A tale of two cities [PublishAheadOfPrint]
Rapid diagnostic tests (RDTs) have revolutionized the management of Gram-negative bacteremia by allowing antimicrobial stewardship teams the ability to escalate therapy and improve patient outcomes through timely organism identification and detection of certain resistance determinants. However, given the complex nature of Gram-negative resistance, stewardship teams are left without clear direction for how to respond when resistance determinants are absent as the safety of de-escalation in this setting is unknown. The primary purpose of this analysis was to determine the negative predictive values (NPV) of resistance marker absence to predict susceptibility in target bug/drug scenarios at two geographically distinct institutions. 1,046 Gram-negative bloodstream isolates that were analyzed with Verigene GN-BC were assessed. Outside of P. aeruginosa the absence of resistance determinants by the RDT largely predicted susceptibility to target antibiotics at both institutions. NPVs for ceftriaxone susceptibility in E. coli and K.pneumoniae in the absence of either CTX-M or a carbapenemase gene were 98% and 93-94%, respectively. Similar results were seen with other target bug/drug scenarios with NPVs of 94-100% demonstrated at both institutions, with the exception of P. aeruginosa, where NPVs were poor likely due to the more complex nature of resistance in this pathogen. The results of this study show that clinicians at both institutions should have confidence in de-escalation in the absence of resistance determinant detection by Verigene BC-GN, and the methodology described within this manuscript can serve as a blueprint for other stewardship programs to employ at their institutions to optimize management of Gram-negative bacteremia.
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MICAFUNGIN ENHANCES THE HUMAN MACROPHAGE RESPONSE TO Candida albicans THROUGH {beta}-GLUCAN EXPOSURE [PublishAheadOfPrint]
Micafungin belongs to the antifungal family of echinocandins, which act as non-competitive inhibitors of the fungal cell-wall β-1,3-D-glucan synthase. Since C. albicans is the most prevalent pathogenic fungus in humans, we study the involvement of Micafungin in the modulation of the inflammatory response developed by human tissue macrophages against C. albicans. The MIC for Micafungin was 0.016 μg/ml on the C. albicans SC5314 standard strain. Micafungin induced a drastic reduction in the number of exponential SC5314 viable cells, the fungicidal effect being dependent on the cellular metabolic activity. Notably, Micafungin also caused a structural remodelling of the cell wall, leading to exposure of the β-glucan and chitin content on the external surface. At the higher doses used (0.05 μg/ml), the antifungal also induced the blowing up of budding yeasts. In addition, preincubation with Micafungin before exposure to human tissue macrophages enhanced the secretion of TNF-α, IL-17A and IL-10 cytokines. Our results strongly suggest that in C. albicans treatment with Micafungin, in addition to having the expected toxic antifungal effect, potentiates the immune response, improving the interaction and activation of human macrophages, probably through the unmasking of β-glucans on the cell wall surface.
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Characteristics of Carbapenemase-Producing Enterobacteriaceae in Wastewater Revealed by Genomic Analysis [PublishAheadOfPrint]
Wastewater is considered a major source of antibiotic-resistant bacteria released into the environment. Here, we characterized carbapenemase-producing Enterobacteriaceae (CPE) in wastewater by whole-genome analysis. Wastewater samples (n = 40) were collected from municipal wastewater treatment plants and hospital wastewater in Japan and Taiwan. Samples were screened for CPE using selective media, and the obtained isolates were sequenced using an Illumina MiSeq. The isolates (n = 45) included the following microorganisms: Klebsiella quasipneumoniae (n = 12), Escherichia coli (n = 10), Enterobacter cloacae complex (n = 10), Klebsiella pneumoniae (n = 8), Klebsiella variicola (n = 2), Raoultella ornithinolytica (n = 1), Citrobacter freundii (n = 1), and Citrobacter amalonaticus (n = 1). Among the 45 isolates, 38 harbored at least one carbapenemase-encoding gene. Of these, the blaGES (blaGES-5, blaGES-6, and blaGES-24) genes were found in 29 isolates. These genes were situated in novel class 1 integrons, but the integron structures were different between the Japanese (In1439 with blaGES-24 and In1440 with blaGES-5) and Taiwanese isolates (In1441 with blaGES-5 and In1442 with blaGES-6). Other carbapenemase-encoding genes (blaVIM-1, blaNDM-5, blaIMP-8, blaIMP-19, and blaKPC-2) were found in one to three isolates. Notably, class 1 integrons previously reported among clinical isolates obtained in the same regions as the present study, namely In477 with blaIMP-19 and In73 with blaIMP-8, were found among the Japanese and Taiwanese isolates, respectively. The results indicate that CPE with various carbapenemase-encoding genes in different genetic contexts were present in biologically treated wastewater, highlighting the need to monitor for antibiotic-resistance in wastewater.
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Plasma levels of rifampicin correlate with the TB drug activity (TDA) assay [PublishAheadOfPrint]
The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource limited settings. In tuberculosis (TB) patients (n=30), TDA and plasma levels of first-line drugs were analysed two hours post dose, two weeks after treatment initiation. Patients with plasma levels of rifampicin below 8 mg/L had significantly lower median TDA (1.40 vs 1.68, p=0.0013). TDA may be used to identify TB patients with suboptimal rifampicin levels during TB treatment.
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Evaluation of the in vitro activity of eravacycline against a broad spectrum of recent clinical anaerobic isolates [PublishAheadOfPrint]
The novel fluorocycline antibiotic, eravacycline, is in development for the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDR Bacteroides spp. and Clostridium difficile. Eravacycline was potent in vitro against all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or β-lactam/β-lactamase inhibitor combinations.
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Efficacy of human-simulated exposures of ceftolozane/tazobactam alone and in combination with amikacin or colistin against multidrug-resistant Pseudomonas aeruginosa in an in vitro pharmacodynamic model [PublishAheadOfPrint]
Combination therapy is an attractive option for the treatment of multidrug resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane/tazobactam (C/T). The in vitro pharmacodynamic chemostat model was employed to compare human simulated exposures of C/T 3g q8h alone or in combination with amikacin 25 mg/kg daily or colistin 360 mg daily against four MDR P. aeruginosa isolates. C/T alone resulted in 24 hour CFU changes of -0.02±0.21, -1.81±0.55, -1.44±0.40, and +0.62±0.05 log10CFU/ml against isolates with C/T MICs of 4, 4, 8 and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed varying results. The addition of amikacin to C/T resulted in -2.00±0.23 (p<0.001, additive), -1.50±0.83 (p=0.687, indifferent), -2.84±0.08 (p=0.079, indifferent), and -2.67±0.54 (p<0.001, synergy) log10CFU/ml reductions, respectively. The addition of colistin to C/T resulted in -3.02±0.22 (p<0.001, additive), -3.21±0.24 (p>0.05, indifferent), -4.6±0.11 (p=0.002, synergy), and -3.01±0.28 (p<0.001, synergy) log10CFU/ml reductions, respectively, against these MDR P. aeruginosa. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 hours, with C/T plus amikacin or colistin was observed against 3 out of 4 MDR P. aeruginosa tested, particularly those strains that were intermediate or resistant to C/T. Further studies assessing combination regimens containing C/T against MDR P. aeruginosa are warranted.
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Gold(III) macrocycles and chelates targeting Mycobacterium tuberculosis and Mycobacterium abscessus: evidence for inhibition of topoisomerase 1A [PublishAheadOfPrint]
Mycobacterium tuberculosis (Mtb) and the fast-growing Mycobacterium abscessus (Mab) are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug resistant Mtb strains and the high level of intrinsic resistance of Mab calls for novel drug scaffolds that effectively target both pathogens. In this study, we have evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase I and II, against Mab and Mtb. We identified a total of 5 non-cytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse Mtb and Mab clinical isolates. Prompted by previous data suggesting that 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the Mtb gyrase. In vitro enzyme assays confirmed potent activity against bacterial topoisomerase IA (Topo1) enzymes, but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against Mtb and Mab that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.
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The amphibian antimicrobial peptide temporin B inhibits in vitro herpes simplex virus type 1 infection. [PublishAheadOfPrint]
The herpes simplex virus type 1 (HSV-1) is widespread in the population and in most cases its infection is asymptomatic. The currently available anti-HSV-1 drugs are acyclovir and its derivatives, although long-term therapy with these agents can lead to drug resistance. Thus, the discovery of novel anti-herpetic compounds deserves additional effort. Naturally occurring antimicrobial peptides (AMPs) represent an interesting class of molecules with potential antiviral properties. To the best of our knowledge this work is the first demonstration of the in vitro anti-HSV-1 activity of Temporin B (TB), a short membrane-active amphibian AMP. In particular, when HSV-1 was pre-incubated with 20 μg/ml TB, significant antiviral activity (5 log reduction of viral titer) was observed. Such an effect was due to the disruption of the viral envelope, as demonstrated by transmission electron microscopy. Moreover, TB partially affected different stages of HSV-1 life cycle, including the attachment, the entry of the virus into the host cell as well as the following post infection phase. Furthermore, its efficacy was confirmed on human epithelial cells, thus suggesting TB as a novel approach for the prevention and/or treatment of HSV-1 infections.
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Aminomethyl spectinomycins as therapeutics for drug-resistant gonorrhea and chlamydial co-infections [PublishAheadOfPrint]
Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial co-infections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great and the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic, spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to that of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial co-infections.
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Identification and Characterization of Key Charged Residues in the Cofilin Protein Involved in Azole Susceptibility, Apoptosis, and Virulence of Aspergillus fumigatus [PublishAheadOfPrint]
Through some specific amino acid residues, Cofilin, a ubiquitous actin depolymoerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae; however, this modulation in a major fungal pathogen, A. fumigatus was still unclear. Hereby, it was found firstly that mutations on several charged residues in cofilin to alanine, D19A;R21A, E48A, and K36A increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks including mitochondrial membrane potential depolarization, the cytochrome c release, upregulation of metacaspases, and DNA cleavage in A. fumigatus. Two of these mutations (D19A;R21A and K36A) increased acetyl-coenzyme A and adenosine triphosphate (ATP) concentrations by triggering fatty acid β-oxidation. The upregulated acetyl-coenzyme A affected the ergosterol biosynthetic pathway, leading to overexpression of cyp51A and -B, while excess ATP fueled ATP-binding cassette transporters. Besides, these two mutations both reduced the susceptibility of A. fumigatus to azole drugs and enhanced the virulence of A. fumigatus in a Galleria mellonella infection model. Taken together, novel and key charged residues in cofilin were identified as essential modules regulating the mitochondrial function involved in azole susceptibility, apoptosis, and virulence of A. fumigatus.
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Integrase-mediated recombination of the bel-1 gene cassette encoding the extended-spectrum {beta}-lactamase BEL-1 [PublishAheadOfPrint]
Integrons are genetic elements that can acquire and rearrange gene cassettes. The blaBEL-1 gene encodes an extended-spectrum β-lactamase, BEL-1, that is present at second position of the variable region of class 1 integrons identified in Pseudomonas aeruginosa. The mobility of the bel-1 gene cassette was analyzed in physiological conditions and with the integrase gene being overexpressed. Cassette mobility in Escherichia coli was detected by excision/integration into the recipient integron In3 on the conjugative plasmid R388, with the over-produced integrase. Despite several antibiotic pressures, the bel-1 cassette remained at the second position in the integron, highlighting its stability in P. aeruginosa. Overexpression of the integrase gene in E. coli induced the bel-1 cassette recombination. However, cassettes containing two genes (blaBEL-1/smr2 or blaBEL-1/aacA4) were excised suggesting that the bel-1 cassette attC site was defective. We showed that bel-1 is a stable gene cassette under physiological growth conditions irrespective of the selective antibiotic pressure, that may be mobilized upon over-overexpression of the integrase gene.
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Resistome analysis of a carbapenemase (OXA-48)-producing and colistin-resistant Klebsiella pneumoniae strain [PublishAheadOfPrint]
Carbapenemase-producing Klebsiella pneumoniae are increasingly reported worldwide (1, 2)....
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In vitro susceptibility of ceftolozane-tazobactam against Burkholderia pseudomallei [PublishAheadOfPrint]
Burkholderia pseudomallei is the cause of melioidosis, a potentially serious and fatal disease characterized by community-acquired pneumonia and/or sepsis mainly in Southeast Asia and Northern Australia, and high case-fatality rates of up to 19% are observed in endemic areas (1).
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In-situ validation of the endothelial cell receptor GRP78 in a case of rhinocerebral mucormycosis -Letter to the Editor- (New-Data Letter) [PublishAheadOfPrint]
Mucormycosis is probably the most devastating and hard to diagnose invasive mold infection caused by fungi belonging to the order Mucorales....
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MEDI3902 correlates of protection against severe Pseudomonas aeruginosa pneumonia in a rabbit acute pneumonia model [PublishAheadOfPrint]
Pseudomonas aeruginosa is among the most formidable antibiotic-resistant pathogens and a leading cause of hospital-associated infections. With dwindling options for antibiotic resistant infections, a new paradigm for treatment and disease resolution is required. MEDI3902, a bispecific antibody targeting the P. aeruginosa type-3-secretion (T3S) protein PcrV and Psl exopolysaccharide, was previously shown to mediate potent protective activity in murine infection models. With the current challenges associated with clinical development of narrow-spectrum agents, robust preclinical efficacy data in multiple animal species are desirable. Here, we sought to develop a rabbit P. aeruginosa acute pneumonia model to further evaluate the activity of MEDI3902 intervention. In the rabbit model of acute pneumonia, prophylaxis with MEDI3902 exhibited potent dose-dependent protection whereas those receiving control IgG developed fatal, hemorrhagic, necrotizing pneumonia between 12 and 54 h after infection. Blood biomarkers (e.g. pO2, pCO2, base excess, lactate, creatinine) were grossly deranged for the vast majority of control IgG-treated animals, but remained within normal limits for MEDI3902-treated animals. In addition, MEDI3902-treated animals exhibited a profound reduction in P. aeruginosa organ burden and a marked reduction in expression of proinflammatory mediators from lung tissue, which correlated with reduced lung histopathology. These results confirm that targeting PcrV and Psl via MEDI3902 is a promising candidate for immunotherapy against P. aeruginosa pneumonia.
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Erratum
In the article, "Building an Outpatient Kidney Palliative Care Clinical Program" by Scherer JS et al (J Pain Symptom Manage 2018;55:108--116.e2), the acknowledgement statement on page 115 should appear as the following:
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Erratum
Please see the letter by Burr and Ford (DOI) and the response (DOI) by Sridharan published in this issue for a description of an error in Sridharan K, Sivaramakrishnan G. Drugs for treating opioid-induced constipation: A mixed treatment comparison network meta-analysis of randomized controlled clinical trials. J Pain Symptom Management. 2017;55:468--479.e1. The revised figures appear below:
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Allele-specific mechanisms of activation of MEK1 mutants determine their properties [Research Articles]
Mutations at multiple sites in MEK1 occur in cancer suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS-RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output and often co-occur with RAS or RAF mutations. They act as amplifiers of RAF signaling. By contrast, another class of mutants delete a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors which bind to the inactivated form of MEK1. All the mutants were sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.
http://ift.tt/2ozbUmY
Genomic and functional fidelity of small cell lung cancer patient-derived xenografts [Research Articles]
Small cell lung cancer (SCLC) patient-derived xenografts (PDXs) can be generated from biopsies or circulating tumor cells (CTCs), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a two-year timeframe, at 89% and 38% efficiency, respectively. Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and cisplatin (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.
http://ift.tt/2CmotLJ
Drug Combo Bests Sunitinib in RCC [News in Brief]
Atezolizumab and bevacizumab delayed tumor growth for longer than sunitinib does.
http://ift.tt/2oA2uHC
STAT5A/B BLOCKADE SENSITIZES PROSTATE CANCER TO RADIATION THROUGH INHIBITION OF RAD51 AND DNA REPAIR
Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double strand DNA break repair in PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacological Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.
http://ift.tt/2CrGKHo
Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma
Purpose: To determine a recommended Phase 2 dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a Phase 1, multicenter, open-label study of oral LY2940680. The maximum tolerated dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naive and previously hedgehog (Hh) inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled. Results: Eighty-four patients were treated (dose escalation, n=25; dose confirmation, n=19; and BCC dose expansion, n=40). Common treatment-emergent adverse events were dysgeusia (41 [48.8%]), fatigue (40 [47.6%]), nausea (38 [45.2%]), and muscle spasms (34 [40.5%]). Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested all doses were biologically active (inhibition median of 92.3% [80.9% to 95.7%]). All clinical responses (per RECIST 1.1) were in patients with BCC (n=47); the overall and estimated response rate was 46.8% (95% CI: 32.1-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh-treatment-naive (11/16) patients. Conclusions:LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh-treatment-naive patients.
http://ift.tt/2sTAUdK
Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.
http://ift.tt/2CllTp2
hPCL3s promotes hepatocellular carcinoma metastasis by activating {beta}-catenin signaling
Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta-catenin degradation, and activated beta-catenin/T-cell factor (TCF) signaling. Downstream of the beta-catenin cascade, interleukin 6 (IL-6) mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL-6 pathway.
http://ift.tt/2oz9ZyM
A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail
Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or transforming growth factor-beta (TGFbeta), known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.
http://ift.tt/2Cloakl
IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma
Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced T-IC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.
http://ift.tt/2oz9WTC
A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol
Abstract
Background
Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC.
Method
Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m2/d, d1–3, plus 5-fluorouracil 1800 mg/m2, continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m2, continuous infusion for 96 h plus paclitaxel 50 mg/m2, d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m2, continuous infusion for 72 h, plus paclitaxel 175 mg/m2 d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events.
Discussion
The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal.
Trial registration
ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012.
http://ift.tt/2sUmqKK
A new tissue segmentation method to calculate 3D dose in small animal radiation therapy
Abstract
Background
In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Zeff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Zeff) in small animal dose calculation.
Methods
The method is based on the relationship found between CBCT number and ρ*Zeff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZeff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZeff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations.
Results
The study of the impact of ρZeff variation over the range of materials, from ρZeff = 2 g.cm− 3 (lung) to 27 g.cm− 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZeff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance.
Conclusions
Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZeff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.
http://ift.tt/2Cn7t7N
Comparing spiking and slow wave activity from invasive electroencephalography in patients with and without seizures
Seizures have long been defined as paroxysmal events typified by abnormally excessive or synchronous brain activity (Fisher et al., 2005). Seizures can occur in healthy brain, or can be the result of disease. By definition, epilepsy requires an increased probability of seizures. Seizure threshold is a clinically useful concept expressing a time-varying probability of seizures. Despite clinical relevance, there remains no clear way of quantitatively assessing seizure probability. As a result, epilepsy patients often undergo long therapy titrations or never have their therapy appropriately optimized.
http://ift.tt/2ClXyPV
Interictal regional paroxysmal fast activity on scalp EEG is common in patients with underlying gliosis
The morphology and the distribution of interictal epileptiform discharges (IEDs) on scalp EEG provide useful information about the syndromic diagnosis of epilepsy and its localization in cases of focal epilepsy (Niedermeyer, 1999). Traditionally, IEDs are considered to have a limited specificity with regard to the underlying etiology of epilepsy. However, certain EEG patterns in the form of continuous or semi-continuous rhythmic IEDs and interictal regional polyspikes on intraoperative electrocorticography and scalp EEG have been demonstrated more commonly in patients with focal cortical dysplasia (FCD) (Ferrier et al., 2006; Gambardella et al., 1996; Noachtar et al., 2008; Palmini et al., 1995; Rosenow et al., 1998).
http://ift.tt/2sUmque
Intra-operative characterisation of subthalamic oscillations in Parkinson’s disease
There is growing interest in the nature of local field potential (LFP) activities recorded from the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) undergoing neurosurgery for deep brain stimulation (DBS). This is fueled by the evidence that oscillatory activity in the beta frequency band is unduly synchronized and strong in these patients and that this relates to deficiency of dopamine in the basal ganglia (Hammond et al, 2007). Thus, the power of beta activity is correlated with the motor impairment in PD and the changes of power engendered by levodopa treatment or DBS correlate with improvements in bradykinesia and rigidity (Ray et al., 2008; Kühn et al., 2008 and 2009; Eusebio et al., 2011).
http://ift.tt/2CnQX7M
Does Acute Radio-Frequency Electromagnetic Field Exposure Affect Visual Event-Related Potentials in Healthy Adults?
It is well established that waking electroencephalogram (EEG) power in the alpha (8-12 Hz) band (Croft et al., 2002; D'Costa et al., 2003; Curcio et al., 2005; Regel et al., 2007; Croft et al., 2010), and sleep EEG in the sleep spindle range (Borbely et al., 1999) are both affected by radio-frequency electromagnetic field (RF-EMF) exposure. These effects persist even after RF-EMF exposure cessation for sleep EEG (Huber et al., 2002; Loughran et al., 2005; Loughran et al., 2012), and also possibly for the waking EEG (Curcio et al., 2005).
http://ift.tt/2sYp4zk
Driving and visual deficits in stroke patients
ABSTRACT Objective: The aim of the present study was to conduct an exploratory assessment of visual impairment following stroke, and to discuss the possibilities of reintroducing patients to the activity of driving. Methods: The Useful Field of View test was used to assess visual processing and visual attention. Results: A total of 18 patients were included in the study, and were assigned to either the drive group (n = 9) or the intention group (n = 9). In the drive group, one patient was categorized as moderate-to-high risk; whereas, in the intention group, one patient was categorized as low-to-moderate risk. Additionally, two patients in the intention group were categorized as high risk. The patients did not perceive their visual deficits as a limitation. Conclusion: Visual attention is an interference factor in terms of the safe performance of driving after a stroke. All patients showed a high level of interest for the independence provided through being able to drive.
RESUMO Objetivo: O objeto deste estudo foi realizar uma avaliação exploratória de déficits visuais decorrentes do AVC e discutir possibilidades de retorno à direção de automóveis. Métodos: Estudo descritivo e observacional. O software UFOV foi utilizado para avaliar o processamento visual e atenção visual. Resultados: Um total de 18 pacientes foram incluídos no estudo, classificados em Grupo Direção – GD (n = 9) e Grupo Pretensão – GP (n = 9). No GD, um paciente foi classificado em moderado a alto risco de acidentes, e um paciente do GP em baixo a moderado risco. Especificamente, no grupo GP dois pacientes foram classificados em alto risco de acidentes. Pacientes não reconhecem os déficits visuais como dificuldades. Conclusão: Atenção visual é um fator de interferência no desempenho seguro da direção após o AVC. Todos os pacientes mostraram alto interesse na independência oferecida pela direção de automóveis.
http://ift.tt/2HO41CF
Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibition
Abstract
Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.http://ift.tt/2HQmheW
Does Parkinson's disease start in the gut?
ABSTRACT Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.
RESUMO O atual entendimento sobre a fisiopatologia da doença de Parkinson (DP) sugere um papel central do acúmulo de alfa-sinucleína na patogenia da DP Esta revisão crítica revisita marcos, teorias e controvérsias a respeito da origem e progressão da sinucleinopatia, apresentando uma atualização das principais evidências sugerindo que o sistema nervoso entérico seria o local inicial deste processo. Apesar das evidências a favor desta teoria serem crescentes e instigantes, as lacunas de conhecimento a este respeito são importantes pontos para estudos futuros.
http://ift.tt/2GPwbvT
Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease
ABSTRACT The present study investigated the effects of carvacrol on motor and memory deficits as well as hyperalgesia in the 6-OHDA-lesioned rat model of Parkinson's disease. The animals were subjected to unilateral microinjection of 6-OHDA into the medial forebrain bundle and treated with carvacrol (25, 50 and 100 mg/kg, ip) for six weeks after surgery. The 6-OHDA-lesioned rats showed contralateral rotations towards the lesion side, which was accompanied by learning and memory deficits in a passive avoidance test and a decrease in tail withdrawal latency in a tail flick test at the end of week 6. The results also showed that treatment with carvacrol at a dose of 25 mg/kg ameliorated memory deficits, with no effect on rotations and hyperalgesia in lesioned rats. In conclusion, carvacrol improves memory impairments in rats with Parkinson's disease; therefore, it may serve as an adjunct therapy for the alleviation of memory deficits in Parkinson's disease patients.
RESUMO O presente estudo investigou os efeitos do carvacrol nos déficits motores e de memória, bem como na hiperalgesia, em um modelo da doença de Parkinson (DP) em ratos com lesões 6-OHDA. Os animais foram submetidos a microinjeção unilateral de 6-OHDA no feixe mediano do prosencéfalo e tratados com carvacrol (25, 50 e 100 mg / kg, ip) durante 6 semanas após a cirurgia. Os ratos com lesões 6-OHDA mostraram rotações contralaterais para o lado da lesão, que foram acompanhadas de déficits de aprendizagem e de memória em um teste de evitação passiva, e de uma diminuição da latência de retirada da cauda em um teste de cauda no final da semana 6. Os resultados também mostraram que o tratamento crônico com carvacrol a uma dose de 25 mg / kg aliviou os déficits de memória, sem efeito sobre rotações e hiperalgesia em ratos lesados. Em conclusão, o carvacrol melhora a deficiência de memória em ratos com DP e, portanto, pode servir como uma terapia complementar para aliviar os déficits de memória em pacientes com DP.
http://ift.tt/2HOtkEE
Effect of virtual reality in Parkinson's disease: a prospective observational study
ABSTRACT Objective: To assess the effectiveness of balance exercises by means of virtual reality games in Parkinson's disease. Methods: Sixteen patients were submitted to anamnesis, otorhinolaryngological and vestibular examinations, as well as the Dizziness Handicap Inventory, Berg Balance Scale, SF-36 questionnaire, and the SRT, applied before and after rehabilitation with virtual reality games. Results: Final scoring for the Dizziness Handicap Inventory and Berg Balance Scale was better after rehabilitation. The SRT showed a significant result after rehabilitation. The SF-36 showed a significant change in the functional capacity for the Tightrope Walk and Ski Slalom virtual reality games (p < 0.05), as well as in the mental health aspect of the Ski Slalom game (p < 0.05). The Dizziness Handicap Inventory and Berg Balance Scale showed significant changes in the Ski Slalom game (p < 0.05). There was evidence of clinical improvement in patients in the final assessment after virtual rehabilitation. Conclusion: The Tightrope Walk and Ski Slalom virtual games were shown to be the most effective for this population.
RESUMO Objetivo: Verificar a eficácia dos exercícios de equilíbrio com realidade virtual (RVi) na doença de Parkinson. Métodos: Dezesseis pacientes foram submetidos a uma anamnese, exames otorrinolaringológico e vestibular, ao Dizziness Handicap Inventory (DHI), Escala de Equilíbrio de Berg (EEB), questionário SF-36 e o Teste de Sentar e Levantar (TSL) que foram aplicados antes e após a reabilitação com RVi. Resultados: Os resultados dos escores finais do DHI e EEB foram melhores após a reabilitação. O TSL apresentou resultado significativo após a reabilitação. O SF-36 demonstrou alteração significativa da capacidade funcional para os jogos Tightrope Walk e Ski Slalom (p < 0,05) e da saúde mental para o jogo Ski Slalom (p < 0,05). O DHI e EEB apresentaram alterações significativas no jogo Ski Slalom (p < 0,05). Houve melhora clínica evidente dos pacientes após reabilitação virtual. Conclusão: Os jogos virtuais Tightrope Walk e o Ski Slalom foram os mais eficazes.
http://ift.tt/2GLhs5c
Relationship between visuospatial episodic memory, processing speed and executive function: are they stable over a lifespan?
ABSTRACT The present study evaluated the association between episodic memory, executive function and processing speed in a sample with different age ranges. We tested the hypothesis that processing speed, executive function and memory are more strongly associated during childhood and old age. We evaluated 571 participants, aged six to 92 years, divided into four age groups: children/adolescents, young adults, middle-aged adults and older adults. Correlation analyses suggested that the shared variance between the processing speed and memory is strong in childhood but weak across other age ranges. Executive function, however, had a stronger association both in childhood and in old age, when compared with the intermediate stages. We conclude that the effects of processing speed and executive function on memory are not stable across human development. These functions may be compensatory mechanisms for memory functioning in childhood and old age.
RESUMO O presente estudo avalia a associação entre velocidade de processamento, funções executivas e memória em uma amostra de diferentes faixas etárias. O estudo testa a hipótese de que a velocidade de processamento, as funções executivas e a memória apresentam associação mais forte na infância e na velhice. Avaliamos 571 participantes, com idade entre seis e 92 anos, divididos em quatro grupos etários: crianças/adolescentes, adultos jovens, adultos de meia-idade e idosos. Análises de correlação sugerem que a variância compartilhada entre velocidade de processamento e memória é forte na infância e fraca nas demais idades. Já as funções executivas apresentaram associação forte com a memória tanto na infância quanto na velhice, quando comparadas aos estágios intermediários. Concluímos que os efeitos da atenção sobre a memória variam em função da idade do participante. Essas funções podem ser mecanismos compensatórios para a memória ao longo do desenvolvimento.
http://ift.tt/2GLFhK1
Naming and verbal learning in adults with Alzheimer's disease, mild cognitive impairment and in healthy aging, with low educational levels
ABSTRACT Language assessment seems to be an effective tool to differentiate healthy and cognitively impaired aging groups. This article discusses the impact of educational level on a naming task, on a verbal learning with semantic cues task and on the MMSE in healthy aging adults at three educational levels (very low, low and high) as well as comparing two clinical groups of very low (0-3 years) and low education (4-7 years) patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) with healthy controls. The participants comprised 101 healthy controls, 17 patients with MCI and 19 with AD. Comparisons between the healthy groups showed an education effect on the MMSE, but not on naming and verbal learning. However, the clinical groups were differentiated in both the naming and verbal learning assessment. The results support the assumption that the verbal learning with semantic cues task is a valid tool to diagnose MCI and AD patients, with no influence from education.
RESUMO A linguagem tem se mostrado uma ferramenta eficiente para diferenciar grupos de idosos saudáveis dos com deficiências cognitivas. O artigo objetiva discutir o impacto do nível educacional na nomeação, na aprendizagem verbal (AV) com pistas semânticas e no MEEM no envelhecimento saudável em três níveis de escolaridade (muito baixa: 0-3 anos, baixa: 4-7 anos e alta: >8 anos) e em dois grupos clínicos de escolaridade muito baixa e baixa (Doença de Alzheimer – DA – e Comprometimento Cognitivo Leve - CCL), comparados a controles saudáveis. Participaram 101 controles, 17 CCL e 19 DA. Comparações entre grupos saudáveis demonstraram um efeito da escolaridade no MEEM, mas não nas tarefas de nomeação e de AV. Considerando as comparações entre os grupos clínicos, tanto a nomeação quanto a AV os diferenciaram. Os resultados corroboram a pressuposição de que a tarefa de AV com pistas semânticas é válida para diagnosticar CCL e DA, não sendo influenciada pela escolaridade.
http://ift.tt/2HMQsn4
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
