The Role of Intravoxel Incoherent Motion MRI in Predicting Early Treatment Response to Chemoradiation for Metastatic Lymph Nodes in Nasopharyngeal Carcinoma

Introduction

Pilot studies have suggested potential clinical applications for intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in head and neck cancers. This study aimed to characterize metastatic lymph nodes using IVIM MRI, and to evaluate the role of IVIM MRI in the prediction of the early treatment response of lymph node metastasis from nasopharyngeal carcinoma (NPC).

Methods

A total of 122 patients with metastatic lymph nodes from NPC underwent two MRI examinations, pre-treatment and post-treatment (at 4 weeks and at ≥2 years from the end of chemoradiotherapy). Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Differences in the initial IVIM parameters [pure molecular diffusion (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f)] between nodes with a partial response (PR) and a complete response (CR) were analyzed in 102 patients after the exclusion of 20.

Results

The initial D*, D, and apparent diffusion coefficient (ADC) did not reveal a significant difference between nodes showing a PR or a CR. The mean initial f value was significantly higher in patients with a PR relative to patients with a CR (p = 0.003), and its sensitivity and specificity in predicting treatment response to chemoradiotherapy were 86.7% and 100%, respectively.

Conclusions

The present study indicated that the initial f value may be more accurate than the initial D*, D, and ADC in the early prediction of treatment response to chemoradiotherapy for metastatic lymph nodes in patients with NPC.

     

Effet des extraits de quelques plantes sur les bactéries pathogènes responsables de gastroentérites

Background

Phytochemicals are natural bioactive compounds that protect plants against the stress. These phytochemicals may also have other biological activities like, antibacterial activity.

Objective

The objective of this work is to study the antibacterial effect of aqueous and hydro-alcoholic extracts prepared from Thymus vulgaris, Aloysia triphylla, Pistacia lentiscus, Olea europaea leaves and Trigonella foenum-graecum seeds on some pathogenic bacteria responsible for gastroenteritis.

Result

The results obtained from the antibacterial effect showed a moderate activity against the strains studied with a diameters of inhibition zones ranging from 07.00 ± 0.8 to 16.00 ± 1.0 mm for aqueous extracts and vary between 07.00 ± 0.9 and 13.00 ± 1.0 mm for hydro-alcoholic extracts.

Conclusion

This study confirms the possibility of using these plants or components in the prevention of several diseases like, gastroenteritis.

     

The Effect of Evolving Strategies in the Surgical Management of Organ-Confined Prostate Cancer: Comparison of Data from 2005 to 2014 in a Multicenter Setting

Introduction

The objective of this study was to evaluate changes of patient characteristics and surgical techniques in radical prostatectomy in Germany within the last decade.

Methods

Data from 44 German prostate cancer centers were included in the study. Patients’ characteristics (age, initial PSA value), surgical techniques (open vs. minimally invasive approaches), perioperative parameters (operating time, rate of nerve-sparing (NS) radical prostatectomies (RPs), hospitalization time, catheter indwelling time, surgical margin status, number of dissected lymph nodes (LN)), and pathological findings (tumor stage, Gleason score) were analyzed.

Results

Data from 11,675 patients who underwent RP between 2005 and 2014 were analyzed. The rate of open RP approaches decreased by 1.7% (p = 0.0164), the rate of minimally invasive approaches increased by 1.8% (p = 0.0164). Robot-assisted RPs (RARP) increased by 4.6% (p < 0.0001). The number of NS procedures and pelvic lymphadenectomy (LA) increased by 4.5% (p < 0.0001) and 4.7% (p < 0.0001), respectively. Catheter indwelling time and hospitalization time decreased by 1 day (p < 0.0001). No change in the rate of positive surgical margins (p = 0.5061) and the ratio of positive lymph nodes removed (p = 0.4628) was observed. The number of Gleason ≤6 tumors decreased significantly (p < 0.0001).

Conclusions

The number of RARP has significantly increased over the past decade and there is a trend towards surgeries on more advanced tumors with higher yields of lymph nodes dissected. At the same time, the rate of nerve-sparing procedures has significantly increased.

     

Carotid artery stiffness evaluated early by wave intensity in normal left ventricular function in post-radiotherapy patients with nasopharyngeal carcinoma

Purpose

This study aims to assess carotid elasticity early in normal left ventricular function in post-radiotherapy patients with nasopharyngeal carcinoma (NPC) by wave intensity.

Methods

Sixty-seven post-radiotherapy patients all with normal left ventricular function were classified into group NPC1 and group NPC2 based on their carotid intima-media thickness. Thirty age- and sex-matched NPC patients without any history of irradiation and chemotherapy were included as a control group. Carotid parameters, including stiffness constant (β), pressure–strain elastic modulus (Ep), arterial compliance (AC), stiffness constant pulse wave velocity (PWVβ), and wave intensity pulse wave velocity (PWVWI) were measured.

Results

There were no significant differences in conventional echocardiographic variables among the three groups. In comparison with the control group, β, Ep, PWVβ, and PWVWI were significantly increased, while AC was significantly decreased in the NPC1 and NPC2 groups, and there were differences between the NPC1 group and NPC2 group (all P < 0.05).

Conclusion

This study suggested that carotid artery stiffness increased with reduced carotid compliance in post-RT with NPC.

     

The value of quantitative shear wave elastography in differentiating the cervical lymph nodes in patients with thyroid nodules

Purpose

This study aimed at evaluating the diagnostic performance of quantitative shear wave elastography (SWE) in differentiating metastatic cervical lymph nodes from benign nodes in patients with thyroid nodules.

Methods

One hundred and forty-one cervical lymph nodes from 39 patients with thyroid nodules that were diagnosed as papillary thyroid cancer had been imaged with SWE. The shear elasticity modulus, which indicates the stiffness of the lymph nodes, was measured in terms of maximum shear elasticity modulus (maxSM), minimum shear elasticity modulus (minSM), mean shear elasticity modulus (meanSM), and standard deviation (SD) of the shear elasticity modulus.

Results

All the patients underwent thyroid surgery, 50 of the suspicious lymph nodes were resected, and 91 lymph nodes were followed up for 6 months. The maxSM value, minSM value, meanSM value, and SD value of the metastatic lymph nodes were significantly higher than those of the benign nodes. The area under the curve of the maxSM value, minSM value, meanSM value, and SD value were 0.918, 0.606, 0.865, and 0.915, respectively.

Conclusions

SWE can differentiate metastasis from benign cervical lymph nodes in patients with thyroid nodules, and the maxSM, meanSM, and SD may be valuable quantitative indicators for characterizing cervical lymph nodes.

     

Reactive Oxygen Species Imaging in a Mouse Model of Inflammatory Bowel Disease

Purpose

Reactive oxygen species (ROS) are important contributors to inflammatory bowel disease (IBD); however, there are insufficient tools for their in vivo evaluation.

Procedures

To determine if a chemiluminescent ROS reporter, coelenterazine, would be a useful tool for the detection of immune cell activation, the macrophage cell line (RAW 264.7) was treated with phorbol myristate acetate (PMA). Additionally, coelenterazine was used to monitor the changes in ROS production over time in a mouse model of IBD.

Results

In vitro, coelenterazine enabled the dynamic monitoring of the RAW 264.7 cell oxidative burst. In vivo, there were early, preclinical, changes in the localization and magnitude of coelenterazine chemiluminescent foci.

Conclusions

Coelenterazine offers a high-throughput method for assessing immune cell activation in culture and provides a means for the in vivo detection and localization of ROS during IBD disease progression.

     

Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery

Purpose

The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma.

Procedures

The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)—score and immunohistochemical analysis in normal pancreatic tissue (n?=?9), pancreatic (n?=?137), and periampullary (n?=?28) adenocarcinoma.

Results

Integrin α_vβ₆, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p?<?0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients.

Conclusions

The results of this study show that integrin α_vβ₆, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

     

Predictive factors for polypharmacy among child and adolescent psychiatry inpatients

Background

Aim was to determine the predictive factors for polypharmacy among inpatient children and adolescents with psychiatric disorders.

Methods

Blinded, case-note review of children and adolescents with ICD 10 diagnosis of psychiatric disorders on psychotropic medication was conducted. Data on demography, illness, and treatment was analyzed with univariate and multivariate techniques.

Results

Proscribing non-pharmacological interventions (OR = 4.7) and pro re nata medication (OR = 3.3), increased the risk of polypharmacy. Prescribing physical restraint reduced the risk of receiving multiple medications (OR = 0.3).

Conclusion

Proscribing non-pharmacological interventions, pro re nata medication and physical restraints increased polypharmacy.

     

Bioluminescence Imaging of Colonization and Clearance Dynamics of <Emphasis Type="Italic">Brucella Suis</Emphasis> Vaccine Strain S2 in Mice and Guinea Pigs

Purpose

The goal of this study was to develop a plasmid-based lux bio-reporter for use to obtain in vivo images of Brucella suis vaccine strain 2 (B.suis S2) infection with high resolution and good definition.

Procedures

The pBBR-lux (pBBR1MCS-2-lxCDABE) plasmid that carries the luxCDABE operon was introduced into B. suis S2 by electroporation yielding B. suis S2-lux. The spatial and temporal transit of B. suis S2 in mice and guinea pigs was monitored by bioluminescence imaging.

Results

The plasmid pBBR-lux is stable in vivo and does not appear to impact the virulence or growth of bacteria. This sensitive luciferase reporter could represent B. suis S2 survival in real time. B. suis S2 mainly colonized the lungs, liver, spleen, and uterus in mice and guinea pigs as demonstrated by bioluminescence imaging.

Conclusion

The plasmid-based lux bioreporter strategy can be used to obtain high resolution in vivo images of B. suis S2 infection in mice and guinea pigs.

     

MRI characteristics of proctitis in Crohn’s disease on perianal MRI

Purpose

Multiple features have been described for assessing inflammation in Crohn’s disease (CD) in MR enterography, but have not been validated in perianal magnetic resonance imaging (MRI). Retrospectively, we studied which MRI features are valuable in assessing proctitis.

Materials and methods

CD patients (≥18 years) who underwent colonoscopy (reference standard) and perianal fistula MRI within 8 weeks were included. Seventeen MRI features were blindly scored by three observers and correlated to endoscopy (regression analysis). Reproducibility (multirater kappa, intraclass correlation coefficient) was determined for all three observer pairs. MRI features were considered relevant when significantly correlated to endoscopy for ≥2 observers, and reproducibility was ≥0.40 for ≥2 observer pairs.

Results

Perianal MRI of 58 CD patients were included. Wall thickness, rectal mural fat, creeping fat, and size of mesorectal lymph nodes showed a significant correlation with endoscopy for ≥2 observers (p = 0.000–0.023, p = 0.011–0.172, p = 0.007–0.011 and p = 0.000–0.005, respectively) with a kappa/intraclass correlation coefficient of ≥0.60 for ≥2 observer pairs. Perimural T2 signal and perimural enhancement significantly correlated to endoscopy (all p values ≤0.05) for all three observers and the reproducibility was ≥0.40 for ≥2 observer pairs. Mural T2 signal and degree and pattern of T1 enhancement showed significant correlation to endoscopy for two observers, but with poor to moderate reproducibility.

Conclusion

Wall thickness, mural fat, and mesorectal features (perimural T2 signal, perimural enhancement, creeping fat, and size of mesorectal lymph nodes) had significant correlation to endoscopy and were reproducible in diagnosing proctitis. Some established luminal features in MRE were considered not useful.

     

Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma

Purpose

In this study, we evaluated a genetic approach for in vivo multimodal molecular imaging of vasculature in a mouse model of melanoma.

Procedures

We used a novel transgenic mouse, Ts-Biotag, that genetically biotinylates vascular endothelial cells. After inoculating these mice with B16 melanoma cells, we selectively targeted endothelial cells with (strept)avidinated contrast agents to achieve multimodal contrast enhancement of Tie2-expressing blood vessels during tumor progression.

Results

This genetic targeting system provided selective labeling of tumor vasculature and showed in vivo binding of avidinated probes with high specificity and sensitivity using microscopy, near infrared, ultrasound, and magnetic resonance imaging. We further demonstrated the feasibility of conducting longitudinal three-dimensional (3D) targeted imaging studies to dynamically assess changes in vascular Tie2 from early to advanced tumor stages.

Conclusions

Our results validated the Ts-Biotag mouse as a multimodal targeted imaging system with the potential to provide spatio-temporal information about dynamic changes in vasculature during tumor progression.

     

Reproducibility of Contrast-Enhanced Ultrasound in Mice with Controlled Injection

Purpose

Sensitivity of contrast-enhanced ultrasound (CEUS) to microvascular flow modifications can be limited by intra-injection variability (injected dose, rate, volume).

Procedures

To evaluate the effect of injection variability on microvascular flow evaluation, CEUS was compared between controlled and manual injections where enhancement was assessed in vitro within a flow phantom, in normal murine kidney (N?=?12) and in murine ectopic tumors (N?=?10).

Results

For both in vitro and in vivo measurements in the renal cortex, controlled injections significantly improved reproducibility of functional parameter estimation. Their coefficient of variation (CV) in the renal cortex ranged from 4 to 19 % for controlled injection vs. 5 to 43 % for manual injections. For measurements in tumors, controlled injection only decreased the CV significantly for the mean transit time. In tumors, multiple injections of contrast agent with a 15-min delay between each were shown to strongly modify contrast uptake by facilitating penetration of microbubbles.

Conclusion

Improved reproducibility of CEUS assessments in murine models should provide more robust quantification of flow parameters and more sensitive evaluation of tumor modifications in therapeutic models.

     

Long-term Efficacy of Safinamide on Parkinson’s Disease Chronic Pain

Introduction

Chronic pain is an important yet overlooked non-motor symptom of Parkinson’s disease (PD), caused by an imbalance of the dopaminergic and glutamatergic systems. Safinamide has a multimodal mechanism of action, dopaminergic (reversible MAO-B inhibition) and non-dopaminergic (modulation of the abnormal glutamate release), that might be beneficial for both motor and non-motor symptoms.

Objectives

To investigate the long-term (2-year) efficacy of safinamide on PD chronic pain and to confirm the positive effects observed after 6 months of treatment.

Methods

This is a post hoc analysis of the data from the 2-year study 018, focused on the reduction of concomitant pain treatments and on the scores of pain-related items of the Parkinson’s disease quality of life questionnaire (PDQ-39).

Results

Safinamide, compared with placebo, significantly improved the PDQ-39 items 37 (“painful cramps or spasm,” p?=?0.0074) and 39 (“unpleasantly hot or cold,” p?=?0.0209) and significantly reduced the number of concomitant pain treatments by 26.2% (p?=?0.005). A significantly greater proportion of patients in the safinamide group was not using pain drugs after 2 years of treatment (p?=?0.0478).

Conclusions

The positive effects of safinamide on PD chronic pain were maintained in the long term. Further investigations are desirable to confirm their clinical relevance.

Funding

Zambon SpA.

     

Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised,double-blind,placebo-controlled trial

Objective

To investigate the effect of enteral Synbiotic 2000 FORTE^® (a mixture of lactic acid bacteria and fibre) on the incidence of ventilator associated pneumonia (VAP) in critically ill patients.

Design

Prospective, randomised, double blind, placebo controlled trial.

Setting

Tertiary referral centre, general Adult Intensive Care Unit (ICU).

Patients and participants

259 enterally fed patients requiring mechanical ventilation for 48 h or more were enrolled.

Intervention

All patients were enterally fed as per a standard protocol and randomly assigned to receive either synbiotic 2000 FORTE^® (twice a day) or a cellulose-based placebo for a maximum of 28 days.

Measurements and results

Treatment group (n = 130) was well matched with placebo group (n = 129) for age (mean 49.5 and 50 years, respectively) and APACHE II score (median 17 for both). Oropharyngeal microbial flora and colonisation rates were unaffected by synbiotics. The overall incidence of VAP was lower than anticipated (11.2%) and no statistical difference was demonstrated between groups receiving synbiotic and placebo in the incidence of VAP (9 and 13%, P = 0.42), VAP rate per 1,000 ventilator days (13 and 14.6, P = 0.91) or hospital mortality (27 and 33%, P = 0.39), respectively.

Conclusions

Enteral administration of Synbiotic 2000 FORTE^® has no statistically significant impact on the incidence of VAP in critically ill patients.

     

Multimodality Imaging of Cancer Superoxide Anion Using the Small Molecule Coelenterazine

Purpose

We evaluated the small molecule coelenterazine as a potential reporter of cancer-associated superoxide anion in cell culture and in mice.

Procedures

The superoxide anion concentrations of various cancer cell lines were quantified by coelenterazine chemiluminescence in vitro. Coelenteramide fluorescence was detected via flow cytometry and fluorescent microscopy. Coelenterazine was used for the in vivo detection of cancer-associated superoxide anion using the 4T1 breast adenocarcinoma mouse model.

Results

Various cell lines in culture demonstrated different superoxide anion concentrations, with a signal range of 3.15?±?0.06 to 11.80?±?0.24 times that of background. In addition to chemiluminescent detection of coelenterazine, we demonstrated fluorescent detection of coelenteramide within the cytoplasm of cells. 4T1 murine mammary adenocarcinoma tumors in mice demonstrated significantly higher 2.13?±?0.19-fold coelenterazine-based chemiluminescence than that of surrounding normal tissues.

Conclusions

Collectively, our results indicate that coelenterazine can be used to assay superoxide anion concentrations in cultured cancer cells and in tumors growing in mice.

     

Radiomic Analysis using Density Threshold for FDG-PET/CT-Based N-Staging in Lung Cancer Patients

Purpose

Mediastinal nodal (N)-staging done by integrated 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) in lung cancer patients is not always accurate. In order to reduce the need for invasive staging procedures, additional surrogate parameters for the detection of malignant lymph node infiltration would be helpful. The purpose of this study was to evaluate if radiomic semi-automated density profiling in mediastinal lymph nodes can improve preclinical N-staging, irrespective of the specific lung cancer entity.

Procedures

This retrospective study was approved by the institutional review board. Two hundred forty-eight histologically proven lymph nodes in 122 lung cancer patients were investigated. In malignantly infiltrated lymph nodes, the specific lung cancer entity was histologically classified; benign lymph nodes were histologically classified as benign. Non-contrast enhanced [¹⁸F]FDG-PET/CT was performed before surgery/biopsy. Lymph node analyses were performed on the basis of FDG uptake and volumetric CT histogram analysis for metric lymph node sampling.

Results

Of the 248 lymph nodes, 118 were benign, 130 malignant. Malignant lymph nodes had a significantly higher median CT density (32.4 Hounsfield units (HU) (min 5.4/max 77.5 HU)) compared to benign lymph nodes (9.3 HU (min ?49.5/max 60.4 HU, p?<?0.05), irrespective of the histological subtype. The discrimination between different malignant tumour subtypes by means of volumetric density analysis failed. Irrespective of the malignant subtype, a possible cutoff value of 20 HU may help differentiate between benign and malignant lymph nodes.

Conclusion

Density measurements in unclear mediastinal and hilar lymph nodes with equivocal FDG uptake in PET might serve as a possible surrogate parameter for N-staging in lung cancer patients, irrespective of the specific lung cancer subtype. This could also help to find possible high yield targets in cases where invasive lymph node staging is necessary.

     

Gallium-68 Complexes Conjugated to Pittsburgh Compound B: Radiolabeling and Biological Evaluation

Purpose

The aim of this work is to develop an efficient and fully automated radiosynthesis of three derivatives of the Pittsburgh compound B labeled with gallium-68 for the detection of amyloid plaques.

Procedures

The radiolabeling of the precursors and purification of the radiolabeled agents by high pressure liquid chromatography has been studied prior to their in vitro and in vivo evaluations.

Results

The complete process led, in 50 min, to pure Ga-68 products in a 12–38 % yield and with appreciable specific radioactivity (SRA, 85–168 GBq/μmol) which enabled us to demonstrate a considerable in vivo stability of the products. Unfortunately, this result was associated with a poor blood–brain barrier (BBB) permeability and a limited uptake of our compounds by amyloid deposits was observed by in vitro autoradiography.

Conclusion

Although we have not yet identified a compound able to significantly mark cerebral amyloidosis, this present investigation will likely contribute to the development of more successful Ga-68 radiotracers.

     

Detection of Brain Tumors and Systemic Metastases Using NanoLuc and Fluc for Dual Reporter Imaging

Purpose

Bioluminescence imaging (BLI) is a technique with a low background noise and high sensitivity which is widely used in mice models in oncology. We aimed to assess BLI efficiency of the new luciferase NanoLuc (Nluc) for glioblastoma cell lines and tumors, including for dual reporter applications of deep brain tumors and systemic metastasis when combined with firefly luciferase (Fluc).

Procedures

U87 cells were genetically modified for constitutive production of either Nluc, Fluc, or both and assayed for luciferase activity and BLI on cell lysates, living cells, subcutaneous tumors, brain tumors, and systemic metastases.

Results

In vitro, light production by Nluc activity is higher than Fluc. In vivo, Nluc allows for tumor detection including for deep brain tumors and systemic metastases.

Conclusions

Nluc appears to be a useful tool to combine with Fluc for dual imaging in vivo using bioluminescence, allowing for the detection of distinct events in deep tissues within the same organism.

     

Targeted Superparamagnetic Iron Oxide Nanoparticles for <Emphasis Type="Italic">In Vivo</Emphasis> Magnetic Resonance Imaging of T-Cells in Rheumatoid Arthritis

Purpose

The purpose of the study is to develop a targeted nanoparticle platform for T cell labeling and tracking in vivo.

Procedures

Through carboxylation of the polyethylene glycol (PEG) surface of SPION, carboxylated-PEG-SPION (IOPC) was generated as a precursor for further conjugation with the targeting probe. The IOPC could readily cross-link with a variety of amide-containing molecules by exploiting the reaction between 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide and N-hydroxysuccinimide. The subsequent conjugation of monoclonal anti-CD3 antibody with IOPC made it possible to construct a magnetic resonance imaging (MRI) contrast agente (CA) that targets T cells, named IOPC-CD3.

Results

IOPC-CD3 was found to have high transverse relaxivity, good targeting selectivity, and good safety profile in vitro. The utility of this newly synthesized CA was explored in an in vivo rodent collagen-induced arthritis (CIA) model of rheumatoid arthritis. Serial MRI experiments revealed a selective decrease in the signal-to-noise ratio of the femoral growth plates of CIA rats infused with IOPC-CD3, with this finding being consistent with immunohistochemical results showing the accumulation of T cells and iron oxide nanoparticles in the corresponding region.

Conclusions

Together with the abovementioned desirable features, these results indicate that IOPC-CD3 offers a promising prospect for a wide range of cellular and molecular MRI applications.