Δευτέρα 13 Ιουνίου 2022

INSP-15. ITCC-P4: A sustainable platform of molecularly well-characterized PDX models of pediatric cancers for high throughputin vivo testing

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Abstract
Thanks to state-of-the-art molecular profiling techniques we by now have a much better understanding of pediatric cancers and what is driving them. On the other hand, we have also realized that pediatric cancers are much more heterogeneous than previously thought. Many new types and subtypes of pediatric cancers have been identified with distinct molecular and clinical characteristics. However, for many if not most of these new types and subtypes there is no specific treatment available, yet. In order to develop specific treatment protocols and to increase survival rates for pediatric cancer patients further, both at diagnosis and relapse/metastasis, we need a large collection of well-characterized preclinical models representing all the different types and subtypes. These models can be used for preclinical drug testing to prioritize the pediatric development of anticancer drugs that would be best targeting pediatric tumor biology. The ITCC-P4 co nsortium, which is a collaboration between many academic centers across Europe, several companies involved in in vivo preclinical testing, and ten pharmaceutical companies, started in 2017 with the overall aim to establish a sustainable platform of >400 molecularly well-characterized PDX models of high-risk pediatric cancers and to use them for in vivo testing of novel mechanism-of-action based treatments. Currently, 340 models have been fully established, including 87 brain tumor models and 253 non-brain tumor models, together representing many different tumor types both from primary and relapsed/metastatic disease. Out of these 340 models, 252 have been fully molecularly characterized, most of them together with their matching original tumors, and almost of all these models are currently being subjected to in vivo testing using three standard of care drugs and six novel mechanism-of-action based drugs. In this presentation, an update on the current status of the ITCC-P4 platfor m and the data we collectively have generated thus far will be presented.
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FULL ISPNO 2022 ABSTRACTS PDF

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LTBK-06. Memantine increases dendritic arborization and integration of immature neurons after cranial irradiation

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Abstract
Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. It is used in the clinical setting in the treatment of Alzheimer's disease and dementias and has been shown to enhance cognition in post-IR cancer survivors. Nevertheless, while an improvement in synaptic plasticity has been documented in association to hippocampal neurogenesis, the exact mechanisms underlying Mem's actions are yet poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippoca mpal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water to obtain a steady-state plasma concentration of the drug. Animals were then sacrificed at different time points and the brains harvested for immunohistochemical staining, bulk-RNA sequencing and electrophysiological studies. Sholl analysis of the morphological data of the new-born neurons of Mem treated animals showed a statistically significant increase in coverage area (500µm2 vs. 250µm2, p= <0,0001) and number of dendrites (15 vs. 5, p= <0,0001) compared to non-treated individuals. Preliminary analysis of the electrophysiological responses revealed no changes in the gamma oscillations in Mem treated irradiated mice. The attained results will shed light on the mechanisms of action and take steps towards establishing Mem as a neoadjuvant therapy for children undergoing IR. Ultimately, we aim to ameliorate IR-associated neurocognitive impairment and improve the quality of life of pediatric cancer survivors.
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Temporomandibular disorders, bite force and osseous changes of the temporomandibular joints in patients with hypermobile Ehlers‐Danlos Syndrome compared to a healthy control group

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SUMMARY

Background

Ehlers-Danlos syndrome (EDS) is a hereditary disorder that affects the connective tissue and collagen structures in the body characterized by joint hypermobility, skin hyperextensibility and tissue fragility.

Objective

The aim was to investigate temporomandibular disorders (TMD), bite force, teeth in occlusal contact and osseous changes of the temporomandibular joints (TMJs) in 26 patients with hypermobile EDS (hEDS), differentiated by a genetic test, compared to 39 healthy controls. METHODS: Clinical examination according to Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), radiological examinations of the TMJs by cone-beam computed tomographic (CBCT) scans, registration of bite force and teeth in occlusal contact was performed. Statistical analyses included Fisher's Exact Test, multiple logistic and linear regression models adjusted for age, gender and Body Mass Index (BMI).

Results

Single symptoms and signs of TMD occurred significantly more often in hEDS (p=0.002; p=0.001; p=0.003; p=<0.0001; p=0.012) and maximum mouth opening was significantly smaller in hEDS compared to controls (p=<0.0001). The DC/TMD diagnosis myalgia, myofascial pain with referral, arthralgia, headache attributed to TMD, disc displacement disorders and degenerative joint disease occurred significantly more often in hEDS compared to controls (p=0.000; p=0.008; p=0.003; p=0.000; p=<0.0001; p=0.010, respectively). No significant differences were found in bite force and in teeth in occlusal contact between the groups (p>0.05). On CBCT of the TMJs, subcortical sclerosis occurred significantly more often in hEDS compared to controls (p=0.005).

Conclusion

Symptoms and signs of TMD and osseous changes of the TMJs occurred significantly more often in hEDS. Bite force and teeth in occlusal contact were comparable to controls.
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Biologic Agents in Plastic Surgery

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Semin Plast Surg 2022; 36: 002-002
DOI: 10.1055/s-0042-1743454



Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

Article in Thieme eJournals:
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Efficacy of dexmedetomidine on postoperative pain in patients undergoing gastric and esophageal endoscopic submucosal dissection: a study protocol for a randomized controlled prospective trial

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Endoscopic submucosal dissection (ESD) is widely used as an effective treatment of early gastric and esophageal tumors, as it is minimally invasive, safe, and convenient. Epigastric pain is a common complicati...
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Dynamic Liver Magnetic Resonance Imaging During Free Breathing: A Feasibility Study With a Motion Compensated Variable Density Radial Acquisition and a Viewsharing High-Pass Filtering Reconstruction

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imageObjective Robust dynamic contrast-enhanced T1-weighted images are crucial for accurate detection and categorization of focal liver lesions in liver/abdominal magnetic resonance imaging (MRI). As optimal dynamic imaging usually requires multiple breath-holds, its inherent susceptibility to motion artifacts frequently results in degraded image quality in incompliant patients. Because free-breathing imaging may overcome this drawback, the intention of this study was to evaluate a dynamic MRI sequence acquired during free breathing using the variable density, elliptical centric golden angle radial stack-of-stars radial sampling scheme, which so far has not been implemented in 4-dimensional applications. Materials and Methods In a prospective pilot study, 27 patients received a routine abdominal MRI protocol including the prototype free-breathing sequence (4DFreeBreathing) for dynamic imaging. This enables more convenient and faster reconstruction through variable density, elliptical centric golden angle radial stack-of-stars without the use of additional reconstruction hardware, and even higher motion robustness through soft-gating. A standard breath-hold sequence performed subsequently served as reference standard. Of the continuous dynamic data sets, each dynamic phase was analyzed regarding image quality, motion artifacts and vessel conspicuity using 5-point Likert scales. Furthermore, correct timing of the late arterial phase was compared with the preexaminations. Results 4DFreeBreathing delivered motion-free dynamic images with high temporal resolution in each subject. Overall image quality scores were rated good or excellent for 4DFreeBreathing and the gold standard without significant differences (P = 0.34). There were significantly less motion artifacts in the 4DFreeBreathing sequence (P 0.99, P = 0.22, respectively). Correct timing of the late arterial phase could be achieved in 27 of 27 (100%) examinations using 4DFreeBreathing versus 35 of 53 (66%) preexaminations using gold standard (P
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Benchmarking Feature Selection Methods in Radiomics

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imageObjectives A critical problem in radiomic studies is the high dimensionality of the datasets, which stems from small sample sizes and many generic features extracted from the volume of interest. Therefore, feature selection methods are used, which aim to remove redundant as well as irrelevant features. Because there are many feature selection algorithms, it is key to understand their performance in the context of radiomics. Materials and Methods A total of 29 feature selection algorithms and 10 classifiers were evaluated on 10 publicly available radiomic datasets. Feature selection methods were compared for training times, for the stability of the selected features, and for ranking, which measures the pairwise similarity of the methods. In addition, the predictive performance of the algorithms was measured by utilizing the area under the receiver operating characteristic curve of the best-performing classifier. Results Feature selections differed largely in training times as well as stability and similarity. No single method was able to outperform another one consistently in predictive performance. Conclusion Our results indicated that simpler methods are more stable than complex ones and do not perform worse in terms of area under the receiver operating characteristic curve. Analysis of variance, least absolute shrinkage and selection operator, and minimum redundancy, maximum relevance ensemble appear to be good choices for radiomic studies in terms of predictive performance, as they outperformed most other feature selection methods.
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Fat Quantification in Dual-Layer Detector Spectral Computed Tomography: Experimental Development and First In-Patient Validation

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imageObjectives Fat quantification by dual-energy computed tomography (DECT) provides contrast-independent objective results, for example, on hepatic steatosis or muscle quality as parameters of prognostic relevance. To date, fat quantification has only been developed and used for source-based DECT techniques as fast kVp-switching CT or dual-source CT, which require a prospective selection of the dual-energy imaging mode. It was the purpose of this study to develop a material decomposition algorithm for fat quantification in phantoms and validate it in vivo for patient liver and skeletal muscle using a dual-layer detector-based spectral CT (dlsCT), which automatically generates spectral information with every scan. Materials and Methods For this feasibility study, phantoms were created with 0%, 5%, 10%, 25%, and 40% fat and 0, 4.9, and 7.0 mg/mL iodine, respectively. Phantom scans were performed with the IQon spectral CT (Philips, the Netherlands) at 120 kV and 140 kV and 3 T magnetic resonance (MR) (Philips, the Netherlands) chemical-shift relaxometry (MRR) and MR spectroscopy (MRS). Based on maps of the photoelectric effect and Compton scattering, 3-material decomposition was done for fat, iodine, and phantom material in the image space. After written consent, 10 patients (mean age, 55 ± 18 years; 6 men) in need of a CT staging were prospectively included. All patients received contrast-enhanced abdominal dlsCT scans at 120 kV and MR imaging scans for MRR. As reference tissue for the liver and the skeletal muscle, retrospectively available non–contrast-enhanced spectral CT data sets were used. Agreement between dlsCT and MR was evaluated for the phantoms, 3 hepatic and 2 muscular regions of interest per patient by intraclass correlation coefficients (ICCs) and Bland-Altman analyses. Results The ICC was excellent in the phantoms for both 120 kV and 140 kV (dlsCT vs MRR 0.98 [95% confidence interval (CI), 0.94–0.99]; dlsCT vs MRS 0.96 [95% CI, 0.87–0.99]) and in the skeletal muscle (0.96 [95% CI, 0.89–0.98]). For log-transformed liver fat values, the ICC was moderate (0.75 [95% CI, 0.48–0.88]). Bland-Altman analysis yielded a mean difference of −0.7% (95% CI, −4.5 to 3.1) for the liver and of 0.5% (95% CI, −4.3 to 5.3) for the skeletal muscle. Interobserver and intraobserver agreement were excellent (>0.9). Conclusions Fat quantification was developed for dlsCT and agreement with MR techniques demonstrated for patient liver and muscle. Hepatic steatosis and myosteatosis can be detected in dlsCT scans from clinical routine, which retrospectively provide spectral information independent of the imaging mode.
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Homoarginine Treatment of Rats Improves Cardiac Function and Remodeling in Response to Pressure Overload

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Abstract

Background

Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms.

Objectives

This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME).

Methods

Male Wistar rats (n=136) underwent a sham operation (SH) or aortic banding (AB). Both groups were equally divided into fourteen subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME over 4 weeks.

Results

HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1·day-1. Combining 800 mg·kg-1·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p=0.0002) and fractional shortening (+41%, p=0.0014). An inverse association was observed with collagen area fraction (-41%, p<0.0001), myocyte cross-sectional area (-22%, p<0.0001) and the molecular markers atrial natriuretic factor (-74%, p=0.0091), brain natriuretic peptide (-42%, p=0.0298), beta-myosin heavy chain (-46%, p=0.0411), and collagen type V alpha 1 chain (-73%, p=0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB.

Conclusion

HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.
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