Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.

BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.

Integration of free-hand 3D ultrasound and mobile C-arm cone-beam CT: Feasibility and characterization for real-time guidance of needle insertion.

This work presents development of an integrated ultrasound (US)-cone-beam CT (CBCT) system for image-guided needle interventions, combining a low-cost ultrasound system (Interson VC 7.5MHz, Pleasanton, CA) with a mobile C-arm for fluoroscopy and CBCT via use of a surgical tracker. Imaging performance of the ultrasound system was characterized in terms of depth-dependent contrast-to-noise ratio (CNR) and spatial resolution. US-CBCT system was evaluated in phantom studies simulating three needle-based procedures: drug delivery, tumor ablation, and lumbar puncture. Low-cost ultrasound provided flexibility but exhibited modest CNR and spatial resolution that is likely limited to fairly superficial applications within a ∼10cm depth of view. Needle tip localization demonstrated target registration error 2.1-3.0mm using fiducial-based registration.

Feasibility of integrating a multi-camera optical tracking system in intra-operative electron radiation therapy scenarios.

Intra-operative electron radiation therapy (IOERT) combines surgery and ionizing radiation applied directly to an exposed unresected tumour mass or to a post-resection tumour bed. The radiation is collimated and conducted by a specific applicator docked to the linear accelerator. The dose distribution in tissues to be irradiated and in organs at risk can be planned through a pre-operative computed tomography (CT) study. However, surgical retraction of structures and resection of a tumour affecting normal tissues significantly modify the patient's geometry. Therefore, the treatment parameters (applicator dimension, pose (position and orientation), bevel angle, and beam energy) may require the original IOERT treatment plan to be modified depending on the actual surgical scenario. We propose the use of a multi-camera optical tracking system to reliably record the actual pose of the IOERT applicator in relation to the patient's anatomy in an environment prone to occlusion problems. This information can be integrated in the radio-surgical treatment planning system in order to generate a real-time accurate description of the IOERT scenario. We assessed the accuracy of the applicator pose by performing a phantom-based study that resembled three real clinical IOERT scenarios. The error obtained (2 mm) was below the acceptance threshold for external radiotherapy practice, thus encouraging future implementation of this approach in real clinical IOERT scenarios.

Intraoperative radiotherapy with electrons: fundamentals, results, and innovation.

RATIONALE AND OBJECTIVES: To analyse the programme activity and clinical innovation and/or technology developed over a period of 17 years with regard to the introduction and the use of intraoperative radiotherapy (IORT) as a therapeutic component in a medical-surgical multidisciplinary cancer hospital. MATERIAL AND METHODS: To standardise and record this procedure, the Radiation Oncology service has an institutional programme and protocols that must be completed by the different specialists involved. For 17 years, IORT procedures were recorded on a specific database that includes 23 variables with information recorded on institutional protocols. As part of the development and innovation activity, two technological tools were implemented (RADIANCE and MEDTING) in line with the standardisation of this modality in clinical practice. RESULTS: During the 17 years studied, 1,004 patients were treated through 1,036 IORT procedures. The state of the disease at the time of IORT was 77% primary and 23% recurrent. The origin and distribution of cancers were 62% gastrointestinal, 18% sarcomas, 5% pancreatic, 2% paediatric, 3% breast, 7% less common locations, and 2% others. The research and development projects have generated a patent on virtual planning (RADIANCE) and proof of concept to explore as a professional social network (MEDTING). During 2012, there were 69 IORT procedures. There was defined treatment volume (target or target region) in all of them, and 43 were conducted by the virtual planning RADIANCE system. Eighteen have been registered on the platform MEDTING as clinical cases. CONCLUSION: The IORT programme, developed in a university hospital with an academic tradition, and interdisciplinary surgical oncology, is a feasible care initiative, able to generate the necessary intense clinical activity for tending to the cancer patient. Moreover, it is a competitive source for research, development, and scientific innovation.

Research opportunities in intraoperative radiation therapy: the next decade 2013-2023.

The reality of intraoperative radiation therapy (IORT) practice is consistent with an efficient and highly precise radiation therapy technique to safely boost areas at risk for local recurrence. Long-term clinical experience has shown that IORT-containing multi-modality regimens appear to improve local disease control, if not survival in many diseases. Research with IORT is a multidisciplinary scenario that covers knowledge from radiation beam adapted development to advance molecular biology for bio-predictability of outcome. The technical parameters employed in IORT procedures are important information to be recorded for quality assurance and clinical results analysis. In addition, specific treatment planning systems for IORT procedures are available, to help in the treatment decision-making process. A systematic revision of opportunities for research and innovation in IORT is reported including radiation beam modulation, delivery, dosimetry and planning; infrastructure and treatment factors; experimental and clinical radiobiology; clinical trials, innovation and translational research development.

Postoperative infections after major heart surgery and prevention of ventilator-associated pneumonia: a one-day European prevalence study (ESGNI-008).

Few data have been published on the prevalence of postoperative infection in patients undergoing major heart surgery (MHS). The degree of compliance with standard measures used to prevent them is unknown. This study assessed the prevalence of infections, particularly ventilator-associated pneumonia (VAP), in patients undergoing MHS in 42 institutions from 13 European countries. On the study day, there were 321 postoperative MHS patients, of whom 164 (51%) were mechanically ventilated. The overall prevalence of infection was 26.8%. Lower respiratory tract infections represented 57% of all the infections present on the study day. Other infections included intravenous-catheter-related bloodstream infections (2.8%), surgical site infections (2.2%), urinary tract infections (0.9%) and postoperative mediastinitis (0.9%). Of the mechanically ventilated patients, 55 (33.5%) were not being nursed in a semi-recumbent position, 36 (22%) had heat-moisture exchangers with no antibacterial filters, and intracuff pressure was not monitored in 78 patients (47.6%). Only 13 patients (8%) were given continuous subglottic suctioning, 64 patients (39%) did not receive postural oscillation, and gastric overdistension was not actively prevented in 23 patients (14%). In conclusion, these data from intensive care units across Europe provide information on postoperative infections in an important subset of the patient population, and stress the need for active interventions to prevent VAP in patients undergoing MHS.

19. Correlation between FDG PET data and EEG dipole modeling.

Purpose: FDG-PET images and EEG dipole modelling were used to localization of interictal epileptogenic foci. A multimodality approach with the analysis of FDG-PET images, EEG dipoles and anatomical images (MRI) were applied to patients with drug-resistant epilepsy.Methods: Source location was determined using Brain Electromagnetic Source Analysis (BESA) program. The dipole location provided by BESA was then transformed into PET co-ordinates using the patient's MRI previously registered with the PET image. As a difference with other methods, no external markers are necessary.Results: The study group includes ten drug-resistant epileptic patients. FDG hypometabolism was found in all patients. Abnormalities in glucose uptake were always ipsilateral to the EEG dipole. However, quantitative analysis of FDG-PET within hypometabolic areas showed no significant correlation between decrease glucose uptake and location of EEG-dipole source. The comparison of the results using both methods shows that the dipole location matches the FDG-PET hypometabolic area for all the patients. Combining the spatial localization on FDG-PET with the temporal accuracy of EEG dipole source aids in the exact localization of the epileptogenic focus.Conclusion: As a conclusion, the results show that projection of EEG dipole data onto FDG-PET may play a key role in the indication of surgery for the treatment of drug-resistant epileptic patients, provided it is simple and easy to perform.