[Neuroendocrine neoplasms : a new era to the top of multidisciplinarity !] / Néoplasies neuroendocrines : une nouvelle ère a l'apogée de la multidisciplinarité !

Neuroendocrine neoplasms are histologically defined by a common neuroendocrine cellular phenotype. These are still considered as rare tumours even though their incidence is increasing. Heterogeneity is everywhere whether in the localization of the primitive cancer, the clinical presentation, the histological classification, the prognosis, as well as in therapeutic options, which clearly justifies specialized multidisciplinary care. Heterogeneity and scarcity explain the still fragmented nature of knowledge in this domain. Thanks to an increase in incidence, a desire for standardization of classification as well as the arrival of major therapeutic advances, such as vectorized internal radiotherapy, the future of neuroendocrine neoplasia seems more than promising and exciting. In our daily clinical practice at CHU Liège, we hope to bring our stone to the building by listing as many cases as possible in national and/or international databases, by centralizing therapeutic discussions within specific multidisciplinary concertations and by participating in multicenter study protocols.

Les néoplasies neuroendocrines sont définies histologiquement par un phénotype cellulaire neuroendocrine commun. Ces néoplasies sont toujours considérées comme des tumeurs rares, bien que leur incidence soit en constante augmentation. L'hétérogénéité est omniprésente, que ce soit dans la localisation du cancer primitif, la présentation clinique, la classification histologique, le pronostic ainsi que dans les diverses options thérapeutiques, justifiant impérativement une prise en charge pluridisciplinaire spécialisée. Cette hétérogénéité et cette rareté expliquent que les connaissances soient parcellaires. Grâce à une majoration d'incidence, une volonté d'uniformisation de classification ainsi que l'arrivée d'avancées thérapeutiques majeures, telles que la radiothérapie interne vectorisée, l'avenir des néoplasies neuroendocrines semble plus que prometteur et palpitant. En pratique clinique quotidienne au CHU de Liège, nous espérons apporter notre pierre à l'édifice en recensant un maximum de cas dans des bases de données nationales et/ou internationales, en centralisant les discussions thérapeutiques au sein de concertations multidisciplinaires dédiées et en participant à des protocoles d'études cliniques multicentriques.

[Multidisciplinary management of the primary liver cancers]. / Prise en charge multidisciplinaire des tumeurs malignes primitives du foie.

In Belgium and around the world, the incidence of primary malignant liver tumours is increasing, both for hepatocarcinoma and cholangiocarcinoma. Their curative treatment is based on multidisciplinary and specialized care, of which surgery (including liver transplantation) remains the cornerstone, often associated with other logoregional treatments, as radioembolisation, radiofrequency ablation, and chemoembolisation. For advanced cases, the prognosis remains poor, in particular due to a certain chemoresistance of these tumours. New treatments include targeted therapies (including various tyrosine kinase inhibitors) and immunotherapy. A specialized multidisciplinary discussion is therefore necessary to define the best therapeutic management, individualized to each patient. In this article, the authors review the most recent data relating to the treatment of hepatocarcinoma and cholangiocarcinoma.

En Belgique et dans le monde, l'incidence des tumeurs malignes primitives du foie augmente, tant pour l'hépatocarcinome que le cholangiocarcinome. Leur traitement curatif repose sur une prise en charge multidisciplinaire et spécialisée, dont la chirurgie (incluant la transplantation hépatique) reste la pièce angulaire, souvent associée à d'autres traitements logo-régionaux (radioembolisation, radiofréquence, chimio-embolisation). Pour les cas avancés, le pronostic reste sombre, notamment en raison d'une certaine chimiorésistance de ces tumeurs. Les nouvelles prises en charge incluent des thérapies ciblées (notamment, divers inhibiteurs de tyrosine kinase) et de l'immunothérapie. Une discussion pluridisciplinaire spécialisée est donc nécessaire pour définir la meilleure prise en charge thérapeutique, individualisée pour chaque patient. Dans cet article, les auteurs revoient les données récentes relatives au traitement de l'hépatocarcinome et du cholangiocarcinome.

Mechanisms of a phosphorothioate oligonucleotide delivery by skin electroporation.

Skin electroporation has great potential for topical delivery of oligonucleotides. Controled therapeutic levels of an intact phosphorothioate oligonucleotide (PS) can be reached in the viable tissue of the skin. The aim of this work was to investigate the transport mechanisms of a PS in hairless rat skin by electroporation, and hence to allow optimization of oligonucleotides (ONs) topical delivery. The pulsing condition used was five exponentially-decaying pulses of 100 V and 500 ms pulse time. The main mechanism of PS transport in the skin viable tissues during pulsing was electrophoresis. The electroosmosis contribution was negligible. Electrophoresis created within minutes a reservoir of PS in the skin viable tissues, which persisted within a therapeutic range of hours. A strong PS/stratum corneum interaction occurred.

Effects of iontophoresis and electroporation on the stratum corneum. Review of the biophysical studies.

This review focuses on the effects induced by iontophoresis and electroporation on the stratum corneum of the skin. Hence, the aims were: (1) to contribute to the understanding of the mechanisms of drug transport by these methods; (2) to evaluate the safety issues associated with current application. Complementary biophysical methods were used to provide a complete picture of the stratum corneum. Even though the mechanism of drug transport is believed to be different, i.e., electrophoresis for iontophoresis and creation of new aqueous pathways for electroporation, the effects on the stratum corneum detected minutes after current application are very similar. For both methods, the major findings were: (1) a disorganisation of the lipid bilayers of the stratum corneum; (2) an increase in skin hydration; (3) a larger decrease in skin resistance induced by electroporation as compared to iontophoresis. These changes were partly reversible and depended on the amount of electrical charges transferred. The mechanisms of stratum corneum perturbations are discussed. These perturbations could explain partly the increase in drug transport. If iontophoresis is considered as a safe method of drug delivery, the data augurs for the safety of electroporation.

Transdermal alniditan delivery by skin electroporation.

The aim of this study was to evaluate the transdermal permeation of alniditan by electroporation and to compare with iontophoretic delivery. The influence of the electrical parameters of electroporation was investigated in vitro using a factorial design study. The transdermal flux of alniditan was enhanced by two orders of magnitude by application of high voltage electrical pulses. The electrical parameters of electroporation-i.e. the voltage, the duration and the number of pulses-allowed a control of drug permeation. Both transport during and after pulsing were shown to be important for alniditan transdermal delivery by electroporation. Electroporation was found more efficient in promoting alniditan permeation than an iontophoresis transferring the same amount of charges.

Electroperturbation of human stratum corneum fine structure by high voltage pulses: a freeze-fracture electron microscopy and differential thermal analysis study.

Application of high voltage pulses (HVP) to the skin has been shown to promote the transdermal drug delivery by a mechanism involving skin electroporation. The aim of this study was to detect potential changes in lipid phase and ultrastructure induced in human stratum corneum by various HVP protocols, using differential thermal analysis and freeze-fracture electron microscopy. Due to the time involved between the moment the electric field is switched off and the analysis, only "secondary" phenomena rather than primary events could be observed. A decrease in enthalpies for the phase transitions observed at 70 degrees C and 85 degrees C was detected by differential thermal analysis after HVP treatment. No changes in transition temperature could be seen. The freeze-fracture electron microscopy study revealed a dramatic perturbation of the lamellar ordering of the intercellular lipid after application of HVP. Most of the planes displayed rough surfaces. The lipid lamellae exhibited rounded off steps or a vanished stepwise order. There was no evidence for perturbation of the corneocytes content. In conclusion, the freeze-fracture electron microscopy and differential thermal analysis studies suggest that HVP application induces a general perturbation of the stratum corneum lipid ultrastructure.

In vivo noninvasive evaluation of hairless rat skin after high-voltage pulse exposure.

Short high-voltage pulses have recently been shown to dramatically increase and expedite transdermal drug transport via a mechanism hypothesized to involve electroporation. This study addresses tolerance issues of the method in vivo in hairless rat. Chromametry, transepidermal water loss (TEWL), laser Doppler flowmetry (LDF) and corneometry were jointly used for noninvasive sensing of skin biophysical parameters. Slight increases in skin redness, TEWL and LDF values followed the application of electric pulses. The changes in skin capacitance were nonsignificant. The magnitude of the alterations depended on the electrical features of the pulses. When compared to iontophoresis, high-voltage pulses did not induce stronger alterations of skin functions. This report provides the first in vivo demonstration of the safety of the high-voltage pulses proposed for transdermal delivery.

In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers.

Theoretically, a positive relation is expected between skin temperature and the percutaneous penetration of topically applied substances. The aim of the present study was to evaluate the influence of the temperature on the in vitro percutaneous penetration of dihydrotestosterone. Hairless rat skin was mounted in static diffusion cells placed in a water bath at different temperatures (28.6, 35.1 and 38.2 degrees C, respectively). Different vehicles were tested as well as the addition of penetration promoting molecules such as oleic acid and limonene. A saline buffer was used as the receptor phase. Penetration through the skin was evaluated by means of scintillation counting of the radiolabelled dihydrotestosterone. Experiments were followed for a period of 29 h. The total amount of penetrant, dihydrotestosterone, as well as the flux, were calculated from these kinetics. Our results demonstrate a temperature effect with the highest penetration at 38.2 degrees C. The vehicle was also found to influence the penetration of dihydrotestosterone in a significant way. Furthermore, limonene presented better penetration promoting properties compared with oleic acid.

Transdermal permeation of alniditan by iontophoresis: in vitro optimization and human pharmacokinetic data.

PURPOSE: The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT1D agonist for the treatment of migraine. METHODS: An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. RESULTS: i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin. ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. CONCLUSIONS: This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.