Algorithm for dermocosmetic use in the management of cutaneous side-effects associated with targeted therapy in oncology.

Currently, numerous patients who receive targeted chemotherapy for cancer suffer from disabling skin reactions due to cutaneous toxicity, which is a significant problem for an increasing number of patients and their treating physicians. In addition, using inappropriate personal hygiene products often worsens these otherwise manageable side-effects. Cosmetic products for personal hygiene and lesion camouflage are part of a patients' well-being and an increasing number of physicians feel that they do not have adequate information to provide effective advice on concomitant cosmetic therapy. Although ample information is available in the literature on pharmaceutical treatment for cutaneous side-effects of chemotherapy, little is available for the concomitant use of dermatological skin-care products with medical treatments. The objective of this consensus study is to provide an algorithm for the appropriate use of dermatological cosmetics in the management of cutaneous toxicities associated with targeted chemotherapy such as epidermal growth factor receptor inhibitors and other monoclonal antibodies. These guidelines were developed by a French and German expert group of dermatologists and an oncologist for oncologists and primary care physicians who manage oncology patients. The information in this report is based on published data and the expert group's opinion. Due to the current lack of clinical evidence, only a review of published recommendations including suggestions for concomitant cosmetic use was conducted.

[An investigational study of acne treatment in France]. / Enquête sur la prise en charge des patients acnéiques en France.

BACKGROUND: Acne is one of the main reasons for dermatological consultation. Management may seem standardized, in particular for mild to moderate juvenile facial acne, where topical treatments are used for mild cases and topical treatments associated with systemic antibiotics are used for moderate cases. The aim of this investigational study was to evaluate current treatment approaches for mild to moderate acne patients by French dermatologists in private practice. METHODS: During this study, more than 252 dermatologists practising in over 144 French cities were asked about their preferred treatments (other than isotretinoin) for young acne patients. A questionnaire containing information about patient characteristics, disease severity and the prescribed therapy was completed by dermatologists at baseline and 2 months later. RESULTS: In total, 3145 acne patients were analyzed. This study showed that in 53% of cases, dermatologists prescribed several topical treatments (up to three) associated with one or several systemic therapies (up to three), in addition to a cosmetic product. In 51% of cases, dermatologists prescribed only application of a dermatological cosmetic product for patients with very mild acne; in 41% of cases, a single treatment, especially a topical treatment, was prescribed for patients with mild acne, and in 59 and 64% of cases, two treatments (a combination of local and systemic therapy) were prescribed respectively for patients with moderate and severe acne. CONCLUSION: This study demonstrated the complexity of management of acne patients by dermatologists, particularly in the case of mild to severe acne. Most notably, such therapeutic complexity raises the question of compliance, a key factor in successful treatment.

Importance of treatment of skin xerosis in diabetes.

BACKGROUND: Cutaneous complications are common in diabetes patients and previous studies have shown that diabetes can affect some biophysical skin characteristics. However, the interest of emollients in diabetes has never been clearly demonstrated; i.e. whether they are able to limit skin complications in diabetes patients. OBJECTIVE: The aim of this study was to evaluate the tolerance and the effect of an emollient on patient with diabetes. METHOD: Forty patients with diabetes applied the emollient twice daily for 1 month on one arm and one leg, in normal conditions. RESULTS: A 1-month treatment with an emollient allows a similar skin hydration rate in diabetics to that in healthy people. This dry skin improvement is accompanied by a significant reduction in pruritus and desquamation, and a significant improvement in the skin barrier function. CONCLUSION: Emollient treatment can be useful in the management of diabetes by limiting skin complications associated with elevated blood sugar.

Photoprotection in moisturizers and daily-care products.

During usual daily activities, an appropriate protection against solar UV exposure should prevent clinical, cellular and molecular changes potentially leading to photoaging. In skin areas regularly exposed to sun, UV-damage is superimposed to tissue degeneration resulting from chronological aging. It is, therefore, important to know if moisturizers and daily-care products containing UVA absorbers combined with UVB ones are able to prevent these skin damages. This review will summarize clinical studies evaluating this topic. These studies demonstrate that broad-spectrum protection in moisturizers or daily-care products can prevent the "silent" sub-erythemal cumulative effects of UVR from inadvertent sun exposure.

Metal hydrides for lithium-ion batteries.

Classical electrodes for Li-ion technology operate via an insertion/de-insertion process. Recently, conversion electrodes have shown the capability of greater capacity, but have so far suffered from a marked hysteresis in voltage between charge and discharge, leading to poor energy efficiency and voltages. Here, we present the electrochemical reactivity of MgH(2) with Li that constitutes the first use of a metal-hydride electrode for Li-ion batteries. The MgH(2) electrode shows a large, reversible capacity of 1,480 mAh g(-1) at an average voltage of 0.5 V versus Li(+)/Li(o) which is suitable for the negative electrode. In addition, it shows the lowest polarization for conversion electrodes. The electrochemical reaction results in formation of a composite containing Mg embedded in a LiH matrix, which on charging converts back to MgH(2). Furthermore, the reaction is not specific to MgH(2), as other metal or intermetallic hydrides show similar reactivity towards Li. Equally promising, the reaction produces nanosized Mg and MgH(2), which show enhanced hydrogen sorption/desorption kinetics. We hope that such findings can pave the way for designing nanoscale active metal elements with applications in hydrogen storage and lithium-ion batteries.

Emollient for maintenance therapy after topical corticotherapy in mild psoriasis.

Emollients or moisturizers can act as an important adjunctive therapy of topical treatment in psoriatic patients. However, the interest of emollients has never been clearly demonstrated; i.e. are they able to improve topical treatment efficacy and/or maintain continuous remission of the disease? The aim of this study was to evaluate the effect of an emollient on patients with mild plaque psoriasis during and after standard local corticosteroid therapy. Results showed that the use of an emollient can limit relapses after the end of corticotherapy, and maintain the improvement obtained after 1 month corticotherapy at clinical level (physician global assessment) and skin dryness.

[Dual pathology]. / Les doubles pathologies.

Dual pathology is defined as the association of two potentially epileptogenic lesions, hippocampal (sclerosis, neuronal loss) and extrahippocampal (temporal or extratemporal). Epileptic activity may be generated by either lesion and the relative importance of every lesion's epileptogenicity conditions the surgical strategy adopted. Most frequently associated with hippocampal sclerosis are cortical dysplasias. The common physiopathology of the two lesions is not clearly established. Extrahippocampal lesions may be undetectable on MRI (microdysgenesis, for example) and ictal discharge patterns may vary among dual pathology patients. The surgical strategy depends on the location of the extrahippocampal lesion and its relative role in seizure generation; however, reported surgical results suggest that simultaneous resection of mesial temporal structures along with the extrahippocampal lesion should be performed.

[Epilepsy surgery in France]. / La chirurgie de l'épilepsie en France Evaluation de l'activité

We report here the results of the first survey on epilepsy surgery activity in France. Data from a questionnaire sent to 17 centers practicing epilepsy surgery were analyzed. All centers responded; however, all items were not completely documented. Over 50 years, more than 5000 patients have been operated on for drug-resistant epilepsy and more than 3000 patients underwent some invasive monitoring, most often SEEG. Currently, nearly 400 patients (including more than 100 children) are operated on yearly for epilepsy in France. Over a study period varying among centers (from two to 20 years; mean, 9.5 years), results from more than 2000 patients including one-third children were analyzed. Important differences between adults and children, respectively, were observed in terms of location (temporal: 72% versus 4.3%; frontal: 12% versus 28%; central: 2% versus 11%), etiology (hippocampal sclerosis: 41% versus 2%; tumors 20% versus 61%); and procedures (cortectomy: 50% versus 23%; lesionectomy: 8% versus 59%), although overall results were identical (seizure-free rates following temporal lobe surgery: 80.6% versus 79%; following extratemporal surgery: 65.9% versus 65%). In adults, the best results were observed following temporomesial (TM) resection associated with hippocampal sclerosis or other lesions (class I: 83% and 79%, respectively), temporal neocortical (TNC) lesional (82%), while resections for cryptogenic temporal resections were followed by 69% (TM) and 63% (TNC) class I outcome. Extratemporal lesional resections were associated with 71% class I outcome and cryptogenic 43%. In children, the best results were obtained in tumor-associated epilepsy regardless of location (class I: 80%). A surgical complication occurred in 8% after resective surgery - with only 2.5% permanent morbidity - and 4.3% after invasive monitoring (mostly hemorrhagic). Overall results obtained by epilepsy surgery centers were in the higher range of those reported in the literature, along with a low rate of major surgical complications. Growing interest for epilepsy surgery is clearly demonstrated in this survey and supports further development to better satisfy the population's needs, particularly children. Activity should be further evaluated, while existing epilepsy surgery centers as well as healthcare networks should be expanded.

[Medicoeconomic assessment of epilepsy surgery in adults with medically intractable partial epilepsy. Three-year outcomes from a multicenter French cohort]. / Evaluation médicoéconomique de la chirurgie des épilepsies partielles pharmacorésistantes de l'adulte. Résultats à trois ans d'une étude prospective multicentrique française.

PURPOSE: To compare resective surgery and medical therapy in a cost-effectiveness analysis in a multicenter cohort of adult patients with partial intractable epilepsy. POPULATION AND METHODS: Adult patients with partial, medically intractable, potentially operable epilepsy were eligible and followed every year over five years. Effectiveness was defined as one year without seizure. The long-term costs and effectiveness were extrapolated over the patients' lifetime with a Markov model. Productivity (indirect costs) and quality of life (QOLIE-31, SEALS) were also assessed. Changes before and after surgery were compared between the two groups. RESULTS: Two hundred and eighty-nine patients were included (119 with surgery, 161 medically treated, six not eligible, three lost to follow-up). One year after surgery, 81% of the patients were seizure-free; at two and three years, this rate was 78%. In the medical group, these rates were 10, 18, and 15%, respectively. The cost of the explorations was euro 8464; including surgery, it was euro 19,700. In the medical group, the average annual direct costs were between 3500 and euro 6000. At two years after surgery, the annual direct cost decreased to euro 2768, at three years, it was euro 1233, predominately antiepileptic drug costs. Surgery became cost-effective between seven and eight years. In the surgical group, all the quality-of-life scores improved at one year after surgery and were stable during the second and third years. CONCLUSION: Surgical therapy was cost-effective at the middle term even though indirect costs were not considered.

Side-effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors.

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

Patterns of dentate granule cell responses to perforant path stimulation in epileptic mice with granule cell dispersion.

In adult mice, intrahippocampal administration of kainic acid induces a structural modification of the granule cell layer reminiscent of granule cell dispersion (GCD) seen in humans with temporal lobe epilepsy. We tested that GCD might be involved in the patterns of granule cell responses to perforant path stimulation by recording field potentials in vivo after kainic acid-induced status epilepticus until the phase of chronic seizure activity in presence of GCD or after its alteration by K252a co-treatment, an inhibitor of tyrosine kinase activities. Stimulation triggered bursts of multiple population spikes, the number of which progressively increased with time whereas their amplitude decreased in parallel with the progressive decrease in granule cell density. The population spike threshold was reached for a lower excitatory synaptic drive than in controls, as assessed by the initial slope of the field excitatory post-synaptic potential. This indicates that, for identical synaptic responses, granule cells were closer to the firing threshold. Fast inhibition, assessed by paired pulse stimulation, was compromised immediately after the initial status epilepticus, consistent with the rapid loss of most hilar cells. Neither the epileptic course nor the epileptiform responses of the granule cells were modified and manipulation by alteration following GCD manipulation while granule cell neuropeptide-Y immunostaining was substantially decreased. In this mouse model of TLE, granule cells display a progressive increase in epileptiform responses to afferent input until the occurrence of spontaneous seizures. The population spike amplitude decreases in parallel with GCD while the granule cell excitability is enhanced. Consequently, data from field potentials in epilepsy experiments should be interpreted with care, taking into account the possible variations in the neuronal density in the recorded area.

[Extra-hippocampal temporal lesions inducing symptomatic drug-resistant epilepsies. Which surgical procedure?]. / Epilepsie temporale pharmaco-résistante symptomatique d'une lésion temporale extra-hippocampique. Quelle stratégie chirurgicale?

In partial symptomatic epilepsy due to discrete brain lesion, total removal of the epileptogenic lesion generally yields major reduction of seizures, achieved in 85% of the patients. However, prognosis is worse in patients with symptomatic temporal lobe epilepsy. Implication of the temporo-mesial structures in the seizures genesis is generally considered. Careful electroclinical and radiological analysis can provide useful but insufficient information. In order to evaluate the criteria we used to guide our surgical strategy, we analyzed retrospectively a series of 47 patients with drug-resistant symptomatic extra hipocampic temporal epilepsy surgically treated either by isolated lesionectomy (group 1, n=17) or by resection of temporo-mesial structures and associated lesionectomy (group 2, n=30). Patients with extrahippocampal lesions and hippocampal sclerosis (dual pathology) were excluded from this study. With a mean follow-up of 72 months, overall results showed that 84% of group 2 patients (Engel's grade Ia) were seizure-free compared with only 47% of group 1 patients. Statistical analysis showed that the type of surgical procedure was the main prognostic factor. In conclusion, the optimal surgical procedure cannot be defined only with the criteria usually retained for temporo-mesial involvement in seizure genesis. Taking into account the prognostic value of such implication, although complex, is of paramount importance. Our results could be explained by the presence of an acquired dual functional pathology.

The measurement of the stratum corneum reservoir. A predictive method for in vivo percutaneous absorption studies: influence of application time.

The relation existing in vivo between the reservoir function of the stratum corneum following a 30-min application time and the total percutaneous absorption of molecules applied for a longer time was studied on hairless rats. One thousand nanomoles of 4 radiolabeled molecules (theophylline, nicotinic acid, acetyl salicylic acid, benzoic acid) were applied on 1 cm2 of back skin for 0.5, 2, 4, and 6 h. The total recovery in excreta and the whole animal body were measured 4 days later in order to determine the level of absorption. A direct proportionality (r = 0.99) between the total percutaneous absorption of these compounds and the duration of their application was observed. This suggests that a constant flux of penetration does exist in vivo. The reservoir function of the stratum corneum was measured by successive stripping of the treated area. Following a 30-min application, a strict correlation (r = 0.99) between the total amounts of molecules penetrated in 4 days and the amounts found in the reservoir of the horny layer was demonstrated. All together these findings show that the simple knowledge of the reservoir effect of the stratum corneum for a molecule applied for 30 min allows the predictive assessment of its total penetration resulting from various times of application.

The hairless rat: a relevant animal model to predict in vivo percutaneous absorption in humans?

Percutaneous absorption of 4 radiolabeled molecules was compared in the hairless rat (back) and in different anatomic sites in human (arm, abdomen, postauricular, forehead). The conditions under which these 4 compounds were administered (area treated, dose, vehicle, contact time, etc.) were similar in both species. The results showed that, in humans and rats, there exists the same rank order in total absorption: benzoic acid sodium salt less than caffeine less than benzoic acid less than acetylsalicylic acid. In both species there was a factor of 3 between the most and the least absorbed molecule. Although skin permeability varied significantly with the physicochemical nature of the compound administered, it also depended on the anatomic site involved. Independent of the molecule studied, the rank order of permeability of the sites tested in humans appeared as follows: arm less than or equal to abdomen less than postauricular less than forehead. There was a factor of 3 between the most and the least permeable sites. For each molecule and each anatomic site, the ratios of total percutaneous absorption human/hairless rat (back) were determined. For a given anatomic site and whatever the molecule tested, these ratios were constant. It thus appears that when conditions are carefully controlled, it may be possible, by measurements on animals, to predict the absorption of a compound in humans. Further experimentation with chemicals of varied physicochemical properties will be required for validation of the model.

In vivo correlation between stratum corneum reservoir function and percutaneous absorption.

A relationship between stratum corneum reservoir function and percutaneous absorption has been established in the hairless rat. Two hundred nanomoles of 10 substances that have a wide range of chemical structures were topically applied for 30 min and the total body distribution was measured after 96 h. The quantity of substance present in the stratum corneum reservoir after 30-min application was measured by liquid scintillation counting after tape-stripping the treated area. A linear relationship exists between the quantity of substance in this reservoir x(nmol X cm-2) and the total amount of radioactivity distributed in the body and excreta y(nmol X cm-2) after 96 h. The relationship is given by: y = 1.644 X x - 0.536 (r = 0.998, p less than 0.001). Apart from the steroids, 80-95% of the compounds were excreted in the urine; and with the exception of thiourea, this elimination was rapid, especially for mannitol and benzoic acid. We confirmed that in terms of penetration there is a factor of 50 between benzoic acid (best) and dexamethasone (worst). Thus the quantity of substance penetrating through intact rat skin can be predicted by measuring the horny layer concentration. The animal data reported here should be verified in humans.

In vivo relationship between horny layer reservoir effect and percutaneous absorption in human and rat.

The in vivo relationship between the reservoir effect of the stratum corneum and the percutaneous absorption was established in both human volunteers and hairless rats. Four doses of [ring-14C]benzoic acid, 125, 250, 500, and 1000 nmol, were applied on 1 cm2 either on the external side of the human arm or on the back of the rat, for 30 min. In both human and rat, the data on percutaneous absorption after 4 days is directly related to the dose administered. In rat, the permeability to benzoic acid is twice that of the human skin and the reservoir effect of the stratum corneum, measured at the end of application (30 min), is also doubled for this molecule in rat. Taking into account these findings and the observed histologic differences between the treated areas of these two species, the molecular reservoir of the horny layer may well be situated within the interlayer spaces. For both species, a linear relationship exists between (x), the amount of substance present in the stratum corneum at the end of application (30 min), and (y), the total amount penetrated in 4 days. The relationship, similar to that obtained in an earlier study on rat with 10 molecules, may be written as follows: y = 1.83 x - 0.52 (r = 0.998, p less than 0.001). Thus the amount of substance liable to penetrate through human skin within 4 days can be predicted by measuring the amount present in the stratum corneum 30 min after application of the drug.

Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase 1 in the human dermis.

Ascorbic acid (vitamin C) is a cofactor required for the function of several hydroxylases and monooxygenases. It is not synthesized in humans and some other animal species and has to be provided by diet or pharmacologic means. Its absence is responsible for scurvy, a condition related in its initial phases to a defective synthesis of collagen by the reduced function of prolylhydroxylase and production of collagen polypeptides lacking hydroxyproline, therefore, they are unable to assemble into stable triple-helical collagen molecules. In fibroblast cultures, vitamin C also stimulates collagen production by increasing the steady-state level of mRNA of collagen types I and III through enhanced transcription and prolonged half-life of the transcripts. The aim of the experimental work has been to evaluate the effect on dermal cells of a preparation of vitamin C topically applied on one side vs placebo on the other side of the dorsal face of the upper forearm of postmenopausal women. Biopsies were collected on both sides and the level of mRNA measured by non competitive reverse transcription-polymerase chain reaction made quantitative by the simultaneous transcription and amplification of synthetic RNA used as internal standards. The mRNA of collagen type I and type III were increased to a similar extent by vitamin C and that of three post-translational enzymes, the carboxy- and amino-procollagen proteinases and lysyloxidase similarly increased. The mRNA of decorin was also stimulated, but elastin, and fibrillin 1 and 2 were not modified by the vitamin. The expression of matrix metalloproteinases 1, 2, and 9 was not significantly changed, but an increased level of tissue inhibitor of matrix metalloproteinase 1 mRNA was observed without modification of tissue inhibitor of matrix metalloproteinase 2 mRNA. The stimulating activity of topical vitamin C was most conspicuous in the women with the lowest dietary intake of the vitamin and unrelated to the level of actinic damage. The results indicate that the functional activity of the dermal cells is not maximal in postmenopausal women and can be increased.

Minimal tissue damage after stimulation of the motor thalamus in a case of chorea-acanthocytosis.

Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus. Postoperative testing showed a progressive improvement in axial truncal spasms. Although relatively high currents were used for 2 years in this patient, postmortem analysis showed minimal tissue damage in the vicinity of the electrode tip. It is concluded that DBS has little impact on the surrounding tissues.

Exploration of hemispheric specialization and lexico-semantic processing in unilateral temporal lobe epilepsy with verbal fluency tasks.

Verbal production has been shown to rely on both hemispheres differentially. To determine how lateralized brain lesions affect the generation of isolated words, we evaluated three subject groups: normal controls (n=22), and patients with right (n=23), and left (n=22) non-operated temporal lobe epilepsy (TLE) using three verbal fluency tasks (letter, phonetic, semantic). LTLE patients produced fewer words than controls in the phonetic, letter, semantic conditions, whereas RTLE patients were only impaired in the semantic task. Hence, there would be a hemispheric specialization in language where phonetic processing involves mostly the left temporal lobe and semantic aspects of production involve both temporal lobes. And, in order to study disruption of semantic lexicon involved in supermarket fluency (to name things which can be bought in a supermarket), specific indicators Tröster et al., (1998) [Tröster AI, Fields JA, Testa JA, Paul RH, Blanco CR, Hames KA, Salmon DP, Beatty WW. Cortical and subcortical influences on clustering and switching in the performance of verbal fluency Tasks, Neuropsychologia 1998;36:295-304.] were exploited. Our results indicated that TLE groups made fewer category shifts than controls. Also, RTLE patients used labels more frequently and produced fewer exemplars. Results show the specificity of processing according to cue, and suggest that the semantic fluency deficits due to TLE be primarily due to an alteration of the mental lexicon.

Effects of temporal versus temporal plus extra-temporal lobe epilepsies on hippocampal ERPs: physiopathological implications for recognition memory studies in humans.

The present experiment was designed to investigate the incidence of temporal and extra-temporal epileptogenic lesions on hippocampal activity related to recognition memory. Hippocampal event-related potentials (ERPs) were recorded during a recognition memory task for pictures in patients with unilateral temporal lobe epilepsy and in patients with combined temporal and extra-temporal (frontal or parietal) epileptogenic foci. In the first group, the comparison between correctly recognized pictures and new distractors revealed that the usual ERP (N400/P600) 'old/new' effects were not dramatically affected by the presence of a temporal epileptogenic lesion. In contrast, these effects were absent in multifocal epilepsy patients, indicating that frontal and parietal brain regions play a part in the modulation of hippocampal ERP and related memory processing. These results suggest that ERP 'old/new' effects are dependent on interactions between frontal, parietal and medial temporal structures. Together with the results of other recent studies devoted to locating the neural sources of N400 and P600, the present findings provide physiopathological evidence that ERP 'old/new' effects are subtended by distributed yet interconnected brain regions that are known to play an important role in recognition memory processing.