Squamous cell carcinoma of the breast, are there two entities with distinct prognosis? A series of 39 patients.

PURPOSE: Squamous cell carcinoma (SCC) of the breast is a rare entity of breast cancer, with a very poor prognosis, and whose pathophysiology is still unwell established. Therapeutic management is very heterogeneous due to its incomplete understanding. Nevertheless, it seems that two histological entities can be distinguished: pure SCC close to the cutaneous origin, and metaplastic squamous breast cancer (MSBC). The aim of this study is therefore to assess the difference in survival according to the histological type (SCC or MSBC) and to describe the demographic, clinical, and therapeutic characteristics of the two underlying populations. METHODS: Our data came from a monocentric retrospective series of 39 patients treated between 1985 and 2018 at the Gustave Roussy Institute (France) for a breast SCC. RESULTS: Of the 39 patients included, 64% had MSBC and 36% had a pure form. The overall and recurrence-free survival at 3 years [CI 95%] was 72.3% [56.9%; 87.0%] and 67.2% [51.2%; 83.2%], respectively. The overall 3-year survival of patients with MSBC was significantly lower than that with pure SCC: HR [CI 95%] 9.5 [1.2; 73.1], p = 0.008. The 3-year recurrence-free survival of patients with MSBC was also poorer: HR [CI 95%] 11.9 [1.6; 90.7], p = 0.002. Patients with MSBC also tended to be younger, have a large lesion size, and be more metastatic. CONCLUSION: The histological nature of SCC seems to bring fundamental new elements to the therapeutic management as it impacts recurrence and survival. It should therefore be better characterized at diagnosis in order to possibly adapt treatments.

Innovative drug vehicle for local treatment of inflammatory skin diseases: Ex vivo and in vivo screening of five topical formulations containing poly(lactic acid) (PLA) nanoparticles.

One of the main goals in the galenic development of innovative topical treatment options for inflammatory skin diseases such as psoriasis and atopic dermatitis is to selectively deliver the drug at the inflammation site. Recent studies have highlighted the beneficial use of polymeric nanoparticles for anti-inflammatory therapy and topical anti-inflammatory drug delivery due to their ability to form a drug reservoir retaining the drug locally at the site of action. Our approach consisted in designing innovative topical semi-solid formulations of poly(lactic acid) (PLA) nanoparticles as anti-inflammatory drug vehicles for local treatment of inflammatory skin diseases. In the course of this work, five topical formulations containing fluorescent PLA nanoparticles were initially developed, and then screened depending on their physico-chemical properties, toxicity and delivery efficacy. The penetration and permeation of a fluorophore vectorized by PLA nanoparticles into healthy and inflammatory skin were assessed using an alternative device to classical Franz cells: VitroPharma. All these investigations led to the selection of two satisfactory formulations out of five initial candidates.

Percutaneous absorption of benzophenone-3 loaded lipid nanoparticles and polymeric nanocapsules: A comparative study.

For the last years, the increase of the number of skin cancer cases led to a growing awareness of the need of skin protection against ultraviolet (UV) radiations. Chemical UV filters are widely used into sunscreen formulations as benzophenone-3 (BP-3), a usually used broad spectrum chemical UV filter that has been shown to exercise undesirable effects after topical application. Innovative sunscreen formulations are thus necessary to provide more safety to users. Lipid carriers seem to be a good alternative to formulate chemical UV filters reducing their skin penetration while maintaining good photo-protective abilities. The aim of this work was to compare percutaneous absorption and cutaneous bioavailability of BP-3 loaded into solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanostructured polymeric lipid carriers (NPLC) and nanocapsules (NC). Particle size, zeta potential and in vitro sun protection factor (SPF) of nanoparticle suspensions were also investigated. Results showed that polymeric lipid carriers, comprising NPLC and NC, significantly reduced BP-3 skin permeation while exhibiting the highest SPF. This study confirms the interesting potential of NPLC and NC to formulate chemical UV filters.

[Injectable hospital preparation of valine labeled with the carbon 13 and nitrogen 15 (5 mg/mL) for a clinical trial on the brain tumor metabolism: Pharmaceutical control of active pharmaceutical ingredient and stability study of the finished product]. / Préparation hospitalière injectable de valine marquée au carbone 13 et à l'azote 15 (5mg/mL) pour un essai clinique sur le métabolisme tumoral cérébral : contrôle pharmaceutique de la substance active et étude de stabilité du produit fini.

INTRODUCTION: The L-Valine labeled (L-[U-(13)C,(15)N] Val) is a stable isotopic tracer administered by parenteral route within the framework of a new clinical research program concerning the brain tumor metabolism. To meet regulatory requirements and have ready to use solution with an expiration date, a pharmaceutical control of active pharmaceutical ingredient followed by stability study of hospital preparation were realised. MATERIALS AND METHODS: After the pharmaceutical control of the L-[U-(13)C,(15)N] Val, the hospital preparation was prepared according to the good manufacturing preparation. Prepared bottles were stored at 5°C±3°C and 25°C±2°C for six months. The stability of the preparation was determined by physico-chemical controls (pH, osmolality, sub-visible particles, L-[U-(13)C,(15)N] Val concentration, sodium concentration, isotopic enrichment) and microbiological (bacterial endotoxin and sterility). RESULTS: Concentrations of L-[U-(13)C, (15)N] Val and sodium does not significantly decrease during the stability study. In parallel, no change in pH and osmolality were highlighted. Isotopic enrichment higher than 99.9% reflected the stability of labeling of L-valine molecule. The sub-visible particles, the bacterial endotoxin and sterility were in accordance with the European Pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The stability of this hospital preparation of L-[U-(13)C, (15)N] Val has been demonstrated for six months at 5°C±3°C and 25°C±2°C, ensuring a parenteral administration as part of the clinical trial.

[Aseptic process validation and stability study of an injectable preparation of fructose (5%)-glycerol (10%) as part of a hospital clinical research program on endoscopic curative treatment for early epithelial neoplastic lesions of the gastrointestinal tract]. / Validation du procédé aseptique et étude de stabilité d'une préparation injectable de fructose (5 %)-glycérol (10 %) dans le cadre d'un programme hospitalier de recherche clinique portant sur le traitement curatif endoscopique des lésions néoplasiques épithéliales précoces du tube digestif.

INTRODUCTION: As part of a hospital clinical research program on endoscopic curative treatment for early epithelial neoplastic lesions of the gastrointestinal tract, a new hospital sterile and non-pyrogenic preparation of fructose (5%)-glycerol (10%) was realized. Under pharmaceutical legislation, the provision of this hospital preparation involves of aseptic process validation and achieve a stability study. MATERIALS AND METHODS: After the aseptic process validation with Mediafill Test, the preparation was made under aseptic conditions associated with a sterilizing filtration according to the good practices preparation. Prepared flexible bags (100mL of solution) were stored for one year in a climatic chamber (25±2°C). To assess stability, the physicochemical controls (fructose concentration, glycerol concentration, hydroxy-methyl-5 furfural [5-HMF] concentration, sodium concentration, pH measure, osmolality and sub-visible particles count) and microbiological (bioburden, bacterial endotoxin and sterility) were performed at regular intervals for one year. RESULTS: Neither significant decrease of fructose concentration, glycerol concentration and sodium concentration nor pH, 5-HMF, osmolality variations out of specifications were observed for one year. The sub-visible particles count, the bacterial endotoxin and sterility were in accordance with the European pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The hospital preparation was stable over one year at 25±2°C, ensuring safe administration in humans within the framework of this clinical research.

[Advantages and special features of hospital preparations of parenteral nutrition in neonatalogy]. / Avantages et spécificités des préparations hospitalières de nutrition parentérale en néonatalogie.

INTRODUCTION: The care of premature infants requires specific, suitable parenteral nutrition, in which the dosage must be frequently adjusted. METHOD: A comparative analysis of four industrial standard parenteral nutrition formulations NP 100®, Pediaven AP-HP Nouveau-né 1®, Pediaven AP-HP Nouveau-né 2® and Numetah G13% E® and of two hospital preparations made specifically in hospital pharmacies produced by two separate university hospitals (Nutrine® HCL and Formule standardisée début de nutrition) was conducted. The comparison between the formulations focused on electrolytic compositions and protein/energy ratio. RESULTS: Formule standardisée début de nutrition and Pediaven AP-HP Nouveau-né 1® are free from (i) sodium and potassium, (ii) potassium respectively. Almost equivalent sodium concentration (19-27 mM) and more variable potassium concentration (∼9-26 mM) characterize the other formulations. Protein/energy ratio of Numetah G13% E®, Nutrine® HCL and Formule standardisée début de nutrition is 58% higher than that of NP 100®, Pediaven AP-HP Nouveau-né 1® and Pediaven AP-HP Nouveau-né 2®. DISCUSSION: Formule standardisée début de nutrition and Pediaven AP-HP Nouveau-né 1® are in accordance with the recommendations about hydro-electrolytic supplies during transition phase. Nutrine® HCL complies best to the recommendations about hydro-electrolytic account during stabilization phase. CONCLUSION: Hydro-electrolytic composition and protein/energy ratio of standard hospital parenteral nutrition formulations comply best to nutritional needs of premature infants.

[Pharmaceutical involvement in academic clinical trials: Quality assessment of pharmaceutical manufacturing operations]. / Implication pharmaceutique dans le cadre d'essais cliniques institutionnels : évaluation de la qualité des opérations de mise sous forme pharmaceutique.

INTRODUCTION: For academic clinical trials, the hospital pharmacy may be required to perform the specific activity of preparing investigational drugs. MATERIAL AND METHODS: With regards to such activity, and in light of the recent changes in the regulatory environment, the main objective of this study was to evaluate whether quality levels and traceability were in compliance with the applicable regulatory standards. In order to do so, two internal audits have been conducted, the first on the compliance of operations with existing regulatory standards and the second on the quality of traceability of the operations. RESULTS: The proportion of academic clinical trials is constantly growing and currently represents 41% of the total clinical trials in the establishment. An average of 29,000 therapeutic units of investigational drugs are prepared each year (84% under the form of capsules). An overall conformity level of 75% and 88% has been identified in the aforementioned audits, respectively. Such audits have also allowed for the identification of weaknesses in current practices as well as potential improvement areas to achieve better compliance. DISCUSSION: The hospital pharmacy can provide expertise for the preparation of specific dosage or drugs that are not available on the market. It also can be involved for the conception of appropriated packaging function of the study design. CONCLUSION: Results of audits encourage us to continue this activity with a satisfactory level of quality in accordance with the necessary requirements to ensure the safety of patients and the quality of clinical trials conducted.

[Injectable preparation of labeled leucine with the carbon 13 for a clinical research program on the Alzheimer disease: pharmaceutical control of raw materials and the finished product and stability study]. / Préparation injectable de leucine marquée au carbone 13 pour un programme de recherche clinique sur la maladie d'Alzheimer : contrôle pharmaceutique des matières premières et du produit fini et étude de stabilité

INTRODUCTION: The L-leucine labeled (L-[U-(13)C] Leu) is a stable isotopic tracer administered by parenteral route within the framework of a new clinical research program concerning the diagnosis of the Alzheimer's disease. To meet regulatory requirements and have ready to use solution with an expiration date, a pharmaceutical control of raw materials and the finished product followed by a stability study were realised. MATERIALS AND METHOD: After the pharmaceutical control of raw materials, the solution of L-[U-(13)C] Leu was prepared according to the good practices preparation. Prepared bottles were stored for 1 year of a share in a climatic chamber (25 °C±2 °C) and the other in a refrigerator (5 °C±3 °C). To assess stability, the physicochemical controls (pH, osmolality, sub-visible particles, L-[U-(13)C] Leu concentration, sodium concentration, isotopic enrichment) and microbiological (bacterial endotoxin and sterility) were performed at regular intervals for 1 year. RESULTS: Neither significant decrease of L-[U-(13)C] Leu concentration and sodium concentration nor pH and osmolality variation were observed for 1 year. Isotopic enrichment higher than 99.9% reflected the stability of labelling of L-leucine molecule. The sub-visible particles, the bacterial endotoxin and sterility were in accordance with the European pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The injectable preparation of L-[U-(13)C] Leu was stable after 1 year for two preservation conditions, ensuring to safety for administration for human within the framework of this clinical research.

Measurement, analysis and prediction of topical UV filter bioavailability.

The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.

Aqueous dispersions of organogel nanoparticles - potential systems for cosmetic and dermo-cosmetic applications.

OBJECTIVE: The preparation and physicochemical characterization of organogel nanoparticles dispersed in water have been developed. These systems could be employed as nanocarrier for cosmetic applications or as hydrophobic reservoirs for drug delivery. METHODS: Gelled particles of organic liquid and 12-hydroxystearic acid (organogelator) were obtained by hot emulsification (T>Tgel), with a surfactant (acetylated glycol stearate) and polymers (sodium hyaluronate and polyvinyl alcohol) as stabilizing agents, and cooling at room temperature (T

[Stability and sterility of parenteral nutrition admixture for patients home care manufactured by the automated compounding BAXA® EM 2400]. / Étude de stabilité et de stérilité des poches de nutrition parentérale pour patients à domicile fabriquées à l'aide de l'automate BAXA® EM 2400.

INTRODUCTION: Initially, parenteral nutrition admixtures are produced by sterile filtration with a stability of 14 days This study was conducted to check the stability (physicochemical and microbiological) when automated compounding BAXA(®) EM 2400 is used. MATERIALS AND METHODS: Forty pockets corresponding to 10 patients have been manufactured in according to Good Manufacturing Practice. Macroscopic and physicochemical tests (determination of electrolytes by atomic absorption spectroscopy, osmolality and pH measurements) were performed at different times (D0, D7, D14). To complete these checks, the emulsions were analyzed (size, stability, optical microscopy) at D0 and D14. Finally, microbiological research (Bact-Alert(®), filtration membrane sterility tests Steritest(®) and plate count agar) was performed. RESULTS: No lipid cluster was observed with an optical microscope. Comparison of data observed for all controls showed no significant difference in the production of D0 by the Wilcoxon test. Microbiology (Bact-Alert filtration membrane sterility tests Steritest(®) and plate count agar) was negative for all samples. Consequently, all mixtures were considered stable. DISCUSSION AND CONCLUSIONS: The automated compounding BAXA(®) EM 2400 ensures quality and safety of production. The results of this study have shown stability and sterility of parenteral nutrition admixtures for 14 days.

Ex vivo absorption of promestriene from oil-in-water emulsion into infant foreskin.

Hypospadias is a birth defect in which the urinary tract opening is not at the tip of the penis. Hypospadias surgery is frequently complicated by healing deficiencies. Topical treatments with oestrogens were reported to improve healing. In the present study, ex vivo percutaneous absorption of promestriene, a synthetic oestrogen resulting of the double esterification of estradiol was conducted as a pre-requisite for further clinical trial in infants. Penetration of promestriene into infant foreskin treated with commercial oil in water emulsion (10 µg mg(-1)) for 24 h was characterized showing controlled release properties enabling epidermal concentration more than six times higher than dermal concentration (4.13±2.46 mg g(-1) versus 0.62±0.84 mg g(-1), respectively). Furthermore, apparent promestriene fluxes into and through the skin (i.e., 1.5 µg cm(-2) h(-1) and<0.89 µg cm(-2) h(-1), respectively) were calculated from (i) drug amount retained into epidermis and dermis, or (ii) the limit of detection into the receptor fluid. In conclusion, less than 2% of initial dose were absorbed within 24h which compared well with others steroids applied topically in colloidal systems.

[Innovative therapeutic strategies for intravesical drug administration]. / Stratégies thérapeutiques innovantes pour l'administration médicamenteuse intravésicale.

INTRODUCTION: Perspectives for innovative pharmaceutical molecules and intravesical administration of pharmacological agents are presented in the present review carried out from a recent literature. MATERIALS AND METHODS: This review of the literature was built by using the PubMed and ScienceDirect databases running 20keywords revealing 34publications between 1983 and 2012. The number of referenced articles on ScienceDirect has increased in recent years, highlighting the interest of scientists for intravesical drug administration and the relevance of innovating drug delivery systems. RESULTS: Different modalities of intravesical administration using physical (e.g., iontophoresis, electroporation) or chemical techniques (e.g., enzyme, solvent, nanoparticles, liposomes, hydrogels) based on novel formulation methods are reported. Finally, the development of biopharmaceuticals (e.g., bacillus Calmette-Guérin, interferon α) and gene therapies is also presented and analyzed in this review. CONCLUSION: The present review exhibits new development in the pipeline for emerging intravesical drug administration strategies. Knowledge of all these therapies allows practitioners to propose a specific and tailored treatment to each patient with limiting systemic side effects.

Impact of intravenous lipid emulsion infusion on the stratum corneum barrier function in patients receiving parenteral nutrition.

The importance of the lipid matrix of stratum corneum (SC) in epidermal barrier function is well documented. Intravenous lipid emulsions (ILE) provide essential fatty acids (EFAs), main components of the SC lipid matrix. The objective of this study was to investigate the influence of ILE upon SC barrier function. The skin barrier was assessed by measuring transepidermal water loss (TEWL). Patients receiving lipid-containing parenteral nutrition (LCPN) were compared to patients receiving lipid-free PN (LFPN). In addition, a before/after LCPN introduction study was set up to limit the influence of inter-individual variability. Twenty-six patients receiving LCPN and seven patients receiving LFPN were included. Median age was not significantly different between the two groups. The TEWL of the LCPN group (9.05 g/m2/h) was significantly lower than the TEWL of the LFPN group (12.1 g/m2/h; Wilcoxon test: p = 0.016). The relative variation of TEWL before and after ILE treatment of 5 studied patients was 21.29 ± 10.28 %. ILE improve epidermal barrier function when compared to lipid-free parenteral treatments. Results of the before/after study confirm this conclusion and the usefulness of ILE intake for preventing excessive TEWL. SC barrier function improvement could be a choice criterion between the different ILE generations, in particular in burn patients and premature neonates.

Commonly used UV filter toxicity on biological functions: review of last decade studies.

Sunscreens provide broad-spectrum UV skin protection and contain more often UV filter combinations. Their efficacy reducing skin photo carcinogenesis and photo ageing is widely documented. However, there are many concerns about UV filter safety. Organic UV filters were the first targeted by scientist concerns, as they were showed to trigger skin allergic reactions. Inorganic UV filters were then at the heart of scientist debate especially because of their nanometric size. Over the last years, many studies have been published tending to highlight that organic as well as inorganic UV filters could lead to variable side effects after sunscreen application. However, these studies are still very controversial due to different experimental conditions and models. This review reveals that complementary studies using standardized methods are mandatory before ascertaining that UV filters threaten human health.

[Depyrogenation test regarding inox and glass containers in the preparation of parenteral nutrition mixtures]. / Test de dépyrogénation des conteneurs en inox et en verre pour la préparation des mélanges pour nutrition parentérale.

INTRODUCTION: The preparation of parenteral nutrition mixture (PNM) in an open chamber requires the use of intermediate containers sterile and non-pyrogenic. A sterilization of containers by moist heat in large autoclaves is the suitable method. However, sterilization by moist heat is not a depyrogenation method. In our study, we report the validation of a sterilization and depyrogenation method for containers by dry heat using a convection oven. MATERIALS AND METHODS: Sterilization and depyrogenation of material by dry heat have been audited by the reduction of at least three logarithms of original endotoxin rate. The containers were initially artificially contaminated with a suspension of endotoxin for 16 hours. Contaminated containers were placed in an oven with revolving heat at 250 °C for 1 hour. After treatment with dry heat, the residual endotoxin levels in the containers were determined by a kinetic chromogenic method. RESULTS: After treatment with dry heat, the average log reductions of endotoxin levels were respectively, for glass and steel containers, 4.78 ± 0.07 and 4.87 ± 0.03. DISCUSSION AND CONCLUSION: The present validation study confirms the effectiveness of treatment with dry heat for sterilization and depyrogenation of glass and steel containers. This method of sterilization and depyrogenation meets the microbiological quality requirements for the preparation of MNP.

[Validation of pharmaceutical quality of a [6,6-(2)H(2)]-glucose parenteral solution used for insulin-resistance measurement during human clinical trials]. / Validation de la qualité pharmaceutique de préparations de [6,6-(2)H(2)]-glucose en solution aqueuse administrées par voie parentérale pour la mesure de l'insulino-résistance dans le cadre d'essais cliniques.

INTRODUCTION: Deuterated glucose ([6,6-(2)H(2)]-glucose) is a stable isotopic tracer administered parenterally in healthy volunteers, obese or diabetic patients in clinical trial to study glucose metabolism during euglycemic hyperinsulinemic clamps. In accordance with the Health Authorities on drug safety, we evaluated the pharmaceutical quality of this preparation for biomedical research with a stability study. METHODS: After pharmaceutical qualification of the raw material, the [6,6-(2)H(2)]-glucose was dissolved in water for injection, then sterile, filtered under positive pressure of nitrogen and then autoclaved. Two batch products (500mg/10mL and 2g/15mL) were sampled to evaluate glucose alteration, isotope shift, limpidity, apyrogenicity and sterility at regular intervals for 2 years. Deuterated glucose solutions were stored in the dark, at +2°C+8°C, in type II glass bottles. RESULTS: Neither significant decrease of glucose concentration nor pH variation were observed for 2 years. The 5-hydroxymethylfurfural concentration was below the human harmful levels, attesting a non-generation of metabolites during autoclaving. Isotopic enrichment higher than 99% reflected the stability of deuterated label on the 6-carbon of glucose molecules. The non-visible particle concentration below the minimal permissible concentration tolerated by the European Pharmacopoeia and the absence of bacterial endotoxin and bacterial growth attested limpidity, apyrogenicity and sterility of the [6,6-(2)H(2)]-glucose solutions. CONCLUSION: After the 2-year study, 500mg/10mL and 2g/15mL deuterated glucose solutions stored in the dark at +2°C+8°C were stable in aqueous solution, allowing to ensure safety administration for human clinical trials using euglycemic hyperinsulinemic clamps.