Lipid organization in xerosis: the key of the problem?

OBJECTIVE: Although xerosis is a common skin disorder among the population, there is no in vivo global study focusing on xerotic skin. Hence, the objective of this study was to characterize xerotic skin from the surface to the molecular scale with in vivo and non-invasive approaches. METHODS: For this purpose, 15 healthy volunteers with normal skin and 19 healthy volunteers with xerotic skin were selected by a dermatologist, thanks to a visual scorage. Firstly, the skin surface was characterized with biometric measurements. Then, the state of skin dryness was assessed by in vivo confocal microscopy. The molecular signature of xerotic skin was then determined by in vivo confocal Raman microspectroscopy. Finally, an identification of stratum corneum (SC) lipids was performed using Normal phase liquid chromatography (NP-LC) coupled to two detectors: Corona and High Resolution/Mass Spectroscopy (HR/MS). RESULTS: Results obtained at the skin surface displayed an increase in the transepidermal water loss (TEWL) and a decrease in the hydration rate in xerotic skin. Confocal microscopy revealed an alteration of the cell shape in xerotic skin. Moreover, confocal Raman microspectroscopy demonstrated directly in vivo and non-invasively the lack of organization and conformation of lipids in this skin. Finally, HPLC analyses revealed that the three ceramide sub-classes (NdS, NS and EOP) significantly decrease in xerosis. Altogether, these results identify parameters for the characterization of xerotic skin compared to normal. CONCLUSION: This study highlighted discriminative parameters from the surface to the molecular level in vivo and non-invasively between xerotic and normal skins. These results will be useful for the development of new cosmetic active ingredients dedicated to xerotic skin.

Examination of the effect of Stratum Corneum isolation process on the integrity of the barrier function: a confocal Raman spectroscopy study.

BACKGROUND: Stratum Corneum (SC) is the most superficial layer of the epidermis. It plays the main barrier role against water loss and the aggression of external chemical and biological substances. Thermal treatment in warm purified water followed by trypsin incubation of excised human skin is a well-established in vitro method for SC removal. Different protocols can be found in literature, but little is described about the effect of temperature and trypsin during isolation process on its barrier function. METHODS: In this study, we have examined the epidermis and SC matrix structural change upon isolation by means of confocal Raman spectroscopy. RESULTS: Several spectral features, i.e. in-depth and planar lateral packing, conformational order and secondary structure have been investigated to reveal modifications in the structural properties of the lipids and proteins in the SC. Thermal treatment at 60°C leads to a losing in compactness and a steeper concentration of the lipid and protein descriptors while the trypsinization step modifies the organization of the proteins and of the lipid barrier, leading to a domain organization. CONCLUSIONS: The present study improves the knowledge of the effects on the barrier function of SC removal protocol.

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Vibrational spectroscopy coupled to classical least square analysis, a new approach for determination of skin moisturizing agents' mechanisms.

BACKGROUND: Skin dryness is an omnipresent symptom in various types of skin disorders. Thereby, a large panel of skin care products is developed for therapeutic purposes. However, there is still a lack of non-invasive methods to determine the mechanisms of action of moisturizers at the molecular level. METHODS: In the present study, confocal Raman spectroscopy coupled to classical least square analyses and ATR-FTIR were used to investigate the effect of different molecules on the stratum corneum (SC) hydration degree and barrier state. First, hygroscopic property was determined by analyzing samples at 90% RH; secondly, the water barrier function was evaluated after the dehydration process (4% RH). The molecules penetration kinetics across SC were also studied for 2 h. RESULTS: Using the present approach, glycerin and propylene glycol were found to be humectants; lanoline showed occlusive action, lactic acid has both humectant and barrier enhancer properties, and ethylhexyl palmitate and caprylic/capric acid triglyceride seemed to be emollients. These observations are in accordance with literature. CONCLUSION: The present method non-invasively characterizes the mechanism of action of tested molecules. This may improve knowledge of new molecules' structure-activity relationship and help make an effective therapeutic concept dealing with the various skin dysfunctions.

Current landscape of ESMO/ASCO Global Curriculum adoption and medical oncology recognition: a global survey.

BACKGROUND: With the implementation of multidisciplinary treatment and development of multiple novel anticancer drugs in parallel with expanding knowledge of supportive and palliative care, a need for separate training and specialisation in medical oncology emerged. A Global Curriculum (GC) in medical oncology, developed and updated by a joint European Society for Medical Oncology/American Society of Clinical Oncology (ESMO/ASCO) GC Task Force/Working Group (GC WG), greatly contributed to the recognition of medical oncology worldwide. MATERIAL AND METHODS: ESMO/ASCO GC WG carried out a global survey on medical oncology recognition and GC adoption in 2019. RESULTS: Based on our survey, medical oncology is recognised as a separate specialty or sub-specialty in 47/62 (75%) countries participating in the survey; with a great majority of them (39/47, 83%) recognising medical oncology as a standalone specialty. Additionally, in 9 of 62 (15%) countries, medical oncology is trained together with haematology as a specialty in haemato-oncology or together with radiotherapy as a specialty in clinical oncology. As many as two-thirds of the responding countries reported that the ESMO/ASCO GC has been either fully or partially adopted or adapted in their curriculum. It has been adopted in a vast majority of countries with established training in medical oncology (28/41; 68%) and adapted in 12 countries with mixed training in haemato-oncology, clinical oncology or other specialty responsible for training on systemic anticancer treatment. CONCLUSIONS: With 75% of participating countries reporting medical oncology as a separate specialty or sub-specialty and as high as 68% of them reporting on GC adoption, the results of our survey on global landscape are reassuring. Despite a lack of data for some regions, this survey represents the most comprehensive and up-to-date information about recognition of medical oncology and GC adoption worldwide and will allow both societies to further improve the dissemination of the GC and global recognition of medical oncology, thus contributing to better cancer care worldwide.

Tumor lysis syndrome after starting treatment with Gleevec in a patient with chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is one of the myeloproliferative disorders. It accounts for 15-20% of all leukemias in adults. The mainstay of diagnosis is the detection of Philadelphia chromosome or one of its products. Tyrosine kinase inhibitors changed the paradigm of treating such disease with the good responses. However, they do have side effects. In our case we will report tumor lysis syndrome happening after starting Imatinib myselate. We did a literature review and looked all the cases that documented this complication.

Primary Ewing sarcoma of the larynx with distant metastasis: a case report and review of the literature.

Extraosseous Ewing sarcoma is a rare, poorly differentiated round-cell tumour that is part of the Ewing sarcoma family of tumours. Here, we present an extremely rare case of primary extraosseous Ewing sarcoma arising in the larynx, with distant metastases. A 53-year-old man with a history of Hodgkin lymphoma treated 4 years earlier with 8 cycles of chemotherapy presented to our medical centre with a 2-week history of hoarseness. On physical examination, he was found to have a right supraglottic mass together with a fixed right vocal cord. Computed tomography imaging of the patient's neck showed a heterogeneously enhancing lesion measuring 5.0×3.8×3.8 cm, centred on the right thyroid cartilage and invading the right true vocal cord. Imaging by integrated fluorodeoxyglucose positron-emission tomography and computed tomography showed active subcarinal and axillary lymph nodes, multiple scattered lung nodules, and multiple bony metastases. Needle core biopsy of the laryngeal mass was diagnostic for Ewing sarcoma. The patient received radiation to the laryngeal area and then alternating cycles of vincristine-actinomycin-D-cyclophosphamide and etoposide-ifosfamide. The patient remains in remission 1 year after completing therapy. As demonstrated in the present report, these tumours can behave very aggressively both locally and by metastasizing to distant organs. Our treatment approach provided favourable results for the patient; however, future reports are needed to further elucidate optimal management.

Neoadjuvant therapy with celecoxib to women with early stage breast cancer.

Cyclooxygenase-2 (COX-2) is preferentially expressed in breast cancer cells compared to normal breast tissue. COX-2 inhibitors are, therefore, potential therapeutic options for patients with breast cancer. Women newly diagnosed with non metastatic breast cancer were enrolled into the study after undergoing a diagnostic core needle biopsy. Patients received celecoxib treatment at 400 mg orally twice a day for 14 days, and then underwent surgical excision of their tumor. Core biopsies obtained at the time of initial diagnostic procedure and surgical excision specimens were stained for Ki-67, as well as COX-2 and cleaved poly (ADP-ribose) polymerase (PARP) expression (as an apoptosis marker). Appropriate negative and positive controls were included. We assessed the difference in Ki-67, COX-2 and cleaved PARP expression levels, before and after treatment using the Wilcoxon's matched-pair ranks test and the McNemar's test with continuity correction. Sixteen patients were enrolled. The median age was 54 years. ER and/or PR expression was present in 81% of tumors; Her-2 neu overexpression was present in 25%. No significant change in COX-2 or cleaved PARP expression was noticed in the post intervention specimen compared to the core biopsies. Surprisingly, there was a significant increase in the Ki-67 expression (p < 0.009). This short term prospective study was conducted to assess the effects of celecoxib, on the proliferative and apoptotic indexes in patients with early stage breast cancer. We have found an increase in the Ki-67 activity, with no significant down regulation of COX-2 or increase in cleaved PARP expression with 14 days of therapy. This could be partly due to the small sample size.

Studying DEHP migration in plasticized PVC used for blood bags by coupling Raman confocal microscopy to UV spectroscopy.

Plasticized PVC is widely used to make medical devices such as tubing, perfusion bags and blood bags. By using confocal Raman microscopy on a PVC sheet plasticized with around 40% of di-(2-ethylhexyl)phthalate (DEHP), we propose a simple and sensitive approach to studying and understanding the diffusion of plasticizers from polymers into the surrounding media. Moreover, we sought to correlate our findings to standard measurements conducted by UV spectroscopy. This study showed differences in the concentration gradient observed due to the diffusion of the plasticizer inside a PVC sheet. We can thus follow the critical DEHP ratios that can impact the diffusion process. Water and ethanol were chosen as storage media: in ethanol, the lowest concentration of DEHP was observed at the surface resulting in the formation of a less plasticized layer near the interface; unlike ethanol, PVC sheets stored in water showed a greater concentration of DEHP on the film surface as an exudation of DEHP onto the surface.

Discrimination and quantification of two isomeric antineoplastic drugs by rapid and non-invasive analytical control using a handheld Raman spectrometer.

Raman spectroscopy is a rapid, non-destructive and non-invasive method that is a promising tool for real-time analytical control of drug concentrations. This study evaluated a handheld Raman device to discriminate and quantify two isomeric drugs used to treat cancer. Doxorubicin (DOXO) and epirubicin (EPIR) samples were analyzed at therapeutic concentrations from 0.1 to 2mg/mL (n=90) and 0.08-2mg/mL (n=90) by non-invasive measurements using a portable Raman spectrometer. The discrimination of these two molecules was demonstrated for all concentrations (n=180) by qualitative analysis using partial least square discriminant analysis (PLS-DA) with 100% classification accuracy, sensitivity and specificity and 0% error rate. For each molecule, quantitative analyses were performed using PLS regression. The validity of the model was evaluated using root mean square error of cross validation (RMSECV) and prediction (RMSEP) that furnished 0.05 and 0.02mg/mL for DOXO and 0.17 and 0.16mg/mL for EPIR after pretreatment optimization. Based on the accuracy profile, the linearity range was from 1.256 to 2.000mg/mL for DOXO (R2=0.9988) and from 0.553 to 2.000mg/Ml for EPIR (R2=0.9240) and repeatability (CV% max of 1.8% for DOXO and 3.2% for EPIR) and intermediate precision (CV% max of 2.8% for DOXO and 4.5% for EPIR) were both acceptable. Despite the narrow validated concentration range for quantitative analysis, this study shows the potential of a handheld Raman spectrometer coupled to chemometric approaches for real-time quantification of cytotoxic drugs, as well for discriminating between two drugs with similar UV absorption profiles. Finally, the use of a handheld spectrometer with the possibility of a direct measurement of substances in containers is a potentially valuable tool for combining patient safety with security of healthcare workers.

Effects of CYP2B6 genetic polymorphisms in patients receiving cyclophosphamide combination chemotherapy for breast cancer.

PURPOSE: The purpose of this study was to measure the frequency of three CYP2B6 [CYP2B6*4 (rs2279343), CYP2B6*5 (rs3211371) and CYP2B6*9 (rs3745274)] alleles in patients with breast cancer receiving cyclophosphamide (CP) therapy and test whether these variants are predictors of CP-associated toxicity and efficacy. METHODS: A total of 145 female breast cancer patients admitted to the American University of Beirut Medical Center for breast cancer-related therapy were included. Chart review was performed for collection of toxicity data. A time-to-event analysis was performed with a subset of 38 patients. RESULTS: The minor allele frequencies of CYP2B6*9, CYP2B6*4 and CYP2B6*5 were 0.27, 0.29 and 0.07, respectively. CYP2B6 *5/*6, *6/*9 or *6/*6 haplotypes were associated with a significantly shorter time to recurrence of the disease. There were no significant associations with myelo-toxicity. CONCLUSIONS: This is the first report on the pharmacogenetic profile of patients with breast cancer and the therapeutic and myelo-toxic behavior of CP in women from an Arab Middle Eastern country. Our results show that genotyping for these CYP2B6 alleles does not help in personalizing therapy from a toxicity perspective, and the association of shorter survival in these subjects with homozygous variants is interesting yet insufficient to justify routine genotyping prior to therapy, or to consider using a higher CP dose. Larger future studies or meta-analyses will be needed to further clarify the potential implication of these genetic polymorphisms.

Heat shock proteins in cancer: targeting the 'chaperones'.

Heat shock proteins (Hsps) are highly conserved proteins working as molecular chaperones for several cellular proteins essential for normal cell viability and growth, and have numerous cytoprotective roles. The expression of Hsps is induced in response to a wide variety of physiological and environmental stress insults, including anticancer chemotherapy, thus allowing the cell to survive lethal conditions. Cancer cells experience high levels of proteotoxic stress and rely upon stress-response pathways for survival and proliferation, thereby becoming dependent on proteins such as stress-inducible Hsps. Owing to the implication of Hsps in cancer, Hsp inhibition has recently emerged as an interesting potential anticancer strategy. Many natural and synthetic Hsp inhibitors molecular compounds are in development and many are being evaluated as potential cancer therapies. One of the Hsps in particular, Hsp90, has several client proteins and is emerging as a particularly exciting cancer target due to the prospect of simultaneously inhibiting chaperoning of numerous oncogenic proteins. This review describes the function of Hsps focusing on current efforts in exploiting the attributes of Hsps as potential targets for anticancer therapy.

Identification of hematite particles in sealed glass containers for pharmaceutical uses by Raman microspectroscopy.

Raman microspectroscopy has been shown to enable the identification of micro-particles inside sealed glass containers for pharmaceutical use without any sample preparation. Raman spectra were collected from unknown particles with a maximum size of 1mm, adsorbed on the inner surface of ampoules. The particles were clearly identified as primarily hematite with traces of magnetite by their characteristic Raman spectral bands. The presence of this deposit was attributed to the projection of iron oxides during the manufacturing process. These oxide particles were not detected by the quality control process of the glass manufacturer, showing that in-process quality controls failed to detect this problem. Particle identification by Raman microspectroscopy appears to be a selective, rapid and reliable analytical procedure for quality control and assurance in the pharmaceutical industry. Identification of the particles was also helpful for evaluating the nature of the contaminant and enables consequences for the toxicological aspects of final product quality to be managed.

Confocal Raman microspectroscopy on excised human skin: uncertainties in depth profiling and mathematical correction applied to dermatological drug permeation.

Confocal Raman microspectroscopy represents the advantage of giving structural and conformational information on samples without any destructive treatment. Recently, several studies were achieved to study the skin hydration, endogenous and exogenous molecules repartition in the skin using the confocal feature of this technique. Meanwhile, when working through a material boundary with a different refractive index, the main limitation remains the spatial precision, especially the distortion in the depth and the depth resolution. Recently, several authors described mathematical models to correct the depth and the resolution values. In this study, we combined theoretical approaches, proposed by different authors with experimental measurements to try to find out the most appropriate approach for correction. We then applied the corrections on in-depth profiles tracking the penetration of Metronidazole, a drug produced by Galderma for rosacea treatment, through excised human skin.

Toxicities related to intraarterial infusion of cisplatin and etoposide in patients with brain tumors.

Chemotherapy for malignant brain tumors has a limited efficacy largely due to restricted blood-brain barrier permeability for chemotherapeutic drugs. Intraarterial chemotherapy (IAC) has the advantage of increased uptake during the first passage of the drugs through tumor capillaries. Initial IAC trials had less than satisfactory results due to unacceptable toxicities. Between 1987 and 1996, 173 patients with primary and metastatic brain tumors were treated with intraarterial (intracarotid and/or intravertebral) cisplatin and etoposide (VP-16). Out of these, 168 patients, who received a total of 438 cycles, were evaluated for the incidence of toxicities. Patients received either cisplatin at 40 mg/m2 and VP-16 at 20 mg/m2 or cisplatin at 60 mg/m2 and VP-16 at 40 mg/m2. Nausea and vomiting were the most common toxicities (42 patients, 14% of cycles). Arterial puncture was associated with a 1.6% incidence of groin hematomas (6 patients), and a 0.7% incidence of failure to canulate the carotid or vertebral arteries (3 patients). Neurologic toxicities included headache (1.4% of cycles, 5 patients), focal seizures (1.4% of cycles, 5 patients), transient confusion and urinary retention/incontinence (1.9% of cycles, 8 patients), and blurred vision (0.9% of cycles, 4 patients). We have not seen visual loss, strokes, major vessel dissection or thrombosis, or myelosuppression. Toxicity incidence was higher in patients with metastatic brain tumors than in those with primary brain tumors (34% versus 17%, p < 0.001). It was also higher in patients who had brain radiation therapy (RT) prior to IAC than in those who had RT concomitant with IAC (31% versus 19%, p = 0.05). No significant difference in toxicity incidence was noticed between patients who received RT concomitant with IAC and those who received RT after IAC (19% and 23% respectively, p = 0.08). Intracarotid chemotherapy given prior to RT resulted in 23 months of median survival for patients with glioblastoma multiforme. Intraarterial chemotherapy with cisplatin and VP-16 is a relatively safe treatment modality, especially in patients with primary brain tumors who have not received brain radiotherapy.

Therapy for patients with high grade astrocytoma using intraarterial chemotherapy and radiation therapy.

BACKGROUND: High grade astrocytomas account for approximately 40% of all primary brain tumors. The median survival is approximately 8-10 months for patients with glioblastoma multiforme and 36 months for patients with anaplastic astrocytoma. The results of systemic chemotherapy in the treatment of brain tumors have been reported to be less than satisfactory, mainly because of the blood-brain barrier impermeability for chemotherapeutic drugs. Intraarterial chemotherapy has been an attractive alternative with which to overcome this problem. METHODS: Eighty-three patients with high grade astrocytoma (glioblastoma multiforme [63 patients] and anaplastic astrocytoma--[20 patients]) were treated with intraarterial (intracarotid and/or intravertebral) chemotherapy and radiation therapy between 1987 and 1997. Patients received cisplatin, 60 mg/m2, and etoposide, 40 mg/m2. Radiation therapy was delivered either after completion of the chemotherapy or concomitantly with the chemotherapy. RESULTS: Thirty-four of 71 evaluable patients with high grade astrocytoma (48%) responded to the chemotherapy. The median survival for patients with glioblastoma multiforme who received chemotherapy prior to radiation therapy was 20 months versus 7 months for those patients who underwent concomitant chemotherapy/radiation therapy. Patients with anaplastic astrocytoma who received chemotherapy prior to radiation therapy had a median survival of 45 months compared with 12 months for patients who received concomitant chemotherapy/ radiation therapy. The toxicity profile has been reported to be mild and well tolerated. CONCLUSIONS: Intraarterial chemotherapy for patients with glioblastoma multiforme, delivered prior to radiation therapy, appears to result in a median survival three times longer than that achieved with concomitant chemotherapy/radiation therapy. In addition, patients appear to survive substantially longer than they do after radiation therapy with the addition of systemic chemotherapy. Side effects are reported to be acceptable.