Early Deaths in Childhood Cancer in Romania-A Single Institution Study.

(1) Background: Survival in childhood cancer has improved significantly over the last decades. However, early deaths (EDs) represent an important number of preventable deaths. Our aim was to provide more insight intoEDs in developing countries. (2) Methods: We conducted a retrospective analysis of patients aged 0-18 years with childhood cancer diagnosed between 1996 and 2008 and admitted in the Institute of Oncology "Prof. Dr. Ion Chiricuta" Cluj-Napoca (IOCN), Romania. After exclusion of patients (pts) older than 18 years at diagnosis, pts with a missing personal identification number and pts with unconfirmed diagnosis of malignancy, we included 783 pts in the final analysis. We defined ED as survival of less than one month after cancer diagnosis. We divided pts in groups according to age, major tumour categories and treatment time periods. (3) Results: ED was registered in 20 pts (2.55%). A total of 16EDs were registered in haematologic malignancies and 4 in solid tumours. Statistical analysis was performed on pts diagnosed with haematological malignancies. A statistically significant higher proportion of patients with performance status (PS) 3 and 4 died within one month after diagnosis (24.1%) than patients admitted with PS 0-2 (1%)-p < 0.01. We found no statistically significant difference regarding ED when comparing male versus female (p = 0.85), age at diagnosis or between the threeperiods of diagnosis (p = 0.7). (4) Conclusions: PS at admission is an important risk factor associated with ED in pts with haematologic malignancies. ED in our institution reflects frequent late presentation for medical care, late diagnosis and referral to specialised centres.

Ketoconazole-p-aminobenzoic Acid Cocrystal: Revival of an Old Drug by Crystal Engineering.

The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. In vitro cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.

Solid Lipid Nanoparticles: Vital Characteristics and Prospective Applications in Cancer Treatment.

Cancer nanotechnology is a new field of interdisciplinary research cutting across biology, chemistry, engineering, and medicine, aiming to lead to major advances in cancer treatment. Over the past several years, solid lipid nanoparticles (SLNs) have attracted the interest of researchers due to their ability to overcome the limitations of classic chemotherapeutics. We reviewed the most recent data on the therapeutic use of SLNs in oncology, presenting their main advantages and disadvantages, along with various production methods and different routes of administration. In accordance with these aspects, the long-term physical stability, the controlled release of the loaded drugs, and the efficient targeted delivery of drugs as methods of surpassing the pharmaceutical limitations of anticancer drugs, natural products and gene therapy have been discussed. In addition, we have also emphasized briefly the crosstalk between SLNs and the new trend in oncology, immunotherapy, as future possible antineoplastic treatment, especially in melanoma. This review highlights the potential of SLNs in providing very positive perspectives for future cancer treatment by improving the efficiency of present chemotherapy and reducing its side effects. SLNs allow targeted delivery of anticancer drugs and could improve the efficiency of current chemotherapy in neoplasia.

Circulating tumor cells in germ cell tumors: are those biomarkers of real prognostic value? A review.

Analysis of circulating tumor cells from patients with different types of cancer is nowadays a fascinating new tool of research and their number is proven to be useful as a prognostic factor in metastatic breast, colon and prostate cancer patients. Studies are going beyond enumeration, exploring the circulating tumor cells to better understand the mechanisms of tumorigenesis, invasion and metastasis and their value for characterization, prognosis and tailoring of treatment. Few studies investigated the prognostic significance of circulating tumor cells in germ cell tumors. In this review, we examine the possible significance of the detection of circulating tumor cells in this setting.

Biphasic pro-melanogenic and pro-apoptotic effects of all-trans-retinoic acid (ATRA) on human melanocytes: time-course study.

BACKGROUND: The effects of retinoids on melanogenesis and their mechanism as depigmenting agents in topical therapy have not been fully elucidated. Conflicting data about their impact on melanogenic pathways have been reported. OBJECTIVE: To investigate the effects of all-trans-retinoic acid (ATRA) on normal human melanocytes from Caucasian subjects. METHODS: We assessed ATRA's cytotoxicity by measuring viability with a cell proliferation assay, and apoptotic effects using Annexin V and γ-H2AX markers. ATRA's melanogenic activity was investigated based on spectrophotometric measurement of melanin content and tyrosinase enzymatic activity. Tyrosinase expression was assessed by Western blotting. We tested the antioxidant activity of superoxide dismutase (SOD) and catalase (CAT) in melanocytes using a spectrophotometric assay. RESULTS: Of the concentrations tested in this 72h time-course study, the 1.0µM ATRA had a well-defined two-stage pro-melanogenic and pro-apoptotic effect on melanocytes. In the first 6h, treated cells showed significant increase (p≤0.01) of melanin content, tyrosinase, SOD, and CAT activities compared to the controls. While overall tyrosinase expression was not affected by ATRA, all other tested parameters decreased progressively beyond the short-term point of 6h. ATRA treatment of over 6h induced melanocyte apoptosis, as shown by the time-dependent decrease in cell viability, coupled with significant increase in Annexin V positive cells and nuclear accumulation of γ-H2AX foci. CONCLUSION: The results obtained using this testing platform show a biphasic ATRA action: immediate pro-melanogenic effect and longer-term exposure pro-apoptotic activity. These data qualify ATRA as a potent tool to better understand the mechanisms that regulate the pigmentary system.

Photochemoprotective effect of Calluna vulgaris extract on skin exposed to multiple doses of ultraviolet B in SKH-1 hairless mice.

UVB is a major cause of nonmelanoma skin cancer in humans. Photochemoprevention represents an important strategy in protecting the skin against the detrimental effects of ultraviolet B (UVB). We investigated the activity of Calluna vulgaris (Cv) delivered via a hydrogel on 3 main pathways (oxidative stress, inflammation, DNA damage) on skin exposed to multiple doses of UVB in SKH-1 mice. Fifty female mice were divided randomly into 5 groups: control, vehicle, UVB irradiated, Cv + UVB irradiated, and Cv + vehicle + UVB irradiated. The extract was applied topically on the skin in a dose of 4 mg polyphenols/cm2 30 minutes before each UVB (240 mJ/cm2) exposure over 10 consecutive days. Malondialdehyde, reduced glutathione, tumor necrosis factor-α, interleukin-6, cyclobutane pyrimidine dimer (CPD) levels, sunburn cell formation and epidermal thickness, and the number of epidermal cell layers in skin were evaluated 24 hours after the last treatment. UVB increased cytokine levels (P < 0.001), formation of CPDs (P < 0.001) and sunburn cells (P < 0.001), and the epidermal thickness and number of epidermal cell layers (P < 0.001) compared with the control group. The topical application of Cv protected the skin against inflammation and DNA damage, as shown by a decreased number of CPDs (P < 0.001) and sunburn cells (P < 0.001). The administration of Cv via hydrogel may be a viable method for chemoprevention..