Laser-induced drug release for local tumor control--a proof of concept.

BACKGROUND: The systemic palliative chemotherapy of locally extended gastrointestinal and hepatobiliary tumors is associated with a considerable burden for the patient. The aim of this project was to develop a new drug release system to improve the local stent therapy in these patients as a proof of concept study. For this purpose, polymer filaments were modified with drug-loaded polymer microgels that allow selective release of the active substance by photochemical triggering using laser radiation. Integrated into a stent system, the better local tumor control could thus contribute to a significant increase in the quality of life of patients. METHODS: A standard mammalian cell line and two carcinoma cell lines were established. By Fluorescence activated cell sorting (FACS), the cytotoxicity of the different materials was determined in vitro before and after drug loading with the chemotherapeutic agent 5-Fluorouracil (5-FU). For this purpose, the locally applied 5-FU concentration was previously determined by Bromdesoxyuridin assay. 5-FU dimer was synthesized by photo-induced dimerization of 5-FU in the presence of benzophenone in methanol. The chemical structure of 5-FU dimer was confirmed with Hydrogen-1 nuclear magnetic resonance and Fluorine-19 nuclear magnetic resonance. 5-FU dimer is nonsoluble in water and can be easily incorporated in polymer microgels modified with hydrophobic binding domains (cyclodextrin). After laser irradiation, 5-FU dimer decomposes and 5-FU can be released from microgels. Finally, the measurements were repeated after this laser-induced drug release. RESULTS: In FACS analysis, neither the microgels nor the microgel cumarin complexes showed a significant difference in comparison with the negative control with H2O and therefore no toxic effect on the cell lines. After loading with the 5-FU dimer, there was no significant cell death (contrary to the pure 5-FU monomer, which dose had been previously tested as highly toxic). After laser-induced dissociation back to monomer and the associated drug release, FACS analysis showed cytotoxicity. CONCLUSIONS: It was possible to develop 5-FU dimerloaded microgels, which show no cytotoxic effect on cell lines before laser irradiation. After dissociation back to 5-FU monomer by selective photochemical triggering using laser irradiation, the active substance was released. Thus, a new drug release system has been created and tested in vitro. For further development, integration into a stent system and for in vivo follow-up evaluation more studies need to be conducted.

Outcome of group physical therapy treatment for non-specific low back pain patients can be predicted with the cross-culturally adapted and validated Hungarian version STarT back screening tool.

PURPOSE: The STarT Back Tool was developed to identify the specific modifiable prognostic factors for non-specific low back pain and to classify the patients into risk groups; low, medium and high risk of chronicity. Applied therapeutic approaches often involve group physical therapy. The aim of this study was the cross-cultural adaptation and validation of the Hungarian version of the STarT Back Tool and to investigate the predictive ability for global treatment outcome. MATERIALS AND METHODS: A prospective cohort study (N = 133) was carried out involving non-specific low back pain patients. Internal consistency, construct validity, reliability and prognostic discriminative ability have been investigated. After 3 months of treatment global outcome was evaluated. RESULTS: A 2-factor structure was found, with moderate internal consistency (Cronbach α = 0.89 for the total and psychosocial subscale 0.62). Between the Hungarian STarT Back Tool, the Oswestry Disability Index, leg pain, low back pain, Tampa Scale for Kinesiophobia, Fear Avoidance Beliefs Questionnaire and the physical subscale of the quality of life questionnaire, significant good to excellent- correlation was found (r > 0.41). The test-retest analysis showed excellent reliability (Intraclass Correlation Coefficient = 0.93) with standard error measurement being 0.49 (minimal detectable change = 1.37). The Area Under the Curve for baseline STarT Back Tool scores was 0.7 and 0.8 for global treatment outcome and distress, respectively. The Area Under the Curve for global treatment outcome versus STarT risk groups proved to be 0.76 representing adequate discriminative ability. CONCLUSION: The successful cross-cultural adaptation was followed by the validity analysis and as a result the Hungarian version of the STarT Back Tool proved to be a reliable and valid tool in the identification of risk groups of chronicity for patients with low back pain. Patients allocated to the high-risk group were more likely experiencing poor outcome at 3 months follow up, thus it can be used to predict outcome if treated with group physical therapy.Implication for rehabilitationLow back pain is a multifactorial disease where physical and psychosocial risk factors play a role in the development and prognosis of the disease.The STarT-H can be considered as a reliable, valid measurement tool in the identification of risk groups of chronicity for patients with low back pain.Clinical relevance of the STarT-H is that it can be used to stratify patients into risk groups of chronicity in different Hungarian speaking healthcare settings.According to our findings the STarT-H can also be applied to predict global treatment outcome in low back pain patients if treated with group physical therapy.

Changes in expression of oncogenes and TP53 tumour suppressor gene as biomarkers in head and neck cancers.

Despite modern diagnostic procedures and up-to-date therapy, the survival of head and neck tumour patients is unfavourable. This can be explained by several factors, one of which is the late recognition of the tumour. This study related to the changes in expression of the c-myc and Ha-ras oncogenes and the p53 tumour suppressor gene as biomarkers in head and neck cancer cases. The gene expressions were investigated on RNA gained from peripheral white blood cells of head and neck cancers patients before and after definitive treatment. The results were compared with those on a control group of patients with non-tumorous diseases. The gene expressions were significantly higher in the cancer group than that in the control group (volunteer medical staff and medical students). After definitive treatment, the expressions of all these genes were decreased in patients in whom there was no recurrence of the tumour, but enhanced in the event of recurrence. Such measurement may serve as reliable biomarkers to monitor tumour development and the efficiency of therapy. The method may also be useful for the early identification of populations exposed to noxe, which may lead to the development of head and neck cancers.

Skin cancer risk factors among primary school children: investigations in Western Hungary.

OBJECTIVE: To evaluate the factors associated with sunburns and with sun protection practice in Hungarian primary school children. METHOD: We investigated children's (the median age: 8, range 5 to 12 years) and parents' assessment of sun sensitivity and sun protection characteristics in cities Gyor and Zalaegerszeg (Hungary) in 2004. This cross-sectional study was part of a programme intended to increase children's and parents' awareness of harmful effects of excessive sunbathing. Analyses were based on 1804 multiple choice questionnaires. RESULTS: At multivariate analysis a significant association between sunburns and fairness of complexion, freckles, use of sunscreens and T-shirts, and higher school-class level was observed. Sunburn was inversely associated with hat-wearing. Parents were more likely to apply sunscreen to children with light eyes and to the younger ones, to protect fair skinned children with T-shirts; to protect males and children with fair skin and light eyes with hats. CONCLUSION: Since environmental factors play an important role in the development of skin cancer, morbidity could be reduced by primary prevention. Sun protection habits should therefore be taught early in life, and parents' behaviour adapted. Phenotype is not only related to sunburns but it also appears to influence parents' sun safety behaviour.

Development of a Polymer-Based Biodegradable Neurovascular Stent Prototype: A Preliminary In Vitro and In Vivo Study.

Biodegradable stents are not established in neurovascular interventions. In this study, mechanical, radiological, and histological characteristics of a stent prototype developed for neurovascular use are presented. The elasticity and brittleness of PLA 96/4, PLDL 70/30, PCL, and PLGA 85/15 and 10/90 polymers in in vitro experiments are first analyzed. After excluding the inapt polymers, degradability and mechanical characteristics of 78 PLGA 85/15 and PLGA 10/90 stent prototypes are analyzed. After excluding PLGA 10/90 stents because of rapid loss of mass PLGA 85/15 stents in porcine in vivo experiments are analyzed. Angiographic occlusion rates 7 d, 1 month, 3 months, and 6 months after stent implantation are assessed. Histological outcome measures are the presence of signs of inflammation, endothelialization, and the homogeneity of degradation after six months. One case of stent occlusion occurs within the first 7 d. There is a prominent foreign-body reaction with considerable mononuclear and minor granulocytic inflammation combined with incomplete fragmental degradation of the struts. It is possible to produce a stent prototype with dimensions that fit the typical size of carotid arteries. Major improvements concerning thrombogenicity, degradation, and inflammatory response are required to produce biodegradable stents that are suitable for neurovascular interventions.

Modelling pH-Optimized Degradation of Microgel-Functionalized Polyesters.

We establish a novel mathematical model to describe and analyze pH levels in the vicinity of poly(N-vinylcaprolactam-co-acetoacetoxyethyl methacrylate-co-N-vinylimidazole) (VCL/AAEM/VIm) microgel-functionalized polymers during biodegradation. Biodegradable polymers, especially aliphatic polyesters (polylactide/polyglycolide/polycaprolactone homo- and copolymers), have a large range of medical applications including delivery systems, scaffolds, or stents for the treatment of cardiovascular diseases. Most of those applications are limited by the inherent drop of pH level during the degradation process. The combination of polymers with VCL/AAEM/VIm-microgels, which aims at stabilizing pH levels, is innovative and requires new mathematical models for the prediction of pH level evaluation. The mathematical model consists of a diffusion-reaction PDE system for the degradation including reaction rate equations and diffusion of acidic degradation products into the vicinity. A system of algebraic equations is coupled to the degradation model in order to describe the buffering action of the microgel. The model is validated against the experimental pH-monitored biodegradation of microgel-functionalized polymer foils and is available for the design of microgel-functionalized polymer components.

Modelling pH-Optimized Degradation of Microgel-Functionalized Polyesters

We establish a novel mathematical model to describe and analyze pH levels in the vicinity of poly(N-vinylcaprolactam-co-acetoacetoxyethyl methacrylate-co-N-vinylimidazole) (VCL/AAEM/VIm) microgel-functionalized polymers during biodegradation. Biodegradable polymers, especially aliphatic polyesters (polylactide/polyglycolide/polycaprolactone homo- and copolymers), have a large range of medical applications including delivery systems, scaffolds, or stents for the treatment of cardiovascular diseases. Most of those applications are limited by the inherent drop of pH level during the degradation process. The combination of polymers with VCL/AAEM/VIm-microgels, which aims at stabilizing pH levels, is innovative and requires new mathematical models for the prediction of pH level evaluation. The mathematical model consists of a diffusion-reaction PDE system for the degradation including reaction rate equations and diffusion of acidic degradation products into the vicinity. A system of algebraic equations is coupled to the degradation model in order to describe the buffering action of the microgel. The model is validated against the experimental pH-monitored biodegradation of microgel-functionalized polymer foils and is available for the design of microgel-functionalized polymer components.

[Molecular epidemiology of cancers and precancerous conditions]. / A daganatok és a daganatmegelózó állapotok molekuláris epidemiológiája.

For many years the molecular biology has been one of the most promising fields of science and its several methods have been used in practice. These new methods of molecular biology made impression on epidemiology and developed a new discipline, called molecular epidemiology. The molecular and predictive epidemiology play more and more important roles in the prevention of cancers. Early biomarkers could identify the high risk population to have the possibilities of primary preventive interventions. It uses both molecular biological methods and the elements of epidemiology. Its specificity is not high enough to establish the diagnosis but it can be used to follow the "minimal residual disease" and with markers of individual susceptibility, to assess the risk of tumors. As to the practice there are many problems because of the limited therapeutic possibilities, but the molecular and predictive epidemiology becomes an important part of medicine in the future.