Účel studie: Hlavním cílem studie bylo odhadnout dosažení patologické kompletní odpovědi nemocných trpících lokálně pokročilým adenokarcinomem rekta po předoperační (neoadjuvantní) chemoradioterapii (CHRT) s využitím individuálních farmakokinetických parametrů 5-fluorouracilu (5-FU). Sekundárním cílem bylo hodnocení bezpečnosti a snášenlivosti léčby. Tato otevřená prospektivní studie podporovaná grantem IGA NS 9693–04/2008 zahrnula 34 dospělých s lokálně pokročilým karcinomem konečníku ozařovaných do celkové dávky 50,4 Gy ve 28 frakcích po 1,8 Gy 10–15 MV paprsky v režimu 5 + 2 (5 dní radioterapie, 2 dny volno) s kontinuálně podávaným 5-FU v i. v. infuzi 200–1000 mg/m2 po dobu 4–5 týdnů kontinuálně 7denní infuzí. Chirurgická resekce následovala 4–6 týdnů po ukončení CHRT a po klinickém restagingu. Hodnocena byla klinická a patologická odpověď na chemoradioterapii pomocí zobrazovacího (MR) a histopatologického vyšetření, vyjádřená v % jako reziduální choroba. Výsledky a závěr: Výsledek dokládá vztah mezi velikostí kumulativní dávky 5-FU a kumulativní AUC 5-FU (r = 0,61, p < 0,001). Podobný vztah byl prokázán mezi kumulativní AUC 5-FU a metabolickým poměrem (poměr dosažených plazmatických koncentrací neaktivního metabolitu dihydrofluorouracilu (5-FUH2) ku koncentracím 5-FU, r = -0,80, p < 0,0001). Kumulativní AUC korelovala se stupněm odpovědi na léčbu (r = – 0,53, p < 0,005) a určovala také stupeň toxicity léčby. Pokud bychom chtěli dosáhnout kompletní patologickou odpověď, pak by denní dávka 5-FU měla být u středně rychlého metabolizéra >350 mg/m2 a kumulativní AUC1–39 dní > 50 mg/L*h. U žádného z nemocných nebyla nalezena mutace v genu pro dihydropyrimidindehydrogenázu (DPD) a multidrug resistance-1 protein (MDR-1), přesto byla nalezena vysoká interindividuální variabilita v dosažených plazmatických koncentracích 5-FU, a to i s ohledem na cirkadiální rytmus kinetiky léčiva., Background and Purpose: The main goal of the present study was to estimate the early patients´response following neoadjuvant chemoradiotherapy (CHRT) based on 5-fluorouracil (5-FU) with curative aim in relation to plasma concentrations and pharmacokinetic parameters of 5-FU. Secondary objectives included evaluation of the safety and tolerability of the regimen. Patients and Methods: This open prospective study enrolles 34 adult patients with locally advanced rectal cancer, who received 5-FU 200 -1000 mg/m2 administered as a continuous i. v. infusion over 4–5 week and radiotherapy delivered with 10–15 MV photon beams at 1.8 Gy/fraction up o 50.4 Gy in 28 daily fractions for 5 days a week. Surgical resection with curative aim followed 4–6 weeks after the completion of CHRT and clinical restaging. Pathologic response evaluation and the rate of tumor regression was evaluated using tumor downstaging by MR, histopathological staging, and expressed as residual disease (%). Results and Conclusion: The outcome evidenced the correlation between the cumulative 5-FU dose and cumulative AUC of 5-FU (r = 0.61; p < 0.001). The similar relationship was demonstrated between the cumulative AUC and metabolic ratio (the plasma concentration od inactive metabolite dihydrofluotouracile 5-FUH2 to 5-FU; r = -0.80; p < 0.0001). The cumulative AUC was correlated with tumor regression rate (r = -0.53; p < 0.005) and determined toxicity grade. To reach pCR, the daily dose of 5-FU in patient with average metabolic ratio of 5-FUH2/5-FU should be >350 mg/m2 and the cumulative AUC1–39days > 50 mg/L*h. No mutation of gene for enzyme dihydropyrimidindehydrogenase (DPD) and mutidrug resistance-1 protein (MDR-1) were identified, although the interindividual variability of 5-FU plasma concentration was high, also with regard to circadial 5-FU pharmacokinetics variability., Jiří Grim, Miloš Hroch, Jaroslav Chládek, Ondřej Slanař, Jiří Petera, Jiřina Martínková, and Literatura 27
The important biological role of saliva in maintaining of the homeostasis of the oral cavity environment, preventing infection and tooth decay is widely accepted. Salivary glands insufficiency may violate the balance between health and disease. Clinical data indicated that the destruction, agenesis and aplasia of salivary gland commonly followed with hypo salivation, low salivary flow, which resulted in severe caries and periodontal disease. Salivary gland dysfunction also frequently found in preterm and low birth weight newborns. But the information about structural background of abnormal salivation in early childhood is still limited. A presence of any correlation between salivary glands structural development and intrauterine restrictions of fetal growth (IUGR) is unclear. The aim of present study was to determine morphological and morphometric peculiarities of human parotid gland in case of IUGR at late gestation. Material and methods: Parotid glands of twenty human fetuses 2022 weeks of gestation with diagnosed IUGR from late abortions material were compared with ten fetal glands in cases of induced abortions due to psychological reasons (control group). Tissue samples were immersionfixed in 10% buffered formalin solution, embedded in paraffin wax. Histological slides were stained routinely with hematoxylin & eosin, with Van Gieson's Stain. Microscopical examination was performed on magnification x 40 and x 100. Stereometric study by point count method at magnification x 40 allowed finding out volume fractions (VF) of glands parenchyma and stroma. VF of lobules components (glands wall, glands lumen, ducts wall, ducts lumen, vessels, intralobular connective tissue) were registered at magnification x100. Morphometry of the secretory portion of the parotid gland was conducted on the Zeiss microscope with the help of the AxioVision Rel.4.8 program. The mature (differentiated) end pieces were measured, including their area (in mkm2), width, height, perimeter (all in mkm). Similar measurements were done in the foci of immature secretory ends of a gland. Additionally the mean height of the epithelial cells layer within the mature secretory end pieces was measured. The differences were analyzed by methods of mathematical statistics using the software Microsoft Excel; data was compared with control measurements by Students ttest. Results: The results of present research have shown the delayed differentiation of fetal parotid glands parenchymal components in case of IUGR. The parenchymal VF did not reach control values. Furthermore, VF of lobules components was also decreased. Ducts lumens appeared to be significantly narrower than at physiological gestation. Interlobular and intralobular connective tissue stroma, in contrast to the controls, occupied vast areas, and their volume fraction was increased. Deficit of the parenchymal components of the gland was enhanced by slower maturation of glands. In cases with IUGR, differentiated glands occupied smaller area, with reduced width, height and perimeter. Epithelium lining the differentiated glands is characterized by significantly lower height compared to the control group. Delayed differentiation resulted in higher proportion of immature glands. Their area, width, height and perimeter increased. IUGR was also accompanied with a variety of pathological changes. Conclusion: Present evidences suggest that IUGR leads to impaired growth and maturation of the parotid gland. Structural immaturity and lack of differentiated parenchymal elements of the organ may form the basis of its secretory functions lesion. The finding tends to support the hypothesis that the mechanism behind the increased risk of dental pathology in preterm, low birth weight and retarded children is centred at structural and functional immaturity of salivary gland., Sergiy Morozov, Olga Reshetnikova, and Literatura