Chemoembolization for Treatment of Hepatocellular Carcinoma - National Registry-Based Analysis.

BACKGROUND: To evaluate survival benefit in patient undergoing transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) by national registry data analysis and comparison of regions with unequal usage of interventional radiology procedures. MATERIALS AND METHODS: A total of 4,343 patients with primary diagnosis of HCC between 2010-2016 were extracted from the databases of The Czech National Cancer Registry. The analysis was supported by data from the National Registry of Paid Health Services and the Death Records Database. Primary treatment option was categorized as liver resection, ablation, TACE and chemotherapy. The regional data analysis provided information of interventional radiology procedures frequency for primary treatment of HCC. The 14 main regions were symmetrically divided to group with well-developed interventional radiology service and low-developed interventional radiology service according the frequency of stage adjusted interventional radiology procedure usage (< 15%, > 15%). Kaplan-Meier and Cox regression were used for survival and hazard ratios (HR) analyses. RESULTS: Only 1,730 patients had assessed any primary treatment option, 16.5 % (285) were treated by TACE. Median of survival were significantly different in regions with well and low developed interventional radiology service for whole study population (13.2 vs. 6.5 months, p < 0.001), patients treated in regions with well-developed interventional radiology service had lower risk of death during treatment (HR 0.73; 0.66-0.81). The patient treated by TACE had median of survival 15.8 months (13.5-18.1), while the survival was not significantly different in region groups. CONCLUSION: The usage of anticancer therapies based on interventional radiology procedures is a huge factor influences the survival of HCC patient according population-based data. Studies gathering data from cancer register databases can provide further information on treatment effectiveness. This work was created at Masaryk University in the project „Oncological radiological interventions and their benefit in complex oncological treatment, comparison of dedicated oncological treatment results data of the Czech republic II“ (MUNI/A/1574/2018), supported by Ministry of Education, Youth and Sports. This publication was additionally suported by Ministry of Health grant No. 15-32484A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 4. 3. 2019.

Methotrexate efficacy, but not its intolerance, is associated with the dose and route of administration.

BACKGROUND: There is a lack of published evidence on the importance of methotrexate (MTX) dose and route of administration on both its efficacy and adverse events in children with Juvenile Idiopathic Arthritis (JIA). We aimed to document our clinical practice based on the treat-to-target approach in order to support the concept that better therapeutic effect achieved with an optimal dose of parenteral MTX is associated with clinically acceptable adverse effects comparable to those reported for oral treatment. METHODS: Study inclusion criteria were indication of new MTX therapy for active arthritis in confirmed JIA patients younger than 18 years. Eligible patients were evaluated prospectively every 3 months for 1 year using standardized instruments for treatment response (American College of Rheumatology Pediatric (ACRPedi) response, Juvenile Arthritis Disease Activity Score (JADAS) 71, Clinically Inactive Disease (CID)) and adverse events (laboratory monitoring, Methotrexate Intolerance Severity Score (MISS)). MTX responders had to achieve at least ACRPedi 70 response. MTX intolerance was defined by MISS ≥ 6. RESULTS: In 45/55 patients (81.8 %) MTX was started as subcutaneous injection. The initial median weekly dose was 14.4 mg/m(2) in parenteral and 11.7 mg/m(2) in oral administration. MTX therapy was effective in the level of ACRpedi70 and CID in 50.9 % and 30.9 % of patients at month 6 and in 70.9 % and 56.4 % after 12 months of the treatment, respectively. MTX intolerance at 6 and 12 months was noted in 25.5 % and 30.6 %, respectively. Management of intolerance included change in the dose and/or route of administration, education and councelling. Adverse events led to MTX withdrawal in 5 patients (9 %) due to toxicity (n = 3) and intolerance (n = 2). We did not find any significant predictive factors for either MTX therapeutic response or intolerance. CONCLUSION: Subcutaneous MTX weekly dose around 15 mg/m(2) is associated not only with a high response rate within the first 12 months of treatment, but also with a relatively low rate of significant adverse effects that would lead to the treatment termination. It allows early recognition of MTX non-responders and addition of biologic therapy. Sustainability of therapeutic effect and longer-term evolution of adverse events will be addressed by an ongoing extension of the study.

[On the importance of standardization in the assessment of population-based cancer patient survival in the Czech Republic -  methodology and results from the Czech National Cancer Registry]. / Význam standardizace v hodnocení populacního prezití onkologických pacientu v CR -  metodický koncept a výsledky analýzy dat Národního onkologického registru.

BACKGROUND: Calculating 5-year overall and relative survival is the standard method for population-based analyses in oncology. Survival rates based on population data do not, however, guarantee standardized benchmarks for comparison of different patient populations, which is especially true when compared populations differ considerably in age structure and representation of clinical stages. In this paper, we present and compare statistical methods for standardization of cancer survival rates. PATIENTS AND METHODS: Using data of the Czech National Cancer Registry, we estimated 5-year overall and relative survival estimates for periods 2001- 2005 and 2006- 2010. To demonstrate the effect of standardization, we calculated crude and age -standardized survival rates as well as survival rates standardized for both age and clinical stage. RESULTS: Our results show that the particular standardization method influences resulting 5-year overall and relative survival rates regarding both within and between time periods comparisons. In addition, our results document a recent improvement in 5-year relative survival between periods 2001- 2005 and 2006- 2010 for 19 of 20 evaluated diagnoses. All most prevalent cancers including prostate, lung, colorectal, breast, kidney, and uterine cancer and melanoma were observed among the diagnoses with statistically significantly improved patient survival. CONCLUSION: Unless the use of standardization to the age and stage of tumor is limited due to a small number of patients in individual age-  and stage- specific subgroups, this method can be considered as a proper statistical methodology for the population assessment of Czech cancer patient survival rates.

[Ranibizumab in the ARMD wet form of age-related macular degeneration treatment - two years results obtained from the AMADEuS Registry]. / Ranibizumab v lécbe vlhké formy VPMD - dvouleté výsledky lécby z registru AMADEuS.

AIM: The aim of this study was the retrospective follow up of Age-Related Macular Degeneration (ARMD) wet form patients treated with ranibizumab during 24 months period. The data were recorded into the AMADEuS (Age-related MAcular DEgeneration in patientS in the Czech Republic) Registry and after their evaluation compared with treatment results obtained from other departments of ophthalmology collaborating in the AMADEuS project or results of some foreign studies as well. PATIENTS AND METHODS: The group consisted of patients registered since October 1, 2008 until June 11, 2012, followed up for 24 months period. There were 90 eyes of 89 patients. All patients were completely examined in the Macular ambulance of the Department of Ophthalmology in the Faculty Hospital Brno-Bohunice, Czech Republic, E.U., and consequently the ranibizumab (Lucentis, Novartis) was applied intravitreally in three initials doses one month apart. Thereafter, ranibizumab was applied "on demand". In 43.3 % of eyes the mostly classical, in 27.8 % of eyes occult, and in 28.9 % of eyes the minimally classical choroid neovascular membrane was present. The initial visual acuity was in 3.3 % of eyes in the range 15 - 30 letters of ETDRS optotypes (20/500 - 20/200), in 61.1 % of eyes in the range 31 - 60 letters (20/200 - 20/63), and the visual acuity better than 61 letters of ETDRS optotypes (better than 20/63) was in 35.6 % of eyes. RESULTS: The average initial best-corrected visual acuity (BCVA) in our group of patients was 54.2 letters of EDTRS (SD ± 14.4). At the visit at three months after the start of the treatment the BCVA was 59.6 letters of EDTRS (SD ± 15.0), at the visit after 6 months 57.3 letters of EDTRS (SD ± 14.7), after one year of the study 54.8 letters of EDTRS (SD ± 16), after 18 months of the study 53.4 letters of EDTRS (SD ± 16,8), and after 24 months of the study was the BCVA 51.7 letters of EDTRS (SD ± 16.9). The average CRT (central retinal thickness) value by means of the OCT (optic coherence tomography) examination was at the beginning of the treatment 311.4 µm (SD ± 117.9), after 3 months of treatment 233.5 µm, (SD ± 85.4), after 6 months of treatment 262.2 µm, (SD ± 102,4), after 12 months 261 µm (SD ± 88,4), after 18 months 254.9 µm (SD ± 70.0), and after 24 months 249 µm (SD ± 87.5). The average number of ranibizumab doses during the follow-up period was 5.6. After the 24 months follow-up period, the gain of 15 or more letters of EDTRS was recorded in 11.1 % of patients, the gain of 1 - 14 letters of EDTRS optotypes was recorded in 32.2 % of patients, the decrease of 14 or less letters of EDTRS optotypes was found in 21.2 % of patients, and the decrease of 15 or more letters was found in our group in 22.2 % of patients. CONCLUSION: The ARMD wet form treatment using ranibizumab is up to date the most effective available therapy. The AMADEuS registry is of great importance in the reviewing of the effectiveness of the ARMD wet form treatment.

[Natural derivatives of 4H-pyran-4-one]. / Prírodné deriváty 4h-pyrán-4-ónu.

The present review paper describes the natural derivatives of 4H-pyran-4-one (simple, benzo- and dibenzo-derivatives). It includes their origin, use, and particularly in the case of flavonoids their biological actions and therapeutic use.

Kojic acid and its derivatives: history and present state of art.

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) represents an attractive polyfunctional skeleton for development of biologically active compounds. The authors prepared a great variety of kojic acid derivatives and selected biological properties have been studied. Thus, kojic acid derivatives are promising compounds that might advantageously be used in human and/or veterinary medicine and also in preparation of new, even more biologically active preparations.

Functionalized alkyl and aryl diselenides as antimicrobial and antiviral agents: synthesis and properties.

The different dialkyl and diaryl diselenides with carbamoyl and sulfamoyl moieties 2, 3, 5 and other substituents in the ortho position of benzene ring 4, 7, 8 as well as derivatives of 1,2,4-benzoselenadiazine (6) were designed as antiviral and antimicrobial agents and synthesized. Some of them, particularly 8a and 8b, were found in the antiviral assay in vitro to be strong inhibitors of cytopathic activity encephalomyocarditis virus (EMCV). The compound 4a and 8a were found to have a broad spectrum of acivity against bacteria, yeasts and pathogenic fungi in vitro.

Stability of the new antileukemic 4-pyranone derivative, BTMP, using HPLC and LC-MS analyses.

The stability of the new antileukemic kojic acid derivative, 5-benzyloxy-2-thiocyanatomethyl-4-pyranone (BTMP) was investigated. The degradation of BTMP was studied using specific and reproducible HPLC and LC-MS methods. Accelerated stability studies of BTMP were conducted in 0.1 M hydrochloric acid solution, physiological phosphate buffer solution (pH 7.5) and basic phosphate buffer solution (pH 9.0) at 30, 40 and 60 degrees C, respectively. The degradation of BTMP was found to follow pseudo-first order kinetics. In basic solution (pH 9.0) BTMP underwent rapid hydrolysis at a degradation rate constant (0.183-0.638 h-1) and degradation half-life (3.67-1.06 h) depending on the temperature setting. On the other hand, BTMP was significantly stable in 0.1 M hydrochloric acid solution (kdeg: 0.0017-0.0052 h-1; degradation half-life t1/2: 408.6-135.7 h), whereas in physiological phosphate buffer solution (pH 7.5), BTMP was only moderately stable (kdeg: 0.006-0.231 h-1; degradation half-life: 117.7-3.0 h). Arrhenius plots were constructed to predict the degradation kinetic parameters of BTMP at 25 degrees C and 4 degrees C. LC-MS analyses confirmed the degradation of BTMP in basic solutions and indicated at least two degradation products; namely 5-benzyloxypyran-2-ol-4-one (m/z 217.8) and 2-thiocyanatomethylpyran-5-ol-4-one (m/z 181.6).

[Kojic acid and its derivatives as potential therapeutic agents]. / Kyselina kojová a jej deriváty ako potenciálne liecivá.

The review paper studies kojic acid, a secondary metabolite of fibrous fungi, as a carrier chemical structure of potential pharmaceuticals. The examined preparative procedures, physico-chemical and biologic properties, and especially the antifungal and antileukemic effects of the parent kojic acid indicate that novel potential drugs can be developed on its basis.

Regulation of selected biological processes in neoplastic cell lines by halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyranone.

The present study was undertaken to investigate the effects of eight halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyranone on a) neoplastic cell growth, b) DNA, RNA, and protein synthesis, c) cytoplasmic phosphorylation, and d) cAMP accumulation in culture medium. Two neoplastic cell lines (the murine leukemia L1210 and the rat pituitary GH4C1) were used in the present study. The inhibitory effects of the halogen derivatives on GH4C1 cell division when compared to L1210 cells were found to be almost equal. Two halogen derivatives (2-chloromethyl-5-hydroxy-4-pyranone and 6-bromo-5-hydroxy-2-hydroxymethyl-4-pyranone) were found to inhibit DNA, RNA and protein synthesis. Moreover, the electrophoretic profile of low molecular mass cytoplasmic proteins was markedly influenced by certain halogen derivatives of 5-hydroxy-hydroxymethyl-4-pyranone in L1210 cells.

5-benzyloxy-2-thiocyanatomethyl-4-pyranone, a novel heterocyclic compound: synthesis, structure determination and effects on neoplastic cell growth.

The present study was undertaken to prepare a novel 4-pyranone compound 5-benzylaxy-2-thiocyanatomethyl-4-pyranone as well as to investigate its effects on neoplastic cell growth. Three cell lines (murine leukemia L1210, human leukemia K562 and rat pituitary GH4C1 cells) were used in our experiments. The cell growth, DNA, RNA, protein synthesis, and cytoplasmatic protein phosphorylation after the treatment of GH4C1 cells with 5-benzyloxy-2-thiocyanatomethyl-4-pyranone were investigated. We found that the above new 4-pyranone derivative at 2.6 microM significantly (p < 0.05) inhibits neoplastic cell growth, and inhibits (p < 0.05) DNA synthesis.

Polarographic behavior of kojic acid and its derivatives, determination of potential carcinogenicity and correlation of these properties with their other attributes.

Polarographic properties of kojic acid [5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one] and 10 of their synthetic derivatives were investigated. It was shown that these compounds are reduced in anhydrous conditions, usually in one two-electron step or in two one-electron steps. The presence of some substituents may change the course of reduction process. The polarography of these compounds in the presence of alpha-lipoic acid showed the kojic acid analog-alpha-lipoic acid complex formation. The determined potential carcinogenic activity of these compounds expressed as a parameter tg alpha is not substantial.

New azidometalkojates and their biological activity.

Azidometalkojates of the general formula MX2 (M = Cu, Mn, Mg, Zn or Ni and X = 5-hydroxy-2-azidomethyl-4H-pyran-4-one) were prepared and tested for antibacterial, antifungal and cytotoxic effects. The mangan and zinc derivatives are not active against any the tested microorganisms. A weak antibacterial activity was found with the copper derivative. The strongest antifungal effects were shown by the nickel derivative while the highest cytotoxic effect on HeLa cells was manifested by the zinc derivative.

Antileukemic activity of 4-pyranone derivatives.

In a search for new compounds possessing antitumor activity, we examined the effects of a group of oxygen containing heterocyclic derivatives on L1210 murine leukemia cell growth. Several 5-hydroxy-2-hydroxymethyl-4-pyranone derivatives were tested in a growth assay employing a human leukemia K562 cells line. IC50 was extrapolated from the growth inhibition curves at compound concentrations ranging from 0.1 to 100 microM. The halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyranone inhibited L1210 cell growth in suspension culture after 96 hr incubation in the following order: 5-hydroxy-2-iodomethyl-4-pyranone (IC50 3.15 microM) > 6-bromo-2-bromomethyl-5-hydroxy-4-pyranone (IC50 3.40 microM) > 6-bromo-5-hydroxy-2-hydroxy-methyl-4-pyranone (IC50 3.75 microM) > 2-bromomethyl-5-hydroxy-4-pyranone (IC50 4.30 microM) > 5-benzyloxy-2-chloromethyl-4-pyranone (IC50 5 microM) > 6-bromo-2-chloromethyl-4-pyranone (IC50 13.50 microM) > 6-chloro-2-chloromethyl-5-hydroxy-4-pyranone (IC50 18 microM) > 2-chloromethyl-5-hydroxy-4-pyranone (IC50 20 microM). The compound, 5-hydroxy-2-hydroxymethyl-4-pyranone has no effect on L1210 cell growth. These results suggest that 5-hydroxy-2-hydroxymethyl-4-pyranone derivatives might represent a new class of compounds with antileukemic activity.

Relationship between antifungal activity and hydrophobicity of kojic acid derivatives.

Twenty three kojic acid derivatives were tested in the agar diffusion test against twenty five dermatophytic fungi. The inhibitory effects at equal doses (10 mg/L) were correlated with the 1-octanol-water partition coefficients of the compounds. An improvement in antifungal activity can be achieved by increasing the hydrophobicity of the compounds.

[Postoperative complications with the use of implants for treatment of retinal detachment]. / Powiklania operacji z uzyciem wszczepów w leczeniu odwarstwien siatkówki.

Complications of the retinal detachment surgery with the use of episcleral and intrascleral implants are presented. The authors are using biological materials (fascia lata, dura mater) as well as alloplastic materials (Lincoff's sponge). Among the postoperative complications following were seen: protracted reactions from the side of the ocular adnexa, intraocular haemorrhages, intravitreal exudates. The most severe from the observed complications was the atrophy of the sclera at the spot of implantation of the silicon sponge.

[Interlocking of twins]. / Verhakung von Zwillingen.

We report about a very rare case of locked twins in cephalic presentations. A difficult forceps was necessary. In spite of cleidotomy and pushing the other twin out of the pelvis the fetus was in a deep distress and the resuscitation was unsuccessful. The second twin followed spontaneously, alive and well.