BACKGROUND: Women diagnosed with breast cancer display higher propensity to develop second primary cancer in the contralateral breast (CBC). Identification of patients with increased risk of CBC and understanding relationships between hormone receptor (HR) statuses of the first and second breast cancers is desirable for endocrine-based prevention strategies. METHODS: Using 1992-2012 data from 13 SEER registries, the risk of developing CBC was determined as ratio of observed and expected second breast cancers (SIR). Association between HR statuses was examined by exploratory data analysis and multivariable logistic regression. RESULTS: Women with ER-positive and ER-negative breast cancers have increased risk of developing CBC with SIR values 2.09 (CI 95 = 1.97-2.21) and 2.40 (CI 95 = 2.18-2.63), respectively. ER statuses of the CBC are moderately positively associated. In metachronous CBC, most cases with ER-positive first cancers had ER-positive second breast cancers (81.6 %; CI 95 = 80.2-82.9 %); however, considerable proportion of cases with ER-negative first cancers had ER-positive second cancers (48.8 %; CI 95 = 46.2-51.4 %). CONCLUSIONS: Some women with ER-negative breast cancers may benefit from endocrine-based prevention of ER-positive CBC.
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu epidemiologie metabolismus patologie chirurgie MeSH
- program SEER MeSH
- radikální mastektomie MeSH
- receptory pro estrogeny metabolismus MeSH
- rizikové faktory MeSH
- sekundární malignity epidemiologie metabolismus patologie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- heterozygot MeSH
- lidé MeSH
- mutace MeSH
- nádory prsu * diagnóza epidemiologie genetika MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
This study examined the biotransformation of phytocannabinoids in human hepatocytes. The susceptibility of the tested compounds to transformations in hepatocytes exhibited the following hierarchy: cannabinol (CBN) > cannabigerol (CBG) > cannabichromene (CBC) > cannabidiol (CBD). Biotransformation included hydroxylation, oxidation to a carboxylic acid, dehydrogenation, hydrogenation, dehydration, loss/shortening of alkyl, glucuronidation and sulfation. CBN was primarily metabolized by oxidation of a methyl to a carboxylic acid group, while CBD, CBG and CBC were preferentially metabolized by direct glucuronidation. The study also screened for the activity of recombinant human cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs), which could catalyze the hydroxylation and glucuronidation of the tested compounds, respectively. We found that CBD was hydroxylated mainly by CYPs 2C8, 2C19, 2D6; CBN by 1A2, 2C9, 2C19 and 2D6; and CBG by 2B6, 2C9, 2C19 and 2D6. CBC exhibited higher susceptibility to CYP-mediated transformation than the other tested compounds, mainly with CYPs 1A2, 2B6, 2C8, 2C19, 2D6 and 3A4 being involved. Further, CBD was primarily glucuronidated by UGTs 1A3, 1A7, 1A8, 1A9 and 2B7; CBN by 1A7, 1A8, 1A9 and 2B7; CBG by 1A3, 1A7, 1A8, 1A9, 2B4, 2B7 and 2B17; and the glucuronidation of CBC was catalyzed by UGTs 1A1, 1A8, 1A9 and 2B7.
- MeSH
- biotransformace MeSH
- glukuronosyltransferasa metabolismus MeSH
- jaterní mikrozomy * metabolismus MeSH
- kyseliny karboxylové MeSH
- lidé MeSH
- systém (enzymů) cytochromů P-450 * metabolismus MeSH
- uridindifosfát metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC. METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided. RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively). CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.
- MeSH
- kohortové studie MeSH
- lidé MeSH
- nádory prsu * genetika radioterapie farmakoterapie MeSH
- prospektivní studie MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Úvod: Vyšetření krevního obrazu (KO) a diferenciálního počtu leukocytů patří mezi základní laboratorní vyšetření. Faktorem, který může negativně ovlivnit validitu výsledků, je čas od odběru vzorku do jeho zpracování (stabilita vzorku). Cílem práce bylo při různé teplotě a délce skladování vzorku analyzovat změny v KO (včetně nových rozšířených parametrů) a v diferenciálním počtu leukocytů stanoveném na hematologickém analyzátoru krvinek i mikroskopicky, včetně kvalitativních morfologických změn. Materiál a metoda: Data byla získána od 20 zdravých dobrovolníků (6 mužů/14 žen), kterým byly odebrány 3 zkumavky venózní krve s K3EDTA. Vzorky krve byly měřeny na hematologickém analyzátoru XE2100 (TOA Sysmex), nátěry periferní krve byly provedeny na nátěrovém a barvícím automatu SP1000i (TOA Sysmex). Vzorky byly opakovaně měřeny v intervalu 20 minut až 72 hodin od odběru a skladovány při laboratorní teplotě (18–25 °C) nebo v lednici (2–8 °C). Výsledky: Statisticky významné změny KO již po 12 hodinách skladování při laboratorní teplotě byly pozorovány v případě přímo měřených parametrů HCT a PCT, stejně jako u parametrů odvozených výpočtem (MCV, MCHC, RDW, PDW, MPV, P-LCR). Všechny pozorované parametry jsou uvedeny v tabulce 1. Významně se měnily v čase i hodnoty RET-He a IPF. Naopak u ostatních parametrů KO nebyly prokázány statisticky významné změny po celou dobu sledování (72 hodin). Parametry diferenciálního počtu leukocytů z analyzátoru byly stabilní po celou dobu sledování, s výjimkou parametru počet monocytů (absolutně i relativně), který byl stabilní pouze při teplotě 2–8 °C. V případě mikroskopického diferenciálního počtu leukocytů docházelo při laboratorní teplotě po 12 hodinách a při teplotě 2–8 °C většinou po 24 hodinách k apoptóze krevních buněk a ke změnám jejich morfologie. Závěr: Naše práce ukázala, že výsledky některých klinicky nejdůležitějších parametrů KO (WBC, HGB, PLT) zůstávají stabilní až 72 hodin od odběru bez ohledu na teplotu skladování vzorku, což může být v některých klinických situacích či z forenzních důvodů důležité. Některé parametry KO ale mají výrazně kratší dobu stability, proto je v běžné praxi nutné se řídit doporučením České hematologické společnosti ČLS JEP, které stanoví stabilitu KO a diferenciálního počtu leukocytů na 5 hodin při teplotě 15–25 °C.
Introduction: Complete blood count (CBC) including the automated differential white blood cell count (WBC differential) represent a routine laboratory test. The time interval between sample collection and testing (sample stability) may have an important effect on the quality of test results. The aim of this study was to analyse changes in CBC (including new advanced parameters) and WBC differential performed both by a haematology analyser and microscopic examination at different storage temperatures over time, including qualitative morphological changes. Materials and methods: Data were obtained from 20 healthy volunteers (6 males/14 females) from whom 3 tubes with K3EDTA venous blood were taken. Blood samples were measured using the XE2100 haematology analyser (TOA Sysmex). Peripheral blood smears were performed on the SP1000i automatic analyser (TOA Sysmex). After collection, samples were repeatedly measured at predetermined time intervals of 20 minutes to 72 hours and stored at room temperature (18°C to 25°C) or refrigerated (2°C to 8°C). Results: Statistically significant changes were observed both in the directly measured parameters (HCT and PCT) and in derived parameters (MCV, MCHC, RDW, PDW, MPV, P-LCR) after 12 hours of storage at room temperature. All observed parameters are given in Table 1. RET-He and IPF parameters also changed significantly over time. In contrast, no significant changes were observed in the remaining CBC parameters. Automated WBC differentials were stable for the duration of the study (72 hours), with the exception of monocyte level count (both absolute and relative), which was stable only at lower storage temperature (2°C to 8°C). Peripheral blood films showed disintegration of leukocytes and changes in their morphology after 12 hours of storage at room temperature and after 24 hours in refrigerated samples. Conclusion: Our study has shown that the results of some clinically important CBC parameters (WBC, HGB, PLT) remain stable for up to 72 hours after collection regardless of storage temperature. This may be important in certain clinical situations or for forensic reasons. However, some CBC parameters have a much shorter period of stability. It is therefore necessary to follow standards for specimen storage and handling in routine practice, which have been published by the Czech Society of Haematology ČLS JEP: The recommended maximum storage interval for CBC and differential counts were 5 hours at 15°C to 25°C.
- Klíčová slova
- stabilita vzorků, uchovávání vzorků, diferenciální počet leukocytů,
- MeSH
- dospělí MeSH
- klinická studie jako téma MeSH
- krevní obraz * MeSH
- lidé středního věku MeSH
- lidé MeSH
- odběr vzorku krve * MeSH
- počet erytrocytů MeSH
- počet leukocytů MeSH
- počet trombocytů MeSH
- referenční hodnoty MeSH
- reprodukovatelnost výsledků * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD > CBG ≥ CBN > CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids' toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 μM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.
- MeSH
- antioxidancia * farmakologie MeSH
- kanabidiol * MeSH
- lidé MeSH
- tetrahydrokanabinol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Myelodysplastický syndrom (MDS) je způsoben klonální poruchou krvetvorby s dysplastickou kostní dření. Projevuje se mono-, bi- nebo pancytopenií v periferní krvi a posléze může akcelerovat v akutní leukémii (AL). Důležitým prvotním vyšetřením, které umožňuje vyslovit podezření na MDS a přispívá k diferenciální diagnostice tohoto syndromu, je krevní obraz (KO), na jehož základě jsou indikována další speciální vyšetření k potvrzení diagnózy MDS. Pečlivé zhodnocení všech parametrů KO však může přispět i k rychlému odhadu prognózy nemocného s MDS. Cílem retrospektivní analýzy souboru 100 MDS nemocných léčených na HOK FN Olomouc v letech 2000–2008 bylo posouzení přínosu vstupních parametrů KO k odhadu rizika přechodu MDS v AL a jejich vlivu na celkové přežití (OS). Statisticky významným nepříznivým ukazatelem pro OS byla trombopenie, neutropenie, vyplavování blastů, počet blastů v periferii ? 5 % a nižší celkový objem trombocytární masy. Příznivým prognostickým faktorem naopak byla makrocytóza a lymfopenie. Nebyla prokázána statistická významnost hodnot hemoglobinu (Hb), středního objemu trombocytů (MPV) a distribuční šíře erytrocytů (RDW). Jako riziko pro vývoj AL se jevila trombopenie, nízký nebo normální objem trombocytární masy, normální střední objem erytrocytů (MCV) či mikrocytóza, vyplavování blastů, neutropenie, lymfocytóza. Ostatní parametry KO (Hb, RDW, MPV) neměly v hodnocené sestavě statisticky signifikantní vliv na riziko vzniku AL. Naše analýza tak potvrzuje význam KO nejen jako základního diagnostického laboratorního vyšetření, ale i jako prognostického ukazatele u nemocných s MDS.
Myelodysplastic syndrome (MDS) is a clonal haematopoietic disorder characterised by dysplastic bone marrow. It manifests as mono-, bi- or pancytopenia in peripheral blood and eventually can progress to leukaemia. The first important laboratory assessment on suspicion of MDS, to enable the differential diagnosis of this syndrome is full blood count (CBC), based on which, other specialised tests are indicated to confirm diagnosis of MDS. The careful evaluation of all parameters of blood count can contribute to rapid estimation of MDS prognosis. The aim of the retrospective analysis of 100 MDS patients examined within the period from 2000–2008 at the Haemato-oncology Department of the University Hospital, Olomouc was to evaluate the initial parameters of blood count for the risk of leukaemia development and overall survival (OS). Statistically significant unfavourable prognostic factors for OS showed thrombopenia, neutropenia, presence of blast cells in peripheral blood, peripheral blast cells ? 5 % and low platelet mass. The favourable factors were macrocytosis and lymphocytopenia. The level of haemoglobin (Hb), MPV and RDW were not shown as statistically significant for the prognosis. The risk factors of leukaemia development were thrombopenia, low or normal platelet mass, normal or low MCV, presence of blasts cells in peripheral blood, neutropenia, and lymphocytosis. Another parameters of CBC (Hb, RDW, MPV) were not statistically significant for leukaemia development in our group. This analysis confirms the importance of CBC not only as a basic diagnostic laboratory test but also as a prognostic indicator for MDS patients.
