BCR internalization
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Klinický průběh BCR/ABL negativních myeloproliferativních neoplazií je často komplikován trombotickými a v menší míře i krvácivými komplikacemi. I přesto, že tato onemocnění jsou všeobecně považována za choroby staršího věku, až 20 % pacientů s esenciální trombocytemií je mladších 40 let. Zvyšování věku rodiček a současně i zlepšení diagnostiky hematologických chorob vedou k narůstající incidenci gravidit u těchto onemocnění. Výskyt těhotenských komplikací je ve srovnání s ostatními graviditami vyšší, reprodukční ztráty u těchto žen jsou 2–3krát častější. Nejčastější komplikací gravidit těchto žen je spontánní abort v 1. trimestru gravidity (25–40 %), pozdní ztráty plodu (8–21 %). Intrauterinní retardace růstu plodu, porod mrtvého plodu a abrupce placenty jsou méně časté. Tyto komplikace vznikají bez ohledu na počet trombocytů, častěji se objevují u pacientek s komplikacemi v předchozích graviditách a s pozitivitou mutace JAK2 V617F. Omezený počet publikovaných dat činí obtížným získat jasný pohled na všeobecné riziko těchto příhod. Terapeutické možnosti představují od podávání kyseliny acetylsalicylové, nízkomolekulárního heparinu až k cytoredukční léčbě cíleně podle zhodnocení rizikových faktorů pacientky. V práci byla hodnocena retrospektivní data skupiny 7 žen s celkovým počtem 14 gravidit při diagnóze BCR/ABL negativního myeloproliferativního onemocnění. Ve shodě s literárními údaji byla zjištěna vyšší incidence těhotenských komplikací, zvláště u pacientek s pozitivitou mutace JAK2 V617F. Nízký počet gravidit v jednotlivých centrech neumožňuje jednoznačné vyjádření nejen k rizikovým faktorům těhotenských komplikací, ale i k terapeutickým doporučením. Limitace publikovaných dat s touto problematikou je výzvou ke spolupráci center nejen na úrovni celostátní, ale i mezinárodní.
The clinical course of BCR/ABL negative myeloproliferative neoplasms is often complicated by thrombotic and to a lesser extent bleeding complications. Although these diseases are generally considered to be diseases of older age, about 20% of patients with essential thrombocythemia are under 40 years. Increasing age of pregnant women and improvement of diagnostics has led to an increased incidence of pregnancy in the course of these diseases. The incidence of pregnancy associated complications is higher compared to other pregnancies, and reproductive losses in these women are 2–3 times more frequent. The most common complications of such pregnancies are spontaneous abortion in the first trimester (25–40%) and late foetal loss (8–21%). Intrauterine foetal growth retardation, stillbirth and placental abruption are less common. These complications arise regardless of the number of platelets and occur more frequently in patients with complications during previous pregnancies and with the presence of JAK2 V617F mutation. The limited number of published data makes it difficult to get a clear view of the overall risk of these events. Therapeutic options range from the administration of aspirin, low molecular weight heparin to targeted cytoreductive depending on the given patient’s risk factors. In this work, we evaluated retrospective data from a group of 7 women with a total number of 14 pregnancies and the diagnosis of BCR/ABL negative myeloproliferative disorders. In concurrence with published data, a higher incidence of pregnancy complications was found, especially in patients with positive JAK2 V617F mutation. The low number of pregnancies in single centres does not allow for any clear conclusions regarding both the risk factors for pregnancy complications and therapeutic recommendations. The limited data published on this issue is a call for cooperation not only at national, but also international level.
- MeSH
- Aspirin terapeutické užití MeSH
- bcr-abl fúzní proteiny * genetika MeSH
- biochemická analýza krve MeSH
- esenciální trombocytemie MeSH
- hematokrit MeSH
- hematologické komplikace těhotenství genetika MeSH
- heparin nízkomolekulární terapeutické užití MeSH
- Janus kinasa 2 genetika MeSH
- kardiovaskulární nemoci MeSH
- komplikace těhotenství * genetika terapie MeSH
- krvácení prevence a kontrola MeSH
- lidé MeSH
- myeloproliferativní poruchy * genetika komplikace terapie MeSH
- počet trombocytů MeSH
- polycytemie MeSH
- porod MeSH
- předčasný porod genetika MeSH
- rizikové faktory MeSH
- samovolný potrat * etiologie genetika MeSH
- statistika jako téma MeSH
- těhotenství MeSH
- trombofilie MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.
BACKGROUND AND OBJECTIVE: The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection. METHODS: Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study. A total number of 100 patients who did not achieve an optimal therapy response or who lost their therapy response were screened for the presence of BCR-ABL1 KD mutations, using direct sequencing. RESULTS: Our data show that pretreatment with non-specific non-TKI drugs prior to TKI therapy does not preferentially select for initial BCR-ABL1 KD mutations, in contrast to first-line imatinib therapy, which shows a clear predominance of T315I or P-loop mutations compared with mutations located in other KD regions. In addition, the median time to detection of P-loop mutations was substantially shorter in patients treated with first-line imatinib than in those pretreated with non-TKI drugs. Furthermore, analysis of CML patients who had recurrent resistance to TKI therapy revealed possible therapy-driven selection of BCR-ABL1 KD mutations. Finally, we confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 KD, since 40.0% of our CML patients who harbored a BCR-ABL1 KD mutation died from CML while receiving TKI treatment. Moreover, among the patients who are still on treatment, 27.8% have already progressed. Our data also confirm the unique position of the T315I mutation with respect to its strong resistance to currently approved TKIs. CONCLUSION: On the basis of the 'real-life' data described in this study, it is possible that the therapy itself results in its failure and selects the most resistant mutations under the selective pressure of the applied therapy regimen in some CML patients who harbor BCR-ABL1 KD mutations.
- MeSH
- bcr-abl fúzní proteiny genetika MeSH
- chronická myeloidní leukemie farmakoterapie genetika MeSH
- dospělí MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- protinádorové látky terapeutické užití MeSH
- senioři MeSH
- tyrosinkinasy genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Measurement of BCR activator of RhoGEF and GTPase -ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL1) mRNA levels by reverse transcription quantitative polymerase chain reaction (RTqPCR) has been critical to treatment protocols and clinical trials in chronic myeloid leukaemia; however, interlaboratory variation remains a significant issue. Reverse transcriptase droplet digital PCR (RTddPCR) has shown potential to improve testing but a large-scale interlaboratory study is required to definitively establish this. In the present study, 10 BCR-ABL1-positive samples with levels ranging from molecular response (MR)1·0 -MR5·0 were tested by 23 laboratories using RTddPCR with the QXDX BCR-ABL %IS kit. A subset of participants tested the samples using RTqPCR. All 23 participants using RTddPCR detected BCR-ABL1 in all samples to MR4·0 . Detection rates for deep-response samples were 95·7% at MR4·5 , 78·3% at MR4·7 and 87·0% at MR5·0 . Interlaboratory coefficient of variation was indirectly proportional to BCR-ABL1 level ranging from 29·3% to 69·0%. Linearity ranged from 0·9330 to 1·000 (average 0·9936). When results were compared for the 11 participants who performed both RTddPCR and RTqPCR, RTddPCR showed a similar limit of detection to RTqPCR with reduced interlaboratory variation and better assay linearity. The ability to detect deep responses with RTddPCR, matched with an improved linearity and reduced interlaboratory variation will allow improved patient management, and is of particular importance for future clinical trials focussed on achieving and maintaining treatment-free remission.
- MeSH
- bcr-abl fúzní proteiny krev MeSH
- buňky K562 chemie MeSH
- chronická myeloidní leukemie krev MeSH
- HL-60 buňky chemie MeSH
- klinické laboratoře MeSH
- lidé MeSH
- lineární modely MeSH
- nádorové biomarkery krev MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody MeSH
- reagenční diagnostické soupravy MeSH
- reprodukovatelnost výsledků MeSH
- testování odbornosti laboratoří * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Geografické názvy
- Asie MeSH
- Evropa MeSH
- Severní Amerika MeSH
PURPOSE: Approximately 1-2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. METHODS: BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). RESULTS: In total, 330 blood samples (2-34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. CONCLUSIONS: Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.
- MeSH
- bcr-abl fúzní proteiny antagonisté a inhibitory genetika MeSH
- chronická myeloidní leukemie farmakoterapie genetika patologie MeSH
- dospělí MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- míra přežití MeSH
- nádorové biomarkery genetika MeSH
- následné studie MeSH
- prognóza MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance.
Článek přehledově pojednává o významu molekulární diagnostiky chronické myeloidní leukemie, molekulárního monitorování účinnosti léčby, zbytkové nemoci a rezistence na terapii a role Národní referenční laboratoře ÚHKT v těchto oblastech vyšetřování. Kvalitativní detekce založená na multiplexové reverzně transkriptázové PCR potvrzuje přítomnost mRNA fúzního genu BCR-ABL ve vyšetřovaném vzorku, a tedy diagnózu chronické myeloidní leukemie. Charakterizace typu přestavby je rovněž významná pro následující monitorování nemoci, které probíhá na úrovni kvantifikace transkriptů BCR-ABL. Kvantitativní stanovování BCR-ABL transkriptů probíhá v pravidelných intervalech a umožňuje sledovat kinetiku nemoci v průběhu léčby na molekulární úrovni. Milníkem úspěšného managementu léčby chronické myeloidní leukemie inhibitory tyrozinových kináz je dosažení velké molekulární odpovědi, která odpovídá úrovni BCR-ABL transkriptů ≤ 0,1 %IS. Tudíž zcela zásadní je sjednocování kvantifikace BCR-ABL mezi laboratořemi, které probíhá na národní a mezinárodní úrovni. Celosvětově je v současné době intenzivně řešena otázka definice a monitorování kompletní molekulární remise, resp. míry hluboké molekulární odpovědi, jelikož s nástupem nové generace léčiv se vyšší procento pacientů dostává do molekulární remise. Nejvíce probádaným a jasně prokázaným mechanizmem rezistence na léčbu TKI jsou mutace kinázové domény v BCR-ABL. Sangerovo sekvenování je zlatým standardem pro rutinní detekci a charakterizace BCR-ABL mutací. V současnosti se do popředí zájmu dostává sekvenování 2. generace, od kterého se očekává možné objasnění vzniku mutací a klonálního vývoje pod tlakem TK inhibitorů a případné dopady této extrémně citlivé technologie na prognózu.
This overview discusses an importance of molecular diagnostics of chronic myeloid leukemia, molecular monitoring of treatment efficacy, residual disease and resistance to therapy and the role of the National reference laboratory ÚHKT in these issues. The qualitative detection based on the multiplex reverse transcriptase PCR confirms the presence of mRNA of the fusion gene BCR-ABL in the examined sample, thus a diagnosis of chronic myeloid leukemia. Characterization of the type of BCR-ABL rearrangement is also important for the subsequent monitoring based on the quantification of BCR-ABL transcripts. The quantitative determination of BCR-ABL transcripts at regular intervals monitors the kinetics of the disease during the treatment at the molecular level. A milestone in the successful management of chronic myeloid leukemia by tyrosine kinase inhibitors is the achievement of the major molecular response, which corresponds to the levels of BCR-ABL transcripts ≤ 0.1%IS. Thus, a fundamental aim is national and international harmonization of BCR-ABL transcripts quantification among laboratories. Currently, definition and monitoring of the complete molecular remission or deep molecular response rates is currently intensively studied worldwide, because of a higher number of patients achieving complete molecular response under 2nd generation TKI. The most studied and proved mechanism of the resistance to TKI therapy are mutations in the kinase domain of BCR-ABL. Sanger sequencing is the gold standard for the routine detection and characterization of BCR-ABL mutations. At present, mutation studies starting with using of the second-generation sequencing, which is expected to help in understanding of mutation development and clonal evolution under the pressure of TK inhibitors and the potential impact of this extremely sensitive technology for the prognosis.
- Klíčová slova
- Sangerovo sekvenování, sekvenování 2. generace, Sangerovo sekvenování, rezistence, real-time RT-PCR, multiplex RT-PCR, kvantifikace, inhibitory tyrozinových kináz, CMR, BCR-ABL,
- MeSH
- bcr-abl fúzní proteiny genetika krev MeSH
- časové faktory MeSH
- chemorezistence genetika MeSH
- chronická myeloidní leukemie * diagnóza farmakoterapie genetika MeSH
- genetická transkripce MeSH
- inhibitory proteinkinas * terapeutické užití MeSH
- laboratoře normy MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- mutace genetika MeSH
- nádorové biomarkery genetika MeSH
- polymerázová řetězová reakce s reverzní transkripcí metody normy MeSH
- referenční standardy MeSH
- regulace genové exprese u leukemie MeSH
- řízení kvality MeSH
- sekvenční analýza metody MeSH
- tyrosinkinasy antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib. METHODS: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily. RESULTS: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile. CONCLUSIONS: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice. TRIAL REGISTRATION: NCT03578367.
- MeSH
- bcr-abl fúzní proteiny antagonisté a inhibitory MeSH
- chronická myeloidní leukemie * farmakoterapie MeSH
- dospělí MeSH
- imatinib mesylát * terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- niacinamid analogy a deriváty MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití MeSH
- pyrazoly MeSH
- pyrimidiny terapeutické užití aplikace a dávkování MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).
- MeSH
- bcr-abl fúzní proteiny * antagonisté a inhibitory genetika MeSH
- chronická myeloidní leukemie * farmakoterapie MeSH
- dospělí MeSH
- imatinib mesylát * terapeutické užití škodlivé účinky MeSH
- inhibitory tyrosinkinasy * aplikace a dávkování škodlivé účinky MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- niacinamid aplikace a dávkování škodlivé účinky analogy a deriváty MeSH
- protinádorové látky * aplikace a dávkování škodlivé účinky MeSH
- pyrazoly * aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
