Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- azacytidin škodlivé účinky MeSH
- bicyklické sloučeniny heterocyklické * MeSH
- lidé MeSH
- následné studie MeSH
- neutropenie * MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- sulfonamidy * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Cyanobacterial blooms are increasing in frequency and intensity globally, and impacting recreational waters as well as waters used for drinking water provisioning. They are sources of bioactive metabolites including retinoids and the neurotoxin anatoxin-a. Here, we investigated the effects of anatoxin-a on a differentiating in vitro human neural stem cell model previously characterised with retinoic acids. Effects on protein and gene expression upon exposure for 9 or 18 days to anatoxin-a alone or in co-exposure with all-trans retinoic acid were evaluated using a panel of neural and glial differentiation biomarkers. Anatoxin-a did not cause distinct developmental neurotoxicity alone, or in co-exposure with retinoic acid. However, in line with its excitotoxicity, in co-exposure with 200 nM all-trans retinoic acid it reduced the differentiation of acetylcholinergic neuron subtypes in the culture at 1000 nM (highest tested concentration). While this could have substantial functional implications for the developing nervous system, there is no indication for developmental neurotoxicity beyond its (excito-)toxicity to acetylcholinergic neurons, which only occurred in co-exposure to all-trans retinoic acid.
- MeSH
- exprese genu MeSH
- lidé MeSH
- neurotoxické syndromy * etiologie MeSH
- retinoidy metabolismus MeSH
- sinice * MeSH
- toxiny kmene Cyanobacteria MeSH
- tretinoin toxicita MeSH
- tropany * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Navzdory narůstajícím léčebným možnostem představuje relaps akutní myeloidní leukemie nadále terapeutickou výzvu. Zavedení venetoklaxu do klinické praxe vedlo k rozšíření armamentária účinných protinádorových léků. Článek přináší dvě kazuistiky ukazující použití kombinace venetoklaxu s azacitidinem u pacientů s opakovaně relabovaným onemocněním.
Despite increasing treatment options, acute myeloid leukemia relapse remains a therapeutic challenge. The introduction of venetoclax into clinical practice led to the expansion of the armamentarium of effective antitumor drugs. The article presents two case reports showing the use of the combination of venetoclax and azacitidine in patients with repeatedly relapsed disease.
- Klíčová slova
- venetoklax,
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- azacytidin farmakologie terapeutické užití MeSH
- dospělí MeSH
- lidé MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- recidiva MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.
- MeSH
- akutní myeloidní leukemie * diagnóza farmakoterapie MeSH
- azacytidin * škodlivé účinky MeSH
- cytarabin škodlivé účinky MeSH
- lidé MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
- MeSH
- akutní myeloidní leukemie * MeSH
- anemie * farmakoterapie MeSH
- azacytidin terapeutické užití MeSH
- cytarabin MeSH
- daunomycin MeSH
- lidé MeSH
- nauzea farmakoterapie MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- venetoklax,
- MeSH
- akutní myelomonocytární leukemie * farmakoterapie MeSH
- azacytidin aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- protokoly protinádorové léčby MeSH
- sulfonamidy terapeutické užití MeSH
- tyrosinkinasa 3 podobná fms antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
V posledních letech byl díky zavedení nových léčebných postupů dosažen signifikantní pokrok v léčbě mnoha hematoonkologických onemocnění. Se zavedením nových léčebných postupů přichází nové otázky ohledně dalšího zvyšování účinnosti léčby a jejího zacílení na nádorovou buňku. Jedním ze sledovaných faktorů jsou parametry nádorového mikroprostředí, které představují cytokiny, chemokiny, solubilní adhezní molekuly, specifické populace T-lymfocytů a další populace antigen prezentujících buněk. V tomto článku přinášíme výsledky naší pilotní studie hladin cytokinů, chemokinů a solubilních adhezních molekul u nemocných s myelodysplastickým syndromem vyššího rizika léčených hypomethylační látkou azacytidin. Analyzujeme faktory související s hladinami sledovaných cytokinů, celkovým přežitím a selháním léčby. Propojením klinických a laboratorních dat se tak snažíme přispět k hlubšímu pochopení problematiky myelodysplastických syndromů a obecně vlivu nádorového mikroprostředí na průběh hematoonkologických onemocnění.
A significant effort has been made to innovative treatment approaches in majority of haematooncologic diseases including myelodysplastic syndromes. Adopting novel therapies brings new questions about enhancing their efficacy. Increasing evidence show a significant role of tumour microenvironment, which compounds of cytokines, chemokines, soluble adhesion molecules, specific T-lymphocyte populations and further populations of antigen presenting cells.In this article, we publish results of our pivotal trial analysing serum levels of cytokines, chemokines and soluble adhesion molecules in patients with high-risk myelodysplastic syndromes treated with hypomethylating agent Azacytidine. We analyse factors associated with levels of measured analytes, overall survival and treatment failure. Incorporating both clinical and experimental data into analyses helps to achieve a deeper insight into biology of myelodysplastic syndromes and the crosstalk of tumour microenvironment and outcome of therapies in general.
Introduction: Spasm of the near reflex usually includes accommodative spasm, esophoria/tropia, and different degrees of miosis. Patients usually refer to distance blurred and fluctuating vision, ocular discomfort, and headaches. The diagnosis is established with refraction with and without cycloplegia; most of the cases have a functional etiology. However, some cases require neurological conditions to be ruled out; cycloplegics have an important diagnostic and therapeutic role. Purpose: To describe a case of bilateral severe accommodative spasm in a healthy 14-year-old teenager. Case presentation: A 14-year-old boy with progressive diminished visual acuity attended for YSP consultation. The diagnosis of bilateral spasm of the near reflex was made, based on a gap refraction of 9.75 D between retinoscopy with and without cycloplegia and esophoria with normal keratometry and axial length. The spasm was eliminated with 2 drops of cycloplegic in each eye separated by 15 days; no clear etiology was found other than the start of school. Conclusion: Clinicians should be aware of pseudomyopia, especially in children with acute changes in visual acuity, who are usually exposed to myopigenic environmental factors that induce overstimulation of the parasympathetic third cranial nerve’s innervation.
- MeSH
- akomodace oka * MeSH
- atropin aplikace a dávkování terapeutické užití MeSH
- esotropie diagnóza etiologie MeSH
- lidé MeSH
- mladiství MeSH
- mydriatika MeSH
- reflex fyziologie MeSH
- refrakce oka MeSH
- spasmus farmakoterapie patofyziologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination - huperzine A and procyclidine - lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota terapeutické užití MeSH
- atropin terapeutické užití farmakologie MeSH
- cholinesterasové inhibitory toxicita MeSH
- jedy * MeSH
- memantin terapeutické užití MeSH
- míra přežití MeSH
- myši MeSH
- oximy terapeutické užití farmakologie MeSH
- procyklidin farmakologie MeSH
- pyridinové sloučeniny farmakologie MeSH
- receptory N-methyl-D-aspartátu MeSH
- soman * toxicita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
