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
Chronická lymfocytární leukemie (CLL) je nejčastější lymfoidní malignitou dospělých v euroamerické populaci a postihuje převážně starší osoby: medián věku v době diagnózy se pohybuje mezi 65 a 72 lety. V současnosti je naprostá většina nemocných diagnostikována v časném asymptomatickém stadiu nevyžadující léčbu. Mimořádným rysem CLL je různorodost prognózy: ani při dlouhodobém sledování zhruba 50 % nemocných neprogreduje a nikdy nedospějí k léčbě, která je zahajována pouze při známkách klinické aktivity. Prognostické faktory, zejména mutace a/nebo delece genu TP53, cytogenetické abnormality a mutační stav variabilní oblasti těžkého řetězce imunoglobulinu (IGHV), jsou velmi užitečné pro upřesnění prognózy jednotlivých pacientů. Tyto ukazatele mohou rovněž pomoci při volbě léčebného přístupu, stávají se tedy prediktivními faktory. Léčebný přístup k CLL za posledních 20 let prodělal vpravdě revoluční změny: od chemoterapie přes chemoimunoterapii přidáním anti-CD20 monoklonálních protilátek rituximabu či obinutuzumabu, které vedlo poprvé v historii léčby CLL k prodloužení celkového přežití až k novým, perorálním cíleným preparátům, zejména režimům založených na inhibitoru BCL-2 venetoklaxu s anti-CD20 protilátkou a inhibitorům Brutonovy tyrozinkinázy ibrutinibu a akalabrutinibu. Tyto cílené inhibitory jsou dnes považovány za standardní volbu u relabované/refrakterní CLL a u velké části nemocných vytlačily chemoimunoterapii též z léčby první linie. Chemoimunoterapii (zejména kombinaci fludarabin - cyklofosfamid - rituximab [FCR] u mladších zdatných nemocných bez komorbidit) lze stále zvážit jako léčebou alternativu u selektované skupiny dosud neléčených nemocných s biologicky velmi příznivou prognózou (mutovaný stav IGHV a příznivá cytogenetika, např. delece 13q).
Chronic lymphocytic leukemia (CLL) is the most common lymphoid malignancy of adults in the Euro-American population and predominantly affects the elderly: the median age at diagnosis is between 65 and 72 years. Most patients are nowadays diagnosed at an early asymptomatic stage and do not require treatment. The heterogeneity of the prognosis of CLL is extraordinary. Even with long-term follow-up, about 50% of CLL patients do not progress and never require treatment, which is initiated only in case of the disease ́s clinical activity. Prognostic factors, especially TP53 gene deletion/mutation, other cytogenetic abnormalities, and mutation status of the immunoglobulin heavy chain variable region (IGHV) are very useful in refining the prognosis of individual patients. These markers can also help to tailor the treatment, thus becoming predictive factors. The therapeutic approach to CLL has undergone truly revolutionary changes over the last 20 years: from chemotherapy to chemoimmunotherapy through addition of the anti-CD20 monoclonal antibodies rituximab or obinutuzumab, which for the first time in the history of CLL treatment has led to prolonged overall survival, to new, oral targeted agents, in particular regimens based on the BCL-2 inhibitor venetoclax with an anti-CD20 antibody and the Bruton's tyrosine kinase inhibitors ibrutinib and acalabrutinib. These targeted inhibitors are now considered the standard choice for relapsed/refractory CLL and have largely replaced chemoimmunotherapy from first-line treatment in the vast majority of patients as well. Chemoimmunotherapy (especially the combination fludarabine-cyclophosphamide-rituximab [FCR] in younger fit patients without comorbidities) can still be considered as a treatment alternative in a selected group of previously untreated patients with a biologically highly very favourable prognosis (mutated IGHV gene and favourable cytogenetics, e.g. del 13q).
- Klíčová slova
- ibrutinib, obinutuzumab, venetoklax,
- MeSH
- antitumorózní látky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- bicyklické sloučeniny heterocyklické aplikace a dávkování terapeutické užití MeSH
- buněčná a tkáňová terapie metody MeSH
- chronická lymfatická leukemie * farmakoterapie genetika patologie MeSH
- cílená molekulární terapie metody MeSH
- inhibitory fosfoinositid-3-kinasy aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- inhibitory tyrosinkinasy aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- proteinkinasa BTK antagonisté a inhibitory MeSH
- protinádorové látky imunologicky aktivní aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory MeSH
- sulfonamidy aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.
- MeSH
- bicyklické sloučeniny heterocyklické škodlivé účinky MeSH
- chlorambucil škodlivé účinky MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- doba přežití bez progrese choroby MeSH
- lidé MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- reziduální nádor farmakoterapie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
Cocaine- and amphetamine-regulated transcript peptide (CARTp) is an anorexigenic neuropeptide whose receptor is undisclosed. Previously, we reported the specific binding of CART(61-102) to pheochromocytoma PC12 cells, where CART(61-102) affinity and the number of binding sites per cell corresponded to ligand-receptor binding. Recently, Yosten et al. designated orphan GPR160 as the CARTp receptor, because the GPR160 antibody abolished neuropathic pain and anorexigenic effects induced by CART(55-102) and exogenous CART(55-102) coimmunoprecipitated with GPR160 in KATOIII cells. As no direct evidence that CARTp is a ligand for GPR160 has been described, we decided to verify this hypothesis by testing CARTp affinity to the GPR160 receptor. We investigated the GPR160 expression in PC12 cells since it is cell line known to specifically bind CARTp. Moreover, we examined the specific CARTp binding in THP1 cells, with high endogenous GPR160 expression and GPR160-transfected cell lines U2OS and U-251 MG. In PC12 cells, the GPR160 antibody did not compete for specific binding with 125I-CART(61-102) or with 125I-CART(55-102), and GPR160 mRNA expression and GPR160 immunoreactivity were not detected. Moreover, THP1 cells did not show any 125I-CART(61-102) or 125I-CART(55-102) specific binding despite GPR160 detection by fluorescent immunocytochemistry (ICC). Finally, no 125I-CART(61-102) or 125I-CART(55-102) specific binding in the GPR160-transfected cell lines U2OS and U-251 MG, selected due to their negligible endogenous expression of GPR160, was detected, despite the detection of GPR160 by fluorescent ICC. Our binding studies clearly demonstrated that GPR160 cannot be a receptor for CARTp. Further studies are needed to identify true CARTp receptors.
- MeSH
- kokain * MeSH
- krysa rodu rattus MeSH
- ligandy MeSH
- proteiny nervové tkáně * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- venetoklax,
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- bicyklické sloučeniny heterocyklické farmakologie terapeutické užití MeSH
- biomedicínský výzkum MeSH
- cytokiny farmakologie terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- sulfonamidy farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
Aktualita z Pražských hematologických dnů – Hematologie 2023
- Klíčová slova
- venetoklax,
- MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- bicyklické sloučeniny heterocyklické farmakologie terapeutické užití MeSH
- chronická myeloidní leukemie * farmakoterapie MeSH
- kongresy jako téma MeSH
- lidé MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- sulfonamidy farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- zprávy MeSH
