Trifluridin/tipiracil (TRI/TIP) se na základě výsledků studie III. fáze RECOURSE stal standardní součástí terapie metastatického kolorektálního karcinomu. Je používán ve 3. linii léčby u pacientů, u kterých selhala předchozí terapie. Ve studii III. fáze SUNLIGHT přidání bevacizumabu k TRI/TIP zlepšilo medián celkového přežití ve srovnání s léčbou samotným trifluridin/tipiracilem na 10,8 měsíce u kombinovaného režimu s bevacizumabem oproti 7,5 měsíce u samotného TRI/TIP (HR: 0,61; 95% CI: 0,49–0,77; p < 0,001). Studie zahrnovala pacienty s histologicky potvrzeným metastatickým kolorektálním karcinomem v pokročilém stadiu, kteří byli léčeni 1–2 liniemi chemoterapie. Přidání bevacizumabu nezvýšilo riziko závažných nežádoucích účinků nebo nežádoucích účinků vedoucích k přerušení léčby. Přínosem je také prodloužení mediánu doby do zhoršení výkonnostního stavu, který dosáhl u kombinované léčby 9,3 měsíce proti 6,3 měsíce u monoterapie (HR: 0,54; 95% CI: 0,43–0,67).
Trifluridine/tipiracil (TRI/TIP) has become a standard part of the treatment of metastatic colorectal cancer based on the results of the phase III RECOURSE trial. It is used as a third-line treatment for patients in whom previous therapy has failed. In the phase III SUNLIGHT trial, the addition of bevacizumab to TRI/TIP improved median overall survival compared with trifluridine/tipiracil alone, 10,8 months for the bevacizumab combination regimen versus 7,5 months for TRI/TIP alone (HR: 0,61; 95% CI: 0,49–0,77; p < 0,001). The study included patients with histologically confirmed metastatic colorectal cancer who were treated with 1 to 2 lines of chemotherapy for advanced disease. The addition of bevacizumab did not increase the risk of serious adverse events or adverse events leading to treatment discontinuation. Another benefit is the prolongation of the median time of deterioration in performance status, which reached 9,3 months with combination treatment versus 6,3 months with monotherapy (HR: 0,54; 95% CI: 0,43–0,67).
- Klíčová slova
- trifluridin/tipiracil,
- MeSH
- antitumorózní látky aplikace a dávkování terapeutické užití MeSH
- bevacizumab farmakologie terapeutické užití MeSH
- klinická studie jako téma MeSH
- kolorektální nádory * farmakoterapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- pyrrolidiny aplikace a dávkování terapeutické užití MeSH
- thymin aplikace a dávkování terapeutické užití MeSH
- trifluridin aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT. METHODS: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question. RESULTS: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided. CONCLUSIONS: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.
Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.
Část pacientů s metastatickým kolorektálním karcinomem v dobrém výkonnostním stavu může být léčena více liniemi systémové léčby. Podle všech mezinárodních i našich doporučení jsou dlouhodobě zavedeným základem 1. a 2. linie režimy založené na fluoropyrimidinu v kombinaci s oxaliplatinou nebo irinotecanem (u nejrizikovějších s oběma preparáty) a cílenou léčbou antiangiogenní, resp. antiEGFR podle stavu RAS a BRAF. V další, 3. linii lze v dnešní době použít multikinázový inhibitor regorafenib, fluoropyrimidin a u selektované populace monoterapii antiEGFR, do popředí se však dostává jeden z novějších preparátů trifluridin/tipiracil (FTD/TPI) podávaný samostatně a na základě posledních výsledků studie SUNLIGHT především v jeho kombinaci s bevacizumabem a dosahující nejlepších dat v počtu odpovědí a přežití.
Some patients still in a good performance status are able to undergo more lines of systemic treatment for metastatic colorectal cancer. Chemotherapy regimens based on fluoropyrimidine in combination with oxaliplatin or irinotecan (in highest risk group with both of them) and targeted treatment of antiangiogenic or antiEGFR drugs according to the RAS a BRAF status are long-term the choice of first and second line treatment reflected in all international and our guideline reccommendations. Multikinase inhibitor regorafenib, fluoropyrimidine or in selected population antiEGFR monotherapy can be used in the next third line of treatment today. However, trifluridin-tipiracil (FTD-TPI) as one of the newest drugs alone or primarily in combination with bevacizumab based on the latest results of SUNLIGHT study is going in the foreground reaching the best response rate and survival.
- MeSH
- antitumorózní látky * aplikace a dávkování MeSH
- bevacizumab aplikace a dávkování MeSH
- kolorektální nádory * farmakoterapie MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé MeSH
- statistika jako téma MeSH
- trifluridin aplikace a dávkování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinická studie MeSH
- Klíčová slova
- Ivosidenib, tipiracil,
- MeSH
- analýza přežití MeSH
- bevacizumab terapeutické užití MeSH
- cholangiokarcinom * farmakoterapie prevence a kontrola MeSH
- isocitrátdehydrogenasa antagonisté a inhibitory fyziologie genetika MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kolorektální nádory * farmakoterapie prevence a kontrola MeSH
- lidé MeSH
- metastázy nádorů MeSH
- multicentrické studie jako téma MeSH
- trifluridin terapeutické užití MeSH
- výchova a vzdělávání MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
BACKGROUND: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. OBJECTIVES: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. METHODS: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). RESULTS: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. CONCLUSION: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.
- MeSH
- dimethyl fumarát terapeutické užití MeSH
- fingolimod hydrochlorid terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- kladribin terapeutické užití MeSH
- lidé MeSH
- recidiva MeSH
- registrace MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- retrospektivní studie MeSH
- roztroušená skleróza * farmakoterapie MeSH
- tablety terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Deoxycytidine analogues (dCas) are widely used for the treatment of malignant diseases. They are commonly inactivated by cytidine deaminase (CDD), or by deoxycytidine monophosphate deaminase (dCMP deaminase). Additional metabolic pathways, such as phosphorylation, can substantially contribute to their (in)activation. Here, a new technique for the analysis of these pathways in cells is described. It is based on the use of 5-ethynyl 2'-deoxycytidine (EdC) and its conversion to 5-ethynyl 2'-deoxyuridine (EdU). Its use was tested for the estimation of the role of CDD and dCMP deaminase in five cancer and four non-cancer cell lines. The technique provides the possibility to address the aggregated impact of cytidine transporters, CDD, dCMP deaminase, and deoxycytidine kinase on EdC metabolism. Using this technique, we developed a quick and cheap method for the identification of cell lines exhibiting a lack of CDD activity. The data showed that in contrast to the cancer cells, all the non-cancer cells used in the study exhibited low, if any, CDD content and their cytidine deaminase activity can be exclusively attributed to dCMP deaminase. The technique also confirmed the importance of deoxycytidine kinase for dCas metabolism and indicated that dCMP deaminase can be fundamental in dCas deamination as well as CDD. Moreover, the described technique provides the possibility to perform the simultaneous testing of cytotoxicity and DNA replication activity.
BACKGROUND: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). OBJECTIVE: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. METHODS: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. RESULTS: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CONCLUSIONS: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.
- MeSH
- imunosupresiva škodlivé účinky MeSH
- kladribin škodlivé účinky MeSH
- kvalita života MeSH
- lidé MeSH
- lymfopenie * chemicky indukované farmakoterapie MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- roztroušená skleróza * farmakoterapie MeSH
- tablety terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- časná diagnóza MeSH
- kladribin * farmakologie terapeutické užití MeSH
- kognice účinky léků MeSH
- kongresy jako téma MeSH
- lidé MeSH
- roztroušená skleróza * diagnóza farmakoterapie komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- zprávy MeSH
DNA damage can impair normal cellular functions and result in various pathophysiological processes including cardiovascular diseases and cancer. We compared the genotoxic potential of diverse DNA damaging agents, and focused on their effects on the DNA damage response (DDR) and cell fate in human lung cells BEAS-2B. Polycyclic aromatic hydrocarbons [PAHs; benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP)] induced DNA strand breaks and oxidative damage to DNA; anticancer drugs doxorubicin (DOX) and 5-bromo-2'-deoxyuridine (BrdU) were less effective. DOX triggered the most robust p53 signaling indicating activation of DDR, followed by cell cycle arrest in the G2/M phase, induction of apoptosis and senescence, possibly due to the severe and irreparable DNA lesions. BrdU not only activated p53, but also increased the percentage of G1-phased cells and caused a massive accumulation of senescent cells. In contrast, regardless the activation of p53, both PAHs did not substantially affect the cell cycle distribution or senescence. Finally, a small fraction of cells accumulated only in the G2/M phase and exhibited increased cell death after the prolonged incubation with B[a]P. Overall, we characterized differential responses to diverse DNA damaging agents resulting in specific cell fate and highlighted the key role of DNA lesion type and the p53 signaling persistence.
