Východiska: Cholangiocelulární karcinom je agresivní maligní onemocnění s rostoucí incidencí a nepříznivou prognózou, přičemž medián přežití u pokročilého onemocnění činí přibližně 12 měsíců. Standardem léčby zůstává systémová chemoterapie na bázi platinového derivátu, avšak její účinnost je limitovaná. Genetické změny jako mutace IDH1 představují potenciální cíle pro cílenou terapii, zejména u pacientů s intrahepatálním cholangiocelulárním karcinomem. Ivosidenib, perorální inhibitor IDH1, prokázal ve studii fáze III ClarIDHy zlepšení přežití bez progrese onemocnění u pacientů s cholangiocelulárním karcinomem a mutací IDH1. Pozorování: Prezentujeme případ 62letého pacienta s pokročilým cholangiocelulárním karcinomem a mutací IDH1, u něhož na standardní chemoterapii po přechodné stabilizaci došlo k progresi. Pro přítomnost alterace IDH1 byl pacient léčen ivosidenibem v druhé linii. Na této léčbě došlo ke stabilizaci nemoci dle RECIST kritérií. Subjektivně však došlo k významnému kvalitativnímu zlepšení. Pacient dosáhl více než trojnásobně delšího přežití bez progrese v porovnání s přežitím dosaženým v rámci klinické studie, a to bez nutnosti redukce dávky. Závěr: Tento případ potvrzuje význam cílené terapie u pacientů s IDH1-mutovaným cholangiocelulárním karcinomem, kde je nejen dosažena objektivní stabilizace nemoci, ale i výrazné subjektivní zlepšení kvality života. Tento přístup podtrhuje význam molekulárního vyšetření a podporuje využití personalizované medicíny v léčbě vzácných typů nádorů, jako je cholangiocelulární karcinom, i přes relativně nízkou frekvenci objektivních odpovědí.
Background: Cholangiocarcinoma is an aggressive cancer with an increasing incidence and a poor prognosis, typically resulting in a median survival of about 12 months for advanced cases. The standard treatment has been platinum-based systemic chemotherapy, although its effectiveness is often limited. Genetic alterations, such as mutations in the IDH1 gene, offer potential targets for targeted therapies, particularly in patients with intrahepatic cholangiocarcinoma. Ivosidenib, an oral IDH1 inhibitor, has shown improved progression-free survival in patients with IDH1-mutated cholangiocarcinoma, according to phase III ClarIDHy study. Observation: We present the case of a 62-year-old patient diagnosed with advanced cholangiocarcinoma and an IDH1 mutation. The patient initially responded to standard chemotherapy, which led to a temporary stabilisation of the disease; however, progression was noted after 6 months. Given the presence of the IDH1 alteration, the patient was treated with ivosidenib as a second-line therapy. This treatment resulted in disease stabilisation according to RECIST criteria. Subjectively, the patient experienced a significant improvement in the quality of life. The patient achieved more than three times longer progression-free survival than was achieved in the clinical trial, without the need for dose reduction. Conclusion: This case highlights the importance of targeted therapy for patients with IDH1-mutated cholangiocarcinoma. Not only was objective disease stabilisation achieved, but there was also a significant subjective improvement in the quality of life. This underscores the value of molecular testing and supports the use of personalised medicine when treating rare cancer types like cholangiocarcinoma, even in instances where objective responses are relatively uncommon.
- Keywords
- ivosidenib,
- MeSH
- Cholangiocarcinoma diagnostic imaging diagnosis drug therapy complications MeSH
- Molecular Targeted Therapy methods MeSH
- Isocitrate Dehydrogenase antagonists & inhibitors genetics therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Femoral Neoplasms diagnostic imaging diagnosis radiotherapy secondary MeSH
- Liver Neoplasms drug therapy secondary MeSH
- Tomography, X-Ray Computed methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Azacitidine therapeutic use MeSH
- Molecular Targeted Therapy * methods MeSH
- Isocitrate Dehydrogenase antagonists & inhibitors MeSH
- Clinical Trials, Phase III as Topic MeSH
- Congresses as Topic MeSH
- Humans MeSH
- Antineoplastic Agents therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Pyridines therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- News MeSH
Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.
- MeSH
- Insulin-Secreting Cells * drug effects metabolism MeSH
- Cell Line MeSH
- Homeostasis * drug effects MeSH
- Insulin * metabolism MeSH
- Rats MeSH
- Humans MeSH
- Organophosphates toxicity MeSH
- Organophosphorus Compounds * toxicity MeSH
- Proinsulin metabolism MeSH
- Flame Retardants * toxicity MeSH
- Insulin Secretion drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Visually Accessible Rembrandt (Repository for Molecular Brain Neoplasia Data) Images (VASARI) features, a vocabulary to establish reproducible terminology for glioma reporting, have been applied for a decade, but a systematic performance evaluation is lacking. PURPOSE: Our aim was to conduct a systematic review and meta-analysis of the performance of the VASARI features set for glioma assessment. DATA SOURCES: MEDLINE, Web of Science, EMBASE, and the Cochrane Library were systematically searched until September 26, 2023. STUDY SELECTION: Original articles predicting diagnosis, progression, and survival in patients with glioma were included. DATA ANALYSIS: The modified Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was applied to evaluate the risk-of-bias. The meta-analysis used a random effects model and forest plot visualizations, if ≥5 comparable studies with a low or medium risk of bias were provided. DATA SYNTHESIS: Thirty-five studies (3304 patients) were included. Risk-of-bias scores were medium (n = 33) and low (n = 2). Recurring objectives were overall survival (n = 18) and isocitrate dehydrogenase mutation (IDH; n = 12) prediction. Progression-free survival was examined in 7 studies. In 4 studies (glioblastoma n = 2, grade 2/3 glioma n = 1, grade 3 glioma n = 1), a significant association was found between progression-free survival and single VASARI features. The single features predicting overall survival with the highest pooled hazard ratios were multifocality (hazard ratio = 1.80; 95%-CI, 1.21-2.67; I2 = 53%), ependymal invasion (hazard ratio = 1.73; 95% CI, 1.45-2.05; I2 = 0%), and enhancing tumor crossing the midline (hazard ratio = 2.08; 95% CI, 1.35-3.18; I2 = 52%). IDH mutation-predicting models combining VASARI features rendered a pooled area under the receiver operating characteristic curve of 0.82 (95% CI, 0.76-0.88) at considerable heterogeneity (I2 = 100%). Combined input models using VASARI plus clinical and/or radiomics features outperformed single data-type models in all relevant studies (n = 17). LIMITATIONS: Studies were heterogeneously designed and often with a small sample size. Several studies used The Cancer Imaging Archive database, with likely overlapping cohorts. The meta-analysis for IDH was limited due to a high study heterogeneity. CONCLUSIONS: Some VASARI features perform well in predicting overall survival and IDH mutation status, but combined models outperform single features. More studies with less heterogeneity are needed to increase the evidence level.
BACKGROUND: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. METHODS: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0-2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union's Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. DISCUSSION: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023.
- MeSH
- Antineoplastic Agents, Alkylating * therapeutic use MeSH
- Time Factors MeSH
- Chemoradiotherapy methods MeSH
- Progression-Free Survival * MeSH
- Glioblastoma * pathology drug therapy mortality radiotherapy therapy MeSH
- Clinical Trials, Phase III as Topic MeSH
- Quality of Life MeSH
- Humans MeSH
- Lomustine * administration & dosage therapeutic use adverse effects MeSH
- Multicenter Studies as Topic * MeSH
- Brain Neoplasms * radiotherapy pathology mortality therapy MeSH
- Pragmatic Clinical Trials as Topic MeSH
- Disease Progression * MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial Protocol MeSH
PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.
- MeSH
- Antineoplastic Agents, Alkylating therapeutic use pharmacokinetics MeSH
- Chemoradiotherapy * methods MeSH
- Disulfiram * therapeutic use pharmacokinetics administration & dosage MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Glioblastoma * radiotherapy genetics mortality therapy drug therapy MeSH
- Isocitrate Dehydrogenase genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Copper * blood therapeutic use MeSH
- Brain Neoplasms * radiotherapy mortality genetics therapy MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Aged MeSH
- Temozolomide * therapeutic use pharmacokinetics administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Clinical Trial, Phase II MeSH
- MeSH
- Leukemia, Myeloid, Acute * genetics congenital MeSH
- Genetic Testing MeSH
- Isocitrate Dehydrogenase genetics MeSH
- Humans MeSH
- Mutation * MeSH
- Nucleophosmin genetics MeSH
- Prognosis MeSH
- Statistics as Topic MeSH
- fms-Like Tyrosine Kinase 3 genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Navzdory lepšímu poznání molekulárních mechanismů podílejících se na patogenezi akutní myeloidní leukemie (AML) a určitému zlepšení přežití pacientů v posledních letech zůstává terapie AML stále klinickou výzvou. Z tohoto důvodu je důležité hledat nové terapie, které umožní dosažení remise. Ivosidenib, perorální inhibitor isocitrátdehydrogenázy 1 (IDH1), představuje cílenou léčbu, která jak u pacientů s nově diagnostikovanou AML s mutací IDH1 (IDH1m AML), tak u pacientů s relabovanou nebo refrakterní (R/R) IDH1m AML prokázala účinnost při použití v monoterapii nebo lépe v kombinaci s azacitidinem, venetoklaxem či intenzivní chemoterapií. Ivosidenib tak dokáže navodit u velké části pacientů s IDH1m AML léčebnou odpověď při zachování přijatelné bezpečnosti a umožní u části nemocných provedení alogenní transplantace krvetvorných buněk s největším kurativním potenciálem. Přehledová práce uvádí výsledky studií, které hodnotily léčbu ivosidenibem u AML.
Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Ivosidenib, an oral isocitrate dehydrogenase isoform 1 (IDH1) inhibitor, represents a targeted drug that has shown efficacy in patients with relapsed/refractory (R/R) and newly diagnosed IDH1 mutated (IDH1m) AML used as monotherapy or better in combination with azacitidine, venetoklax or intensive chemotherapy. Ivosidenib can induce a treatment response in a large subset of IDH1m AML patients while maintaining acceptable safety and allowing allogeneic hematopoietic stem cell transplantation with the highest potential to cure. The review highlights the study results that evaluated the treatment with ivosidenib in AML patients.
- Keywords
- ivosidenib,
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Glycine analogs & derivatives pharmacology therapeutic use MeSH
- Enzyme Inhibitors pharmacology therapeutic use MeSH
- Clinical Studies as Topic MeSH
- Drug Interactions MeSH
- Humans MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Antineoplastic Protocols MeSH
- Pyridines pharmacology therapeutic use MeSH
- Practice Guidelines as Topic MeSH
- Check Tag
- Humans MeSH
Isocitrátdehydrogenáza 1 a 2 (IDH1 a IDH2) jsou klíčové metabolické enzymy, které přeměňují isocitrát na α-ketoglutarát (αKG). Somatické bodové mutace na klíčovém argininovém zbytku (R132) v aktivním místě metabolického enzymu IDH1 vedou ke změně funkce IDH1, kdy buňka s touto mutací metabolizuje isocitrát nikoli na αKG, ale na D-2-hydroxyglutarát (2-HG), který je onkometabolitem způsobujícím zvýšenou methylaci lysinu histonu H3 a hypermethylaci DNA. Důsledkem jsou rozsáhlé epigenetické změny, které vedou ke globální dysregulaci genové exprese, zástavě diferenciace a inhibici apoptózy. Mutace IDH1 v R132 se vyskytují u 6 až 10 % pacientů s nově diagnostikovanou akutní myeloidní leukemií. Ivosidenib je inhibitorem enzymu IDH1 s mutací R132 (mIDH1). Léčba ivosidenibem vede u pacientů s akutní myeloidní leukemií k inhibici mIDH1 a normalizaci koncentrace αKG a 2-HG. Výsledkem je obnova diferenciace nádorových buněk. Na základě výsledků klinické studie AG120-C-001 schválil v červenci 2018 americký Úřad pro kontrolu potravin a léčiv ivosidenib v monoterapii pro léčbu dospělých s relabující nebo refrakterní akutní myeloidní leukemií (acute myeloid leukemia, AML) s mIDH1. Navazující klinická studie fáze 3, AGILE, srovnávající účinnost kombinace ivosidenib plus azacitidin oproti azacitidinu v monoterapii (plus placebo) u pacientů s AML s mIDH1 prokázala významně lepší léčebné výsledky při použití kombinovaného režimu. Úřad pro kontrolu potravin a léčiv v USA v květnu 2022 a následně Evropská léková agentura v květnu 2023 schválily ivosidenib v kombinaci s azacitidinem pro léčbu nově diagnostikované AML s mIDH1.
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the key metabolic enzymes that convert isocitrate to α-ketoglutarate (αKG). Somatic point mutations at a key arginine residue (R132) in the active site of the metabolic enzyme IDH1 lead to a change in IDH1 function, when cells with this mutation metabolize isocitrate not to αKG but to D-2-hydroxyglutarate (2-HG), which is an oncometabolite causing increased methylation of histone H3 lysine and thus DNA hypermethylation. The consequence is extensive epigenetic changes that lead to global dysregulation of gene expression, arrest of differentiation and inhibition of apoptosis. IDH1 mutations in R132 occur in 6-10% of patients with newly diagnosed acute myeloid leukemia (AML). Ivosidenib is an inhibitor of the enzyme IDH1 with the R132 mutation (mIDH1). Treatment with ivosidenib results in inhibition of mIDH1, normalization of αKG and 2-HG concentrations in leukemic cells of patients with AML, and, finally, restoration of leukemic cell differentiation. Based on the results of the AG120-C-001 clinical trial, the U.S. Food and Drug Administration (FDA) approved ivosidenib monotherapy in July 2018 for the treatment of adults with relapsed or refractory AML with mIDH1. A subsequent phase 3 clinical trial, AGILE, designed to compare the efficacy of the combination of ivosidenib plus azacitidine versus azacitidine monotherapy (plus placebo) in patients with AML with mIDHI, demonstrated significantly better treatment outcomes of the combination regimen. The FDA in the US in May 2022 and subsequently the European Medicines Agency in May 2023 approved ivosidenib in combination with azacitidine for the treatment of newly diagnosed AML with mIDHI.
Many types of tumors harbor a mutation in the gene for the metabolic enzyme isocitrate dehydrogenase result-ing in the production of the oncometabolite d-2-hydroxy glutarate with a pleiotropic effect on the cell. The paper provides an overview of the latest knowledge of the me-chanism of carcinogenesis, of specific drugs suppressingd-2-hydroxy glutarate production and of the causes of resistance complicating treatment based on specific inhibi-tors of oncogenic forms of isocitate dehydrogenase.
