INTRODUCTION: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. METHODS: Patients aged ≥ 18 years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8 Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. RESULTS: Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0 months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. CONCLUSION: SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. TRIAL REGISTRATION: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.
- Publikační typ
- časopisecké články MeSH
Cholangiokarcinom patří mezi zhoubná nádorová onemocnění s velmi nepříznivou prognózou, pětileté přežití se týká méně než 10 % pacientů. Pokrok v oblasti molekulárních analýz těchto nádorů však velmi rozšířil možnosti cílené léčby. K nejčastěji identifikovaným změnám cholangiokarcinomu patří mutace isocitrátdehydrogenázy 1 (IDH1). Ivosidenib (Tibsovo®) jako cílený inhibitor této enzymatické varianty může nyní uplatnit svoji účinnost.
Patients suffering from cholangiocarcinoma have very unfavorable prognosis, 5 years survival is usually less than 10 %. Progress in molecular testing of this tumors revealed better possibilities of targeted therapy. One of the most represented changes is isocitrate dehydrogenase-1 (IDH-1) mutation. Selective inhibitor of mutated IDH-1 enzyme ivosidenib (Tibsovo®) is effective choice of treatment of this disease.
- Klíčová slova
- ivosidenib,
- MeSH
- cholangiokarcinom * diagnóza farmakoterapie genetika MeSH
- cílená molekulární terapie * klasifikace metody MeSH
- isocitrátdehydrogenasa antagonisté a inhibitory genetika MeSH
- lidé MeSH
- míra přežití MeSH
- mutace účinky léků MeSH
- nežádoucí účinky léčiv klasifikace MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Telomeric sequences, the structures comprised of hexanucleotide repeats and associated proteins, play a pivotal role in chromosome end protection and preservation of genomic stability. Herein we address telomere length (TL) dynamics in primary colorectal cancer (CRC) tumour tissues and corresponding liver metastases. TL was measured by multiplex monochrome real-time qPCR in paired samples of primary tumours and liver metastases along with non-cancerous reference tissues obtained from 51 patients diagnosed with metastatic CRC. Telomere shortening was observed in the majority of primary tumour tissues compared to non-cancerous mucosa (84.1%, p < 0.0001). Tumours located within the proximal colon had shorter TL than those in the rectum (p < 0.05). TL in liver metastases was not significantly different from that in primary tumours (p = 0.41). TL in metastatic tissue was shorter in the patients diagnosed with metachronous liver metastases than in those diagnosed with synchronous liver metastases (p = 0.03). The metastatic liver lesions size correlated with the TL in metastases (p < 0.05). Following the neoadjuvant treatment, the patients with rectal cancer had shortened telomeres in tumour tissue than prior to the therapy (p = 0.01). Patients with a TL ratio between tumour tissue and the adjacent non-cancerous mucosa of ≥ 0.387 were associated with increased overall survival (p = 0.01). This study provides insights into TL dynamics during progression of the disease. The results show TL differences in metastatic lesions and may help in clinical practice to predict the patient's prognosis.
Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.
- Publikační typ
- časopisecké články MeSH
Colorectal cancer (CRC) is the fourth most commonly diagnosed malignant condition in the world. Micro RNAs (miRNAs) as well as epithelial to mesenchymal transition (EMT) play an important role in the pathogenesis of CRC. We performed a comparative analysis of the expression of selected miRNA genes and EMT markers in bioptic samples from patients (n = 45) with primary CRC or metastatic (m)CRC to the regional lymph node using reverse transcription-quantitative PCR and IHC staining. Results: Out of all miRNA analyzed, the miR-17 expression was most significantly different and associated with lower risk of CRC spread to the lymph node. In addition, significant relationships were found between the tumor side localization and several miRNAs expressions (miR-9, miR-29b, miR-19a, miR-19b, miR-21, miR-106a, miR-20a and miR-17). In addition, of the examined EMT markers, only VEGFA expression correlated with tumor progression (tumor grade G2). In the examined set of patient samples and their matched healthy tissue, several specific molecular markers (miRNAs associated with EMT and tumor progression) were identified with a promising prognostic potential. Their further examination in larger patient cohorts is planned to validate the present data.
Diagnóza adenokarcinomu slinivky břišní (PDAC) patří v solidní onkologii dlouhodobě mezi ty nejzávažnější. Zvyšující se incidence a trvale vysoká mortalita vede k intenzivnímu výzkumu tohoto velmi zhoubného onemocnění. Mezi základní modality léčby s největší účinností se nadále řadí chemoterapie, ve specifických případech doplněná o radioterapii. Použití cílené léčby je též omezené. Velké naděje jsou tak stejně jako u ostatních nádorových onemocnění vkládány do renesance imunoterapie. Následující článek si klade za cíl zevrubné shrnutí dosud získaných poznatků o léčbě pacientů s PDAC právě modulací imunitního systému a nastínění nových možností a současných trendů.
Pancreatic ductal adenocarcinoma has been long count to one of the most severe diagnosis in solid oncology. Increasing incidence and persistently high mortality lead to intensive research into this highly malignant disease. Chemotherapy, in specific cases supplemented with radiotherapy, is still the most effective treatment modality. The use of targeted therapy is also limited. As with other cancers, great hopes are placed in the renaissance of immunotherapy. The following article aims to provide a brief summary of the knowledge so far gained on the treatment of patients with PDAC by modulating the immune system and outlining new possibilities and current trends.
- MeSH
- adenokarcinom farmakoterapie MeSH
- imunoterapie metody MeSH
- lidé MeSH
- nádory slinivky břišní * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- adjuvantní chemoterapie metody MeSH
- biologická terapie metody MeSH
- kolorektální nádory * diagnóza komplikace terapie MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé MeSH
- metastázy nádorů diagnóza patologie terapie MeSH
- paliativní péče MeSH
- PET/CT metody MeSH
- progrese nemoci MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- antitumorózní látky škodlivé účinky terapeutické užití MeSH
- bevacizumab terapeutické užití MeSH
- fatální výsledek MeSH
- kolorektální nádory * chirurgie farmakoterapie patologie terapie MeSH
- kombinovaná terapie * MeSH
- lidé MeSH
- metastázy nádorů terapie MeSH
- nádory jater sekundární terapie MeSH
- progrese nemoci MeSH
- senioři MeSH
- trifluridin terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
