BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

• Klíčová slova
• BRAF, KRAS, NRAS, PIK3CA, PTEN, anti‐EGFR therapy, invasion front, metastatic cancer, morphological sampling, tumour heterogeneity,
• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• fosfohydroláza PTEN genetika   MeSH
• GTP-fosfohydrolasy genetika   MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• kolorektální nádory * genetika   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pilotní projekty MeSH
• protinádorové látky * terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• fosfohydroláza PTEN MeSH
• GTP-fosfohydrolasy MeSH
• inhibitory proteinkinas * MeSH
• KRAS protein, human MeSH Prohlížeč
• protinádorové látky * MeSH
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny p21(ras) MeSH

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.

• Klíčová slova
• CSF sampling site, Droplet digital PCR, Glioma, Liquid biopsy, Longitudinal monitoring, Targeted therapy,
• MeSH
• cirkulující nádorová DNA mozkomíšní mok   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• gliom * genetika   patologie   diagnóza   MeSH
• histony * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádorové biomarkery * genetika   mozkomíšní mok   MeSH
• nádory mozku * genetika   diagnóza   patologie   MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• tekutá biopsie metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• cirkulující nádorová DNA MeSH
• H3-3A protein, human MeSH Prohlížeč
• histony * MeSH
• nádorové biomarkery * MeSH
• protoonkogenní proteiny B-Raf * MeSH

INTRODUCTION: Papillary thyroid carcinoma (PTC) frequently harbors the BRAF V600E mutation. Recent research suggests that aggressive behavior in BRAF V600E+ PTC may be due to an undetected mutation in the TERT gene. This study aims to observe the clinicopathological features of BRAF V600+ PTC and correlate them with surgical treatment complications. METHODS: A retrospective analysis was conducted on the BRAF V600E+ PTC cohort from July 2019 to January 2023. The histopathological features and surgical treatment (total thyroidectomy - group A, total thyroidectomy + central block neck dissection - group B) complications were correlated. Patients with TERT and TP53 mutation were excluded. Next-generation sequencing and real-time PCR were used for genetic analysis. RESULTS: Out of 121 PTCs, 65 cases showed BRAF V600E mutation with the following features: intracapsular spread (13.8%), extracapsular spread (27.7%), extrathyroidal spread (15.4%), multifocality (26.2%), angioinvasion (12.3%), and local metastasis (27.7%). The incidence of surgical complications in group A/B was: reversible recurrent laryngeal nerve (RLN) paresis 3.7/7.1%, RLN paresis permanent 0/2.4%, paresthesia 6.8/23.8%, hypocalcemia 36.4/61.9% on day 1 and 27.3/33.3% on day 3, and bleeding 2.3/9.5%. There was no significant difference in clinicopathological features between the BRAF V600E+ and BRAF V600E- PTC groups. Group B had a significantly higher incidence of hypoacalcaemia on postoperative day 1 (p = 0.047). CONCLUSION: The BRAF V600E mutation will certainly remain important in the preoperative diagnosis of PTC. The more radical surgical procedures currently recommended may be abandoned in the future, particularly elective CLND, which has a higher risk of postoperative complications.

• Klíčová slova
• BRAF V600E, Cancer, Clinicopathologic features, Complications, Mutation, Papillary Thyroid Carcinoma (PTC), Surgery, TERT, Thyroid,
• MeSH
• dospělí MeSH
• krční disekce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• nádorový supresorový protein p53 * genetika   MeSH
• nádory štítné žlázy * genetika   chirurgie   patologie   MeSH
• papilární karcinom štítné žlázy * genetika   chirurgie   patologie   MeSH
• pooperační komplikace * etiologie   MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• telomerasa * genetika   MeSH
• tyreoidektomie škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 * MeSH
• protoonkogenní proteiny B-Raf * MeSH
• telomerasa * MeSH
• TERT protein, human MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč

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
• alkylační protinádorové látky terapeutické užití   farmakokinetika   MeSH
• chemoradioterapie * metody   MeSH
• disulfiram * terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• glioblastom * radioterapie   genetika   mortalita   terapie   farmakoterapie   MeSH
• isocitrátdehydrogenasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď * krev   terapeutické užití   MeSH
• nádory mozku * radioterapie   mortalita   genetika   terapie   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• senioři MeSH
• temozolomid * terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• disulfiram * MeSH
• isocitrátdehydrogenasa MeSH
• měď * MeSH
• protoonkogenní proteiny B-Raf MeSH
• temozolomid * MeSH

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.

• Klíčová slova
• DUSP6, ERK, MAP kinase, eIF4F, melanoma,
• MeSH
• eukaryotický iniciační faktor 4F * metabolismus   genetika   MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• fosfatasa 6 s dvojí specificitou metabolismus   genetika   MeSH
• GTP-fosfohydrolasy * metabolismus   genetika   MeSH
• lidé MeSH
• MAP kinasový signální systém * genetika   MeSH
• melanom * genetika   metabolismus   patologie   MeSH
• membránové proteiny * metabolismus   genetika   MeSH
• mutace * MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny B-Raf * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• DUSP6 protein, human MeSH Prohlížeč
• EIF4E protein, human MeSH Prohlížeč
• eukaryotický iniciační faktor 4F * MeSH
• extracelulárním signálem regulované MAP kinasy MeSH
• fosfatasa 6 s dvojí specificitou MeSH
• GTP-fosfohydrolasy * MeSH
• membránové proteiny * MeSH
• NRAS protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf * MeSH

BACKGROUND: Melanoma is the most aggressive skin cancer with ability to recur also after early-stage tumor surgery. The aim was to identify early-stage melanoma patients at high risk of recurrence using liquid biopsy, estimating of mutated BRAF ctDNA and the level of tumor marker S100B in plasma. METHODS: Eighty patients were enrolled in the study. BRAF V600E mutation was determined in FFPE tissue and plasma samples using ultrasensitive ddPCR with pre-amplification. The level of S100B was determined in plasma by immunoassay chemiluminescent method. RESULTS: The best prediction of melanoma recurrence after surgery was observed in patients with combined high level of S100B (S100Bhigh) and ctDNA BRAFV600E (BRAFmut) in preoperative (57.1% vs. 12.5%, p = 0.025) as well as postoperative blood samples (83.3% vs. 14.3%, resp., p = 0.001) in comparison with low S100B and BRAF wild-type. Similarly, patients with preoperative and postoperative S100Bhigh and BRAFmut experienced worse prognosis (DFI p = 0.05, OS p = 0.131 and DFI p = 0.001, OS = 0.001, resp.). CONCLUSION: We observed the benefit of the estimation of combination of S100B and ctDNA BRAFmut in peripheral blood for identification of patients at high risk of recurrence and unfavorable prognosis. SIGNIFICANCE: There is still no general consensus on molecular markers for deciding the appropriateness of adjuvant treatment of early-stage melanoma. We have shown for the first time that the combined determination of the ctDNA BRAFmut oncogene (liquid biopsy) and the high level of tumor marker S100B in pre- and postoperative plasma samples can identify patients with the worst prognosis and the highest risk of tumor recurrence. Therefore, modern adjuvant therapy would be appropriate for these patients with resectable melanoma, regardless of disease stage.

• Klíčová slova
• BRAF V600E, S100B, ctDNA, ddPCR, melanoma,
• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * genetika   krev   MeSH
• melanom * genetika   krev   patologie   diagnóza   chirurgie   MeSH
• mutace * MeSH
• nádorové biomarkery * krev   genetika   MeSH
• nádory kůže * krev   genetika   patologie   diagnóza   chirurgie   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf * genetika   krev   MeSH
• S-100 kalcium vázající protein G, podjednotka beta * krev   genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• tekutá biopsie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• nádorové biomarkery * MeSH
• protoonkogenní proteiny B-Raf * MeSH
• S-100 kalcium vázající protein G, podjednotka beta * MeSH
• S100B protein, human MeSH Prohlížeč

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

• Klíčová slova
• Claudin 18, Colorectal carcinoma, Cytokeratin 7, Mucin, NGS, SATB2,
• MeSH
• dospělí MeSH
• fenotyp MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   metabolismus   MeSH
• imunohistochemie * MeSH
• keratin-7 metabolismus   genetika   MeSH
• kolorektální nádory * genetika   patologie   metabolismus   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 4 genetika   metabolismus   MeSH
• mucin 5AC genetika   metabolismus   MeSH
• mucin 6 genetika   metabolismus   MeSH
• mutace MeSH
• nádorové biomarkery * genetika   metabolismus   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory MeSH
• vazebné proteiny DNA v oblastech připojení k matrix * genetika   metabolismus   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• fosfatidylinositol-3-kinasy třídy I MeSH
• keratin-7 MeSH
• KRAS protein, human MeSH Prohlížeč
• MUC4 protein, human MeSH Prohlížeč
• MUC5AC protein, human MeSH Prohlížeč
• MUC6 protein, human MeSH Prohlížeč
• mucin 4 MeSH
• mucin 5AC MeSH
• mucin 6 MeSH
• nádorové biomarkery * MeSH
• PIK3CA protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny p21(ras) MeSH
• SATB2 protein, human MeSH Prohlížeč
• transkripční faktory MeSH
• vazebné proteiny DNA v oblastech připojení k matrix * MeSH

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

• Klíčová slova
• CP: Cancer, ERK pathway, KRAS mutation, RAF inhibitors, cell-line-specific mechanistic model, drug combinations, pancreatic ductal adenocarcinoma, synergy, targeted therapy resistance,
• MeSH
• duktální karcinom slinivky břišní * farmakoterapie   patologie   metabolismus   MeSH
• inhibitory proteinkinas * farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém * účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní * patologie   farmakoterapie   metabolismus   MeSH
• protoonkogenní proteiny p21(ras) metabolismus   genetika   MeSH
• raf kinasy metabolismus   antagonisté a inhibitory   MeSH
• synergismus léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• inhibitory proteinkinas * MeSH
• KRAS protein, human MeSH Prohlížeč
• protoonkogenní proteiny p21(ras) MeSH
• raf kinasy MeSH

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

• Klíčová slova
• BRAF-mutant, Binimetinib, Encorafenib, Melanoma,
• MeSH
• benzimidazoly * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• karbamáty * aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   genetika   mortalita   MeSH
• mladý dospělý MeSH
• mutace * MeSH
• nádory kůže farmakoterapie   genetika   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   škodlivé účinky   MeSH
• vemurafenib * aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• binimetinib MeSH Prohlížeč
• BRAF protein, human MeSH Prohlížeč
• encorafenib MeSH Prohlížeč

Mutations in cancer-related genes are now known to be accompanied by epigenetic events in carcinogenesis by modification of the regulatory pathways and expression of genes involved in the pathobiology. Such cancer-related mutations, miRNAs and gene expression may be promising molecular markers of the most common papillary thyroid carcinoma (PTC). However, there are limited data on their relationships. The aim of this study was to analyse the interactions between BRAF mutations, selected microRNAs (miR-21, miR-34a, miR-146b, and miR-9) and the expression of selected genes (LGALS3, NKX2-1, TACSTD2, TPO) involved in the pathogenesis of PTC. The study cohort included 60 primary papillary thyroid carcinomas (PTC) that were classified as classical (PTC/C; n=50) and invasive follicular variant (PTC/F; n=10), and 40 paired lymph node metastases (LNM). BRAF mutation status in primary and recurrent/persistent papillary thyroid carcinomas was determined. The mutation results were compared both between primary and metastatic cancer tissue, and between BRAF mutation status and selected genes and miRNA expression in primary PTC. Furthermore, miRNAs and gene expression were compared between primary PTCs and non-neoplastic tissue, and local lymph node metastatic tumor, respectively. All studied markers showed several significant mutual interactions and contexts. In conclusion, to the best our knowledge, this is the first integrated study of BRAF mutational status, the expression levels of mRNAs of selected genes and miRNAs in primary PTC, and paired LNM.

• Klíčová slova
• BRAF, MicroRNA, LGALS3, NKX2-1, Papillary thyroid carcinoma, TACSTD2, TPO,
• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy * genetika   patologie   MeSH
• mikro RNA * genetika   MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory štítné žlázy * genetika   patologie   MeSH
• papilární karcinom štítné žlázy * genetika   patologie   MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• mikro RNA * MeSH
• nádorové biomarkery MeSH
• protoonkogenní proteiny B-Raf * MeSH