Circulating tumor DNA (ctDNA) represents a promising tool for dynamic molecular profiling in metastatic colorectal cancer (mCRC), enabling monitoring of clonal tumor evolution and the detection of mechanisms of acquired resistance during treatment. The relevance of ctDNA has increased, particularly in the context of anti-EGFR therapy, where the emergence of RAS gene mutations constitutes a key resistance mechanism. The aim of this study was to evaluate the clinical utility of reassessing mutational status using ctDNA prior to rechallenge with anti-EGFR therapy in later treatment lines in patients with mCRC. A total of 17 patients with confirmed RAS and BRAF wild-type status in tumor tissue before initiation of first-line therapy were included in the analysis. All patients received anti-EGFR monoclonal antibody-based therapy in the first line and subsequently underwent ctDNA analysis from peripheral blood prior to initiation of third-line treatment using the Idylla™ qPCR platform. RAS gene mutations were detected in ctDNA in 4 patients, while 13 patients retained a wild-type status. Patients without detectable mutations achieved longer progression-free survival in the third-line setting compared with patients harboring RAS mutations. Overall survival from the start of third-line therapy was also prolonged in the wild-type ctDNA group. These findings suggest that the absence of resistant RAS clones in ctDNA may predict greater clinical benefit from anti-EGFR rechallenge. Liquid biopsy-based retesting may therefore represent an important tool for treatment individualization in later lines of mCRC therapy. This study also illustrates the translational potential of ctDNA analysis, linking dynamic molecular characterization of tumor evolution with clinically relevant treatment decision-making and the implementation of personalized oncology approaches.

Paclitaxel (PTX) resistance is a pivotal factor contributing to the poor prognostic outcome of patients with triple-negative breast cancer (TNBC). M2-type tumor-associated macrophages (M2-TAMs), a key component of the breast tumor microenvironment, foster chemoresistance through the release of multiple cytokines. The chemokine XC motif chemokine ligand 2 (XCL2) is significantly elevated in M2-polarized TAMs, but its role in PTX resistance remains unclear. Human THP-1 monocytes were first differentiated into M0 macrophages (PMA), followed by M2 polarization with IL-4 and IL-13, with polarization efficiency confirmed by flow cytometry. Cell viability and apoptosis were measured using the CCK-8 assay and flow cytometry, respectively. The binding relationship between transcription factor 4 (TCF4) and the never in mitosis gene A-related kinase 2 (NEK2) promoter was investigated by ChIP and dual-luciferase reporter assays. Our results showed that M2-TAM-secreted XCL2 reduced PTX-induced apoptosis and enhanced TNBC cell viability. Mechanistically, XCL2 was associated with XCR1 activation and subsequent β-catenin nuclear translocation, which may enable TCF4 to transcriptionally upregulate NEK2. As expected, TCF4 knockdown in TNBC cells reduced PTX resistance, while this effect was reversed by NEK2 overexpression. In addition, NEK2 knockdown in TNBC cells reversed the promoting effect of M2-CM on PTX resistance in TNBC. In vivo, M2-TAMs were associated with accelerated tumor growth under PTX treatment, whereas XCL2 knockdown restored PTX efficacy. To conclude, M2-TAM-derived XCL2 enhanced PTX resistance in TNBC cells by activating the β-catenin/TCF4/NEK2 pathway. Targeting this signaling may provide novel strategies to overcome PTX resistance in TNBC.

We explored the relationships between tissue carcinoembryonic antigen (t-CEA) and serum CEA (s-CEA) and further pursued their association with long-term survival among postoperative colorectal cancer (CRC) patients. All patients underwent determination of s-CEA levels and t-CEA expression. Pearson correlation analysis was performed to quantify the interactions between two variables. Kaplan-Meier survival analysis and time-dependent receiver operating characteristic (ROC) analyses were performed. Prognostic factors were subjected to analysis using multivariable Cox regression to form prognostic nomograms. The results showed the positive rate of t-CEA overexpression recorded at 90.96%. No significant correlation was shown between the two variables. CRC patients with high t-CEA expression revealed a significantly poorer overall survival (OS) and progression-free survival (PFS). In unadjusted Kaplan-Meier survival analyses, elevated s-CEA levels were associated with significantly poorer PFS (p = 0.033) but not OS (p = 0.077). Crucially, multivariable Cox proportional hazards regression confirmed that high t-CEA expression, rather than s-CEA, served as a robust independent prognostic factor for both OS (HR = 2.887, p = 0.017) and PFS (HR = 2.500, p = 0.002). Nomograms comprising t-CEA were constructed with superior utility in predicting the survival probability of CRC patients. To conclude, our study demonstrates the superior prognostic value of t-CEA as an independent prognostic factor for CRC compared to s-CEA.

Gliomas, the most prevalent primary malignant brain tumors, are characterized by highly invasive growth patterns. Emerging evidence indicates that long non-coding RNAs are essential for regulating key oncogenic pathways. This study focuses on lncRNA LAMTOR5 antisense RNA AS1 (LAMTOR5-AS1, also known as SLC16A4-AS1), seeking to elucidate its regulatory functions in gliomas and assess its potential as a prognostic biomarker. LAMTOR5-AS1 expression in normal brain tissues and glioma samples was assessed using quantitative real-time polymerase chain reaction (qRT-PCR). The Cancer Genome Atlas (TCGA) glioma dataset was mined for COX regression and Kaplan-Meier survival analyses to check LAMTOR5-AS1 correlation with clinical outcomes. The competing endogenous RNA (ceRNA) function of LAMTOR5-AS1 targeting miR-4653-5p was determined using anti-AGO2 immunoprecipitation assays and dual-luciferase reporter assays. The oncogenic properties of LAMTOR5-AS1 in glioma were systematically detected through in vivo and in vitro phenotype experiments. The results revealed that glioma tissues had higher levels of LAMTOR5-AS1 expression, which had a positive correlation with glioma grade and indicated a poor outcome. LAMTOR5-AS1 knocking down inhibits the malignant progression of glioma cells. Mechanistically, it was demonstrated that the LAMTOR5-AS1 regulates TCF7 level via sponging miR-4653-5p, which was correlated with the malignant progression of glioma cells. To conclude, through the miR-4653-5p/TCF7 axis, LAMTOR5-AS1 serves as ceRNA and modulates the progression of glioma.

Cisplatin remains a cornerstone of chemotherapy for gastric cancer, but acquired resistance frequently limits its therapeutic efficacy. Vitamin D3/cholecalciferol (VD3) is widely used as a nutritional supplement; however, its influence on cisplatin responsiveness in gastric cancer cells remains unclear. In this study, gastric cancer cell lines were treated with cisplatin in the presence or absence of VD3, and cell viability, apoptosis, reactive oxygen species (ROS) accumulation, DNA damage-associated signaling, and transcriptomic changes were evaluated. VD3 significantly attenuated cisplatin-induced cytotoxicity in AGS, HGC-27, and MKN-45 cells. Co-treatment with VD3 reduced cisplatin-induced apoptosis, ROS accumulation, PARP cleavage, and γH2AX activation. Transcriptomic analysis showed that VD3 markedly reduced the number of cisplatin-responsive differentially expressed genes and altered gene programs associated with extracellular matrix organization, steroid metabolism, DNA damage response, and ABC transporter-related pathways. These findings suggest that VD3 exposure can attenuate cisplatin-induced cellular responses in gastric cancer cells and modulate transcriptional programs associated with cisplatin treatment. Given that the study was performed under in vitro conditions, further investigations are required to determine the underlying mechanisms and the potential clinical relevance of these observations.

The aim of this study was to evaluate the efficacy and safety of afatinib combined with oral metronomic vinorelbine as a second-line treatment for patients with advanced lung squamous cell carcinoma (LSCC). A retrospective analysis was conducted on 38 patients with advanced LSCC who had failed first-line platinum-based doublet chemotherapy combined with immunotherapy between January 2022 and June 2024. All patients received afatinib (30 mg or 40 mg orally once daily) combined with oral metronomic vinorelbine (20 mg or 30 mg orally three times weekly on Monday, Wednesday, and Friday) until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR), and treatment-related adverse events (TRAEs). Based on the data, the ORR was 26.3%, and the DCR was 68.4%. The median PFS was 5.0 months (95% CI: 4.7-5.4), and the median OS was 9.0 months (95% CI: 8.6-10.0). Grade ≥3 TRAEs occurred in 23.7% (9/38) of patients, including diarrhea (5.3%), rash (5.3%), neutropenia (5.3%), stomatitis (2.6%), and fatigue (2.6%). No grade 4-5 TRAEs or treatment-related deaths occurred. To conclude, the combination of afatinib and oral metronomic vinorelbine demonstrates promising antitumor activity and a manageable safety profile as a second-line treatment for advanced LSCC. This combo could represent an option as second-line after failure of chemo+IO.

Wilms' tumor (WT) represents a kidney carcinoma predominantly affecting children aged five years and younger. Heterogeneous nuclear ribonucleoprotein D (hnRNPD), an RNA-binding protein, has been implicated in oncogenic processes across various tumor types, whereas its expression pattern and biological function in WT remain largely unknown. hnRNPD expression within WT tissues was evaluated using publicly available databases, and co-expressed genes were identified through bioinformatic analysis. In vitro, hnRNPD expression in WT cell lines 17.94 and HFWT was modulated via gene silencing or overexpression. We subsequently carried out functional assays to assess cell proliferation and apoptosis. Molecular experiments were conducted to determine p38 mitogen-activated protein kinase (p38 MAPK) pathway activation status within cells with altered hnRNPD expression. Furthermore, SB203580 was utilized to pharmacologically inhibit this pathway to investigate the mechanism of hnRNPD in regulating WT cell proliferation. Data showed that hnRNPD was upregulated in WT tissues and cells. Silencing hnRNPD significantly inhibited WT cell proliferation and promoted apoptosis. Conversely, overexpression of hnRNPD produced the opposing effects. MAPK14, the gene encoding the p38α isoform of p38 MAPK, was identified as a core gene within the hnRNPD co-expression network. Furthermore, the phosphorylation level of p38 MAPK in WT cells was markedly elevated compared to that in normal cells. However, inhibition of the p38 MAPK pathway using SB203580 suppressed WT cell proliferation. Notably, SB203580 effectively counteracted the pro-proliferative effect of hnRNPD overexpression on malignant WT cell growth. In conclusion, hnRNPD is highly expressed in WT and plays a significant role in promoting the malignant proliferation of WT cells. The underlying molecular mechanism involves the regulation of p38 MAPK signaling pathway activation.

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Mortality rates and limited therapeutic options justify the development of reliable preclinical research models, as their translational value remains limited. Simple in vitro models do not recapitulate tumor heterogeneity, while in vivo research faces ethical concerns and interspecies differences. Patient-derived organoids offer a physiologically more relevant platform that retains the genetic, epigenetic, and phenotypic characteristics of the original tumor. Tumor-derived organoids enable precise investigation of novel treatments, functional genomics, and modeling of cancer development. Integration with CRISPR/Cas9 gene editing further enables accurate manipulation of specific genes to study carcinogenesis and therapeutic resistance. This review highlights recent advances in the use of organoids for colorectal cancer research and explores the potential of gene-edited organoids to discover the genetic and molecular mechanisms underlying colorectal cancer development, progression, and treatment resistance.

In a recent study, the exogenous administration of angiotensin 1-7 (Ang 1,7) together with melatonin, 5-methoxytryptamine, and cannabidiol increased 1-year survival in advanced cancer patients, underlining the utility of neuromodulation in oncology. We now report a single-arm interventional study to evaluate the effectiveness of introducing Ang 1-7 in the neuroimmune regime, including pineal indoles and cannabinoids. Two cohorts of patients with advanced solid tumors refractory to standard oncologic treatments and with an estimated life expectancy of less than six months were studied. The full neuroimmune regimen cohort consisted of 100 consecutive patients treated over the last three years with Ang 1-7, pineal indoles, and cannabinoids, while the comparator cohort included 212 consecutive patients treated between 2015 and 2019 with pineal indoles and cannabinoids alone. Gastroprotected capsules of Ang 1-7 coupled with cyclodextrin were administered at 0.5 mg p.o. twice/day. Melatonin (100 mg) and 5-methoxytryptamine (20 mg) were given p.o. at bedtime and in the early afternoon, respectively. Cannabidiol or cannabigerol (in the case of glioblastoma) was given at 20 mg p.o. twice/day. Clinical response, disease control, and overall survival, along with the lymphocyte-to-monocyte ratio, were evaluated. In the full regimen cohort, disease control was achieved in 67 of 100 patients, with objective tumor regression observed in 23%. In the comparator cohort, disease control was obtained in 111 of 212 patients, with objective regression in 8%. Three-year overall survival was significantly higher in the full regimen cohort (37%) compared with the comparator cohort (19%). Both treatments were associated with a significant increase in the lymphocyte-to-monocyte ratio, suggesting an improvement in systemic immune status. The addition of Ang 1-7 to a neuroimmune regimen combining pineal indoles and cannabinoids was associated with improved disease control and long-term survival in patients with end-stage solid tumors lacking effective therapeutic options.

Hepatoblastoma (HB) is the most common pediatric liver malignancy. We investigated the role of SMAP1 in HB proliferation and its mechanism. Sixty-seven HB tissues were analyzed for SMAP1 expression via immunohistochemistry and correlated with clinical outcomes. qRT-PCR quantified SMAP1 mRNA in HB cell lines versus normal hepatocytes. SMAP1 was knocked down (siRNA/lentivirus) or overexpressed (plasmid) in HB cells; proliferation was assessed by CCK-8 and colony formation. A nude-mouse xenograft model was used to evaluate tumorigenicity. Western blotting determined C-Kit and ERK/MAPK pathway activity after SMAP1 modulation. Rescue experiments used ERK activator C16-PAF, inhibitor U0126, or C-Kit inhibitor ISCK03. SMAP1 was upregulated in HB and predicted poor prognosis. Knockdown reduced C-Kit, p-C-Kit, and p-ERK1/2, inhibited proliferation and colony formation, and suppressed xenograft growth. Overexpression produced opposite effects. U0126 reversed ERK1/2 phosphorylation and p-Rb in SMAP1-overexpressing cells, whereas C16-PAF restored ERK signaling and c-Myc/p-Rb in knockdown cells. ISCK03 blocked C-Kit/ERK activation prompted by SMAP1 overexpression. SMAP1 drives HB progression by activating C-Kit-ERK/MAPK signaling, representing a potential therapeutic target.

Periostin is an extracellular matrix protein involved in processes ranging from early embryonic development to life-threatening cancer progression. Instead of acting as a single entity, it exists in numerous alternatively spliced isoforms, primarily differing in their C-terminal region, which drives diversification and context-dependence in its biological functions. Despite growing interest, inconsistencies in nomenclature and fragmented data still complicate the interpretation of isoform-specific roles. Therefore, the aim of this review is to provide a structured overview of periostin isoforms, focusing on their roles in development and carcinogenesis, while addressing challenges in their nomenclature. During embryogenesis, expression of periostin is dynamically regulated across developmental stages and tissues. Distinct isoforms exhibit specific patterns, both spatially and temporally, that reflect specialized functions during organogenesis (particularly in the cardiac, neural, and skeletal systems), and as experimental evidence points out, certain exons play critical roles in morphogenesis. Regulatory mechanisms influencing these patterns persist beyond development and are often changed in pathological conditions. In oncological diseases, expression of periostin isoforms varies widely between tumor types and microenvironments. Many isoforms are present in malignant as well as in adjacent non-malignant tissues, with differences in their relative abundance. Functionally, exon 17-containing variants tend to influence tumor cell-intrinsic properties, while variants with exon 21 are more closely linked to stromal interactions and modulation of the tumor microenvironment. Interesting is also the fact that periostin can exert both tumor-promoting and tumor-limiting effects, depending on the isoform and biological context. Taken together, periostin isoforms represent a complex regulatory system whose better understanding and standardized classification may enhance their potential in diagnostics and therapy.

Circulating tumor plasma cells (CTPCs) in peripheral blood provide a direct readout of myeloma dissemination. While CTPCs are increasingly recognized as prognostically relevant in newly diagnosed multiple myeloma (NDMM), practical cutoffs vary across cohorts and detection methods. Here, we evaluated baseline CTPCs quantified by a single-tube 10-color next-generation flow cytometry (NGF) approach in 55 consecutive patients with symptomatic treatment-indicated NDMM. Progression-free survival (PFS) from diagnosis was analyzed using Kaplan-Meier method and compared across pragmatic CTPCs cutoffs (0.02%, 0.05%, and 0.07%) and the cohort median (0.0159%). The median follow-up by reverse Kaplan-Meier analysis was 27.9 months (interquartile range IR 20.2-31.9). The recently proposed 0.02% CTPCs threshold showed a non-significant PFS separation (median PFS 27.3 vs. 40.3 months for >0.02% vs. ≤0.02%; log-rank p=0.068; hazard ratio HR 2.23, 95% confidence interval CI 0.92-5.42). CTPCs dichotomized at 0.05% significantly stratified PFS (log-rank p=0.007), whereas 0.07% and the median cutoff yielded borderline separation. Patients with >0.05% CTPCs at diagnosis showed a significantly shorter PFS compared to those with ≤0.05% CTPCs (median PFS 14.3 vs. 40.3 months). Patients with >0.05% CTPCs were at a significantly higher risk of event (HR 3.07, 95% CI 1.29-7.31, p=0.011). Peripheral blood normal plasma cells and bone marrow tumor plasma cells showed additional associations with PFS, while bone marrow normal plasma cells did not. R2-ISS stage and high-risk cytogenetics did not stratify PFS in this cohort. To conclude, these findings support the clinical relevance of baseline CTPCs quantification in real-world NDMM, but this small single-center cohort does not formally validate any specific cutoff or establish a new clinical cutoff.

Until 2020, patients with acute myeloid leukemia (AML) who were not suitable for intensive treatment were mostly limited to symptomatic and palliative care, or to low-intensity regimens including low-dose cytosine-arabinoside (ARA-C) and azacitidine (AZA) monotherapy, which didn't bring much benefit. The situation changed with the arrival of venetoclax, a Bcl-2 inhibitor that causes leukemic cells to rapidly undergo apoptosis. The aim of our retrospective study was to summarize the treatment outcomes of all newly diagnosed patients with AML, unsuitable for intensive chemotherapy, treated with a combination of venetoclax and AZA at the Department of Hematology and Transfusion Medicine, University Hospital in Bratislava from January 1, 2021, to December 31, 2025. A total of 108 patients underwent treatment with a median follow-up of 35.9 months; median age was 69.5 years (47-84 years), and median number of cycles was 3 (1-34). Induction mortality rate was 7.4%, and tumor lysis syndrome occurred in 4.5%. The overall response rate, which included the number of complete remissions, complete remissions with incomplete hematopoietic recovery, and morphologically leukemia-free status (CR/CRi/MLFS), was 64%, the median overall survival was 9 months, and disease-free survival was 8 months. As of December 31, 2025, 23 patients are alive, and 85 have died. The main cause of death was the progression of the disease. The main contribution of our study is the finding that shortening the duration of venetoclax treatment maintains efficacy. There was no significant difference in remission rate achieved or in overall survival based on the number of days of venetoclax administration (<14 vs. 14 vs. 21 vs. 28 days). The combination of AZA and venetoclax in AML has proven to be highly effective in inducing complete remission, usually immediately after the first cycle. Unfortunately, remission is not long-lasting, relapses are frequent, and the median overall survival in real-world data is 7.9 to 13.6 months.

Circular RNAs (circRNAs) are a subclass of non-coding RNAs, playing an important regulatory role in tumor progression. Accumulating evidence has revealed that circRNAs can be regulated by m6A machinery, influencing their expression and biological functions. However, the functions and mechanisms of m6A-mediated circRNAs in nasopharyngeal carcinoma (NPC) remain to be elucidated. In this study, the sequence of hsa_circ_0005882 (circ_0005882) was determined by Sanger sequencing, and its localization in both the cytoplasm and nucleus was confirmed by fluorescence in situ hybridization. Furthermore, m6A RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) and the single-base elongation- and ligation-based qPCR amplification (SELECT) assays revealed that circ_0005882 may harbor m6A modifications. Overexpression of circ_0005882 significantly suppressed NPC cell proliferation. Mechanistically, the m6A reader YTHDF2 binds to circ_0005882 to promote its degradation, thereby reducing circ_0005882 stability. Additionally, circ_0005882 functions as a sponge for miR-654-3p, contributing to the inhibition of NPC proliferation. These findings collectively demonstrate that circ_0005882, which is negatively regulated by YTHDF2, functions as a tumor suppressor by sponging miR-654-3p to inhibit NPC cell proliferation, unveiling a novel regulatory model centered on the YTHDF2/circ_0005882/miR-654-3p axis in NPC pathogenesis.

Gastric cancer (GC) is a highly heterogeneous and aggressive malignancy with a poor prognosis, especially in advanced stages. Apatinib and cinobufagin (CS-1) have shown promising antitumor potential. However, the therapeutic efficacy and underlying mechanisms of their combined use in GC remain unclear. GC cell lines (AGS and GPM-1) were treated with apatinib, CS-1, or both. Cell viability, proliferation, migration, apoptosis, stemness, and pyroptosis-related protein expression were evaluated using cell counting kit-8 (CCK-8), colony formation, wound healing assays, flow cytometry, tumorsphere assays, and western blotting. The role of mouse double minute 2 homolog (MDM2) in modulating treatment response was investigated via overexpression experiments. Antitumor efficacy in vivo was assessed using a subcutaneous xenograft mouse model, and tumor apoptosis and proliferation were analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemistry. Combined treatment with apatinib and CS-1 significantly inhibited GC cell viability, proliferation, migration, and stemness, while inducing apoptosis and pyroptosis more effectively than either agent alone. Mechanistically, the combination therapy downregulated MDM2 expression and upregulated cleaved caspase-3 (C-caspase-3) and gasdermin E-N (GSDME-N). Overexpression of MDM2 partially reversed these effects both in vitro and in vivo, leading to reduced apoptosis, pyroptosis, and antitumor efficacy. Apatinib combined with CS-1 synergistically suppresses GC progression by inducing MDM2/C-caspase-3/GSDME-regulated pyroptosis. These findings highlight MDM2 as a critical therapeutic target and provide novel insights into the molecular mechanisms underlying the combined use of targeted agents and natural compounds in GC therapy.