Search Results (250)

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is associated with poor prognosis and limited systemic options. This narrative review focuses on lenvatinib (LEN), a multitarget tyrosine kinase inhibitor that significantly prolongs progression-free survival. Evidence from the SELECT trial and real-world data indicates that its benefits can be enhanced through early initiation, maintenance of a high relative dose intensity, and proactive toxicity management. Planned drug holidays help sustain treatment while avoiding prolonged unplanned interruptions. In selected patients with locally advanced, initially unresectable disease, neoadjuvant LEN may enable conversion surgery, facilitating subsequent treatments. However, the current data are mainly from case series and early-phase studies. After dose reduction, re-escalation can restore disease control, and LEN rechallenge after a drug-free interval may restore sensitivity in later lines. Thus, LEN should be integrated into personalized multidisciplinary care to optimize outcomes across treatment courses. Nevertheless, key limitations remain, as much of the supporting evidence is derived from post hoc or retrospective analyses. Prospective studies are required to validate the optimization strategies, define stage-specific benefits, and determine their impact on overall survival. Full article

Tyrosine kinase inhibitors (TKIs), either as single agents or in combination with other drugs, have become a gold standard in many oncological pathologies. The identification, analysis, and clinical management of their multiple and various systemic adverse events are a clear requirement and represent a true challenge in daily practice. For this narrative review, registration clinical trials that have led to the approval of certain TKI protocols in the setting of renal cell carcinoma (RCC) were identified via the latest version of the National Comprehensive Cancer Network (NCCN) kidney cancer guidelines. The following keywords were used: Axitinib, Cabozantinib, Lenvatinib, Pazopanib, Sorafenib, Sunitinib, and Tivozanib. RCC therapies have been proven to frequently induce oral symptoms and pathologies such as stomatitis, dysgeusia, xerostomia, osteonecrosis of the jaws, oral dysesthesia, geographic tongue, and dental and periodontal damage. The aim of this review is to emphasize the mechanisms of these common drug-induced buccodental toxicities associated with TKI therapies in RCC and to draft a general clinical management of these adverse events, in order to improve patients’ quality of life and treatment adherence. Full article

Hepatocellular carcinoma (HCC) is the main leading cause of cancer-related deaths. Treatments for advanced HCC include multikinase inhibitors (Sorafenib or Lenvatinib), with limited response rates and serious side effects, or immunotherapy applicable to a small fraction of patients. Thus, new strategies are needed to improve the management of HCC. We evaluate here the efficacy and safety of XON9, a first-in-class glyco-humanized polyclonal antibody (GH-pAb). Cytotoxic activity of XON9 against Hep3B, Huh7, HepG2 or primary hepatocytes was investigated. Apoptosis, caspase activity, production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were evaluated. Efficacy of XON9 was then assessed in vivo in NMRI nude mice, while pharmacokinetics and safety were evaluated in a non-human primate. XON9 showed a potent complement-dependent cytotoxicity (CDC) against Hep3B and Huh7 (EC50 < 10 µg/mL), and to a less extent against HepG2. XON9 induced apoptosis of HCC cells with activation of caspases 8 and 9, increase in ROS and drop in MMP. Overall, in vitro lytic activity of XON9 was superior to that of Sorafenib. In vivo, XON9 significantly reduced tumor progression and outperformed Sorafenib. No toxicity was observed after repeated injections of XON9 in a non-human primate. XON9 represents a promising and selective immunotherapy against refractory HCC. Full article

Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness is limited by acquired resistance. This study explores the potential of OPCs to overcome Lenvatinib resistance in HCC. Methods: To evaluate the potential of OPCs to overcome Lenvatinib resistance in HCC, we established Lenvatinib-resistant Huh-7 and PLC-PRF-5 cell lines and conducted systematic cell culture experiments to assess their antitumor effects. Furthermore, genome-wide transcriptomic profiling, network pharmacology approaches, and pathway enrichment analysis were performed to identify resistance-associated signaling pathways that could serve as therapeutic targets. Results: The combination of OPCs and Lenvatinib demonstrated a significant synergistic anti-proliferative effect in resistant hepatocellular carcinoma cells, with the most synergistic dose combinations showing Bliss synergy scores exceeding 10. Transcriptomic profiling revealed that the adhesion molecule ITGA3 is a key factor in Lenvatinib resistance and contributes to the acquisition of anoikis resistance. The combination treatment suppressed ITGA3–EGFR–AKT signaling, restored anoikis sensitivity, significantly reduced spheroid formation (fold change = 0.10–0.12; p < 0.001), and markedly increased apoptosis (fold change = 2.7–5.0; p < 0.001). Conclusions: This study is the first to demonstrate that OPCs can overcome chemotherapy resistance by targeting the integrin pathway, providing scientific evidence for their potential use as an adjunctive therapy for chemotherapy-resistant HCC. Full article

Endometrial cancer represents one of the most common gynecological cancers in women. In recent years, there has been increasing interest in immunotherapy, including the use of pembrolizumab, particularly for the treatment of cancers with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H). A systematic review of the literature from 2020 to 2025 was conducted according to the PICO model. Six studies were included in this review, comprising four randomized clinical trials (RCTs) and two pre-specified subgroup analyses derived from previous RCTs involving a total of 3684 patients with early-stage or advanced disease or metastatic or recurrent endometrial cancer. Interventions included the use of pembrolizumab in monotherapy and in combination with chemotherapy or lenvatinib. Pembrolizumab showed a significant improvement in progression-free survival (PFS) and overall survival (OS) in the dMMR patient groups. Therapeutic benefit was limited in the proficient mismatch repair (pMMR) groups. The incidence of side effects was high but comparable to the control group. Pembrolizumab, especially in combination therapy with lenvatinib, is a promising therapeutic option for patients with dMMR/MSI-H endometrial cancer. The results suggest a potential long-term treatment effect, although the limitations of the RCT and the variability in the therapeutic regimens require further research. Full article

Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated antioxidant capacity. However, its mechanistic integration with radiotherapy remains incompletely understood. Methods: We compared the effects of three clinically approved VEGFR-targeting tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib, and ripretinib, on NSCLC cell viability with and without radiation. Subsequent mechanistic studies focused on cabozantinib and included ferroptosis rescue assays (ferrostatin-1, deferoxamine), lipid ROS quantification, glutathione assays, clonogenic survival, co-immunoprecipitation of BECN1–SLC7A11 complexes, and BECN1 knockdown by siRNA and shRNA. Results: All three TKIs were evaluated for cytotoxicity, but only cabozantinib significantly reduced NSCLC cell viability in combination with radiation in a ferroptosis-dependent manner. Cabozantinib inhibited STAT3 phosphorylation and downregulated MCL1, resulting in the release of BECN1. This allowed BECN1 to bind and suppress SLC7A11, disrupting system Xc⁻ function, depleting glutathione, and promoting lipid ROS accumulation. Genetic silencing of BECN1 reversed these effects and restored redox balance and clonogenic capacity. Lenvatinib and ripretinib failed to elicit similar responses, indicating that the inhibition of non-VEGFR targets (e.g., MET, AXL) may be essential for ferroptosis induction by cabozantinib. Conclusions: Cabozantinib enhances the radiosensitization of NSCLC cells through ferroptosis induction mediated by the suppression of the STAT3/MCL1/BECN1/SLC7A11 axis. These findings uncover a novel mechanism linking kinase inhibition to redox imbalance and suggest that the pharmacologic modulation of ferroptosis using multi-target TKIs may represent a rational approach to overcome radioresistance in NSCLC. Full article

Background: Atezolizumab plus bevacizumab and lenvatinib are standard treatments for advanced hepatocellular carcinoma, but conventional tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin have a limited ability to reflect treatment responses. Circulating tumor cells with cancer stem cell characteristics have emerged as promising biomarkers. We examined the dynamics of cancer stem cell-related circulating tumor cell subsets and tumor markers at early and maximal response phases in patients with unresectable hepatocellular carcinoma undergoing systemic therapy. Methods: Sixty-two patients treated with either atezolizumab plus bevacizumab or lenvatinib were retrospectively analyzed. Peripheral blood was collected at baseline, during the early phase (during one to three months), and at maximal response. Circulating tumor cell subsets expressing cancer stem cell markers (CD90, epithelial cell adhesion molecule; CD133, vimentin) were assessed using multiparametric flow cytometry and compared with alpha-fetoprotein and des-gamma-carboxy prothrombin. Results: Early decreases in CD90-positive circulating tumor cells after therapy were associated with tumor shrinkage, longer periods of progression-free survival in both groups, and prolonged overall survival in the atezolizumab plus bevacizumab group. By contrast, early changes in alpha-fetoprotein and des-gamma-carboxy prothrombin were not consistently related to tumor size, progression-free survival, or overall survival. At maximal response, changes in CD90-positive circulating tumor cells reflected tumor burden more accurately than alpha-fetoprotein or des-gamma-carboxy prothrombin. Conclusions: These findings indicate that cancer stem cell-related circulating tumor cell subsets, particularly CD90-positive cells, may serve as valuable biomarkers for monitoring treatment response and predicting prognosis in unresectable hepatocellular carcinoma. CD90-positive circulating tumor cells perform dynamic monitoring superior to conventional markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin. Full article

Background: Hepatocellular carcinoma (HCC) larger than 10 cm has a poor prognosis, with high recurrence rates, particularly distant metastases. This study examined whether lenvatinib treatment followed by liver resection improves the outcomes for large HCCs compared with upfront surgery. Methods: We retrospectively analyzed 30 patients with HCC larger than 10 cm who underwent hepatectomy at our institution between January 2008 and December 2023. The study cohort included 30 patients: 9 received preoperative lenvatinib treatment followed by hepatectomy (LEN group), while 21 patients underwent upfront surgery (UFS group). We compared the clinicopathological characteristics, surgical outcomes, recurrence patterns, and survival between the two groups. Results: The median duration of lenvatinib administration was 1.8 months, with partial response in two patients (22.2%) and stable disease in seven patients (77.7%). While lenvatinib treatment significantly decreased serum albumin levels (p < 0.05) and increased ALBI scores (p = 0.03), the surgical outcomes including blood loss, operation time, and complication rates were comparable between the two groups. The 3-year recurrence-free survival rate was significantly higher in the LEN group compared with the UFS group (66.7% vs. 16.1%, p = 0.027). The 3-year overall survival rate was also higher in the LEN group, though not statistically significant (85.7% vs. 56.1%, p = 0.059). Notably, distant metastasis rates were lower in the LEN group compared with the UFS group (11.1% vs. 47.6%, p = 0.10). Conclusions: Preoperative lenvatinib treatment followed by hepatectomy for large HCC (> 10 cm) may reduce recurrence, particularly distant metastases, and potentially improve long-term survival. This approach may be a promising strategy for large HCCs, which traditionally have a poor prognosis with upfront surgery alone. Full article

Background: Renal cell carcinoma (RCC) is a common malignancy with a rising global incidence. While cytoreductive nephrectomy (CRN) was historically a cornerstone in the management of metastatic RCC (mRCC), its role has been questioned following pivotal trials such as CARMENA and SURTIME. With the advent of immune checkpoint inhibitors (ICIs) and targeted therapies, the contemporary relevance of CRN coupled with first-line immunotherapy and targeted therapy combination regimens warrants re-evaluation. Methods: This retrospective cohort study utilized the TriNetX research network to identify patients aged 18–90 years diagnosed with mRCC between 2005 and 2024 who received first-line systemic therapies. Patients were stratified into two cohorts based on receipt of CRN status within one year of diagnosis. Propensity score matching (1:1) was done to adjust baseline characteristics. Kaplan–Meier survival analysis and Cox proportional hazards modeling were used to compare five-year overall survival between the groups. Results: Among 5960 eligible patients, 1776 (888 CRN matched to 888 who did not) formed the cohort of analysis. The CRN group demonstrated significantly higher five-year survival (57.7% vs. 45.0%, p < 0.0001) with a hazard ratio of 1.56 (95% CI: 1.33–1.83). Subgroup analyses showed consistent survival benefits across all four NCCN-recommended first-line regimens—Axitinib + Pembrolizumab: 64.0% (CRN) vs. 53.3% (no CRN), p = 0.01; Cabozantinib + Nivolumab: 50.1% vs. 40.4%, p = 0.004; Lenvatinib + Pembrolizumab: 37.4% vs. 22.8%, p = 0.012; Nivolumab + Ipilimumab: 56.4% vs. 46.1%, p = 0.005. Conclusions: In the era of modern immunotherapy and targeted agents, CRN remains associated with improved survival in patients with mRCC receiving NCCN-recommended first-line regimens. These findings support the continued evaluation of CRN as a component of multimodal therapy, particularly in patients with favorable risk profiles. Full article

Endometrial carcinoma (EC) is the most common gynaecological malignancy in developed nations, exhibiting significant molecular heterogeneity that impacts prognosis and treatment response, particularly in advanced or recurrent settings. Traditional classification is increasingly supplemented by molecular subtyping (POLE-ultramutated, MSI-high/dMMR, NSMP, p53-mutated/CNH), which provides crucial prognostic information and predicts benefit from immunotherapy. This review summarizes the landscape of predictive biomarkers for immune checkpoint inhibitor (ICI) therapy in EC, emphasizing a new therapeutic scenario for advanced and recurrent EC. Mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), leading to high tumor mutational burden (TMB) and increased neoantigen production, is the most established predictor, resulting in FDA approvals for pembrolizumab and dostarlimab in this subgroup. POLE mutations also confer hypermutation and high immunogenicity, predicting a favorable ICI response. Other biomarkers, including PD-L1 expression and TMB, show variable correlation with response and require further standardization. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs), also influences treatment outcomes. Clinical trials have demonstrated significant survival benefits for ICIs combined with chemotherapy (e.g., dostarlimab/pembrolizumab + carboplatin/paclitaxel) in first-line settings, especially for dMMR/MSI-H EC, and for ICI combinations with targeted agents (e.g., lenvatinib + pembrolizumab) in previously treated patients. Integrating molecular classification and validated biomarkers is essential for optimizing patient selection and developing personalized immunotherapy strategies for EC. Full article

Background: Lenvatinib is a receptor tyrosine kinase inhibitor indicated for advanced radioiodine-refractory thyroid cancer (RAI-RTC). It is recommended to start at 24 mg per day; however, in patients who are at risk of severe adverse events, it may be reasonable to start at lower doses. Patients and Methods: We included 15 patients with RAI-RTC who started lenvatinib at a very low/low dose and evaluated the efficacy and safety. Results: Eight patients (53.3%) did not show progression of the disease, and about half of the patients (53.3%) were alive at the last follow-up visit. Up to 26.6% of patients achieved a partial response to therapy, with a notable volume reduction in the local and metastatic lesions. However, 80% of patients experienced adverse events, mainly of a moderate grade. Conclusions: Although these findings are based on a small sample size and a single-center study, treatment with lenvatinib at very low/low doses in fragile patients seems to be a promising strategy for the management of RAI-RTC, balancing effective disease control with a favorable safety profile. Full article

This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro-computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively (p < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment. Full article

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) may have distinct biological characteristics influencing systemic treatment response. However, the prognostic impact of MASLD vs. alcohol-related HCC in patients receiving lenvatinib remains unclear. This study aimed to assess lenvatinib’s effectiveness and safety in these populations. Methods: A multicenter cohort of 378 HCC patients treated with lenvatinib (2019–2024) was analyzed. Propensity score matching was performed based on age, sex, tumoral stage, alpha-fetoprotein levels and Child–Pugh class. Survival was estimated using Kaplan–Meier analysis and compared with the log-rank test. Results were expressed as HR and 95% CI. Results: After matching, 115 patients per group were compared. Median OS was 21 months (95% CI: 20–23) in the group with metabolic dysfunction-associated steatohepatitis (MASH) and 19 months (95% CI: 18–21) in the group with alcohol etiology (p = 0.18). In multivariate analysis, only Child–Pugh class (HR 2.67, 95% CI: 1.84–5.41) and tumor stage (HR 2.18, 95% CI: 1.57–6.93) resulted as significant predictors of OS. Median PFS was 9 months (95% CI: 8–9) in patients with MASH and 9 months (95% CI: 7–10) in patients with alcohol etiology (p = 0.33). Only the Child–Pugh class was a significant predictor of PFS in univariate analysis (HR 1.56, 95% CI: 1.15–3.41; p = 0.03). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Lenvatinib is effective in patients with both MASH- and alcohol-related HCC, with no difference in oncological outcomes between the two groups. Full article

Thyroid cancer (TC) invariably remains the most prevalent endocrine cancer in the world. Major histological forms of TC include papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid carcinoma (ATC), each of which has a unique clinical and molecular profile. The incidence rate of TC is higher in females, and unfortunately, it has tended to increase over the last several years. Yet the treatment of advanced or aggressive TC forms has improved recently because of developments in immunotherapy and targeted medicines, including PD-1 inhibitors and tyrosine kinase inhibitors (e.g., lenvatinib, sorafenib). Imaging, fine-needle aspiration biopsies, and molecular testing are implemented in the diagnostic process, e.g., in search of mutations that might affect prognosis and provide the most successful treatment option. Chemotherapy, immunotherapy, radioactive iodine therapy (RAI), surgery (such as a total thyroidectomy), and molecularly targeted therapies are currently standard treatment modalities in TC. Optimizing patient outcomes requires better diagnostic precision and individualized treatment regimens based on the genetic profile and tumor subtype. To improve survival and quality of life, it is critical to comprehend the complex etiology of TC and the changing therapeutic landscape. Full article