Search Results (266)

Solid-organ transplant (SOT) recipients have an increased risk of malignancies and poor oncological prognosis compared to the general population. A central reason for both is that various factors unique to transplantation coalesce to dampen anti-tumor immunity. These include graft or immunosuppressive therapy-related T-cell dysfunction, microenvironmental changes in grafts due to ischemic/reperfusion injuries peri-transplant and comorbidities such as metabolic syndrome. Both innate and adaptive immunity are heavily implicated in cytotoxicity effected by systemic therapeutic agents, not just immune checkpoint inhibitors (ICIs) but also conventional chemotherapy and targeted therapies. Hence, impaired anti-tumor immunity may also affect the treatment efficacy of these agents. Generally, clinical data for systemic therapies in transplant recipients is constrained to retrospective and heterogenous case reports and series only, with a low level of evidence and significant risk of bias. For ICIs, the efficacy in SOT recipients is relatively well preserved in cutaneous squamous cell carcinomas but seems diminished in other tumor types compared to non-transplant recipients. Data for other agents are limited, but the efficacies of chemotherapy in SOT recipients with colorectal cancer and sorafenib/lenvatinib in LT recipients with recurrent hepatocellular carcinoma seem preserved. Given the prevailing trend of broadening the use of transplantation in patients with cancer, further clinical and translational studies to develop strategies to enhance anti-tumor immunity while ensuring graft preservation are urgently needed. Full article

Background/Objectives: Understanding the mechanisms of drug response plays an essential role in predicting effects prior to drug administration and advancing personalized medicine by optimizing treatment strategies. This study aimed to identify gene combinations that can predict the antitumor activity of lenvatinib, which is a multi-targeted tyrosine kinase inhibitor. Methods: Cancer- and drug-response-related gene sets were identified by mapping gene expression profiles of previously reported syngeneic mouse tumor models onto a protein–protein interaction network and extracting subnetworks comprising nodes where high expression levels were clustered. The scores for these network modules were calculated using the expression data of mouse tumor models prior to drug administration. These scores were used to train a machine learning (ML) model of drug response to lenvatinib by narrowing down the parameter space using hepatocellular carcinoma patient-derived xenograft (HCC PDX) models acquired in this study. Results: Using this integrative framework, we identified several network modules including those involved in the nerve growth factor signaling pathway, Wnt signaling pathway, and interleukin signaling pathways, that were consistently prioritized as informative features across PDX models and human patient data from The Cancer Genome Atlas. Conclusions: These network modules exhibit biological functions that are linked to the known targets of lenvatinib in the cancer cells or the tumor microenvironment, highlighting their potential relevance as determinants of drug response. Full article

Renal cell carcinoma (RCC) is the most common kidney cancer, with increasing global incidence. Despite advances with VEGF-targeted tyrosine kinase inhibitors (TKIs) and immunotherapies, therapeutic resistance remains frequent, limiting long-term benefits. This highlights the need for potential biomarkers of tumor aggressiveness and therapeutic candidates, such as glucose-6-phosphate dehydrogenase (G6PD), whose altered expression has been associated with several cancers. We evaluated G6PD gene and protein expression in 121 RCC samples through immunohistochemistry and assessed functional role in vitro approaches. 786-O and ACHN cells were treated with the inhibitor G6PDi-1 and the anti-VEGF cabozantinib/lenvatinib. G6PD mRNA levels were higher in tumors than in non-neoplastic tissues, indicating shorter overall survival in clear cell (ccRCC) and papillary (pRCC) subtypes. Immunolabeling confirmed a higher expression in pRCC and associations with pathological features. CRISPR and RNAi datasets revealed a stronger G6PD dependency in the ccRCC. A high gene expression was observed in lenvatinib non-responder cell lines, and DepMap dose–response curves indicated modest responses to VEGF inhibitors. In vitro, ACHN was more sensitive to VEGF inhibition, particularly cabozantinib, whereas G6PDi-1 had stronger effects in 786-O, impairing viability, migration, and clonogenic capacity. Our findings support G6PD as a biomarker of tumor aggressiveness and G6PDi-1 as a potential therapeutic in RCC models. Full article

Lenvatinib is an oral multi-kinase inhibitor which is used for the treatment of renal cell carcinoma, non-iodine avid differentiated thyroid cancer, hepatocellular carcinoma, and endometrial cancer. We present a series of three (3) patients who, whilst on treatment with Lenvatinib, developed symptoms and radiological findings of acalculous cholecystitis. A radiological review of another nineteen (19) Lenvatinib-treated patients in our center was undertaken, with another three (3) patients exhibiting radiological features of acalculous cholecystitis with gallbladder wall thickening and pericholecystic fluid collection but without abdominal pain or clinical symptoms of cholecystitis. A literature review is also presented of all previous publications of Lenvatinib-induced acalculous cholecystitis, including the results of two pharmacovigilance studies. This review provides evidence that Lenvatinib-induced acalculous cholecystitis is not as rare as initially thought from the Lenvatinib licensing studies; hence, this is an adverse event that merits more attention. Oncologists using Lenvatinib should be aware of this potential toxicity and be familiar with its management. Full article

Background: Atezolizumab plus bevacizumab (ATZ/BEV) is widely used as first-line therapy for advanced hepatocellular carcinoma (HCC); however, optimal subsequent treatment after ATZ/BEV failure remains unclear. Methods: Between October 2020 and August 2024, 165 patients with unresectable HCC treated with first-line ATZ/BEV were retrospectively analyzed. After excluding patients with insufficient follow-up, outcomes were compared between those who received lenvatinib (LEN) as second-line therapy (n = 49) and those who did not (n = 95). Results: Median overall survival (OS) was significantly longer in the LEN group than in the non-LEN group (20.9 vs. 8.47 months, p < 0.01). LEN administration was independently associated with improved OS (hazard ratio 0.48), and this benefit remained significant after inverse probability weighting adjustment (adjusted hazard ratio 0.50). Among LEN-treated patients, a lower albumin–bilirubin score before ATZ/BEV and a total LEN dose ≥ 400 mg were independent prognostic factors. Conclusions: Lenvatinib as second-line therapy after ATZ/BEV was associated with improved survival in unresectable HCC. Preservation of liver function and the ability to maintain adequate lenvatinib exposure were associated with favorable outcomes, likely reflecting baseline prognosis and treatment feasibility rather than lenvatinib-specific predictive factors. Full article

Background and aim: Recent preclinical studies have confirmed that inhibiting the MAP kinase pathway can induce the re-differentiation of radioiodine (RAI)-refractory (RAIR) follicular cell thyroid cancers (TCs). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myo-inositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells. Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into two groups: (1) a control group in which patients are treated with KIs (subgroup a: trametinib plus dabrafenib; subgroup b: lenvatinib); (2) a group in which patients (divided into the two subgroups) are treated with the same KIs in addition to MI. After 30 days of MI treatment, all patients, treated with levothyroxine (L-T4) at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). On day 35, the patients will be subjected to whole-body scintigraphy, with hybrid imaging where possible (SPECT/CT), after the administration of diagnostic activity (185–222 MBq of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0); after 30 days of MI therapy; and then on days 31, 32, 33, 34, and 35 after MI therapy. Quality of life (QoL) will be assessed at the beginning of the MI treatment and at the end of its administration. The primary endpoint is the restoration of 123-I uptake in RAIR-TC patients already on KI therapy alone and on KI therapy plus MI. The restoration of 123-I uptake in target lesions will be evaluated. Conclusions: MI may have a synergistic effect at the cellular level, and the possible increase in the re-differentiation of RAIR-TC in patients treated with KIs plus MI may have great clinical relevance. The re-uptake of RAI will be evaluated as the primary endpoint, and Tg values and QoL will be evaluated as the secondary endpoints. The main limitation of this study is that we do not investigate any clinical effects. We will have to postpone the clinical analysis to a later date after the administration of RAI for therapeutic purposes. Full article

Background/Objectives: Head and neck cancer (HNC) represents the seventh most common cancer diagnosis globally, yet current treatments, including surgery, radiation, and immunotherapy, have shown limited improvement in outcomes. Drug repurposing offers a cost-effective strategy to identify new therapeutic options by leveraging existing medications with known safety profiles. Within this study, we developed the GARD pipeline (Genomic Alteration-based Repurposing for Drugs), designed to uncover repurposing candidates for HNC using genomic and network-based approaches. Methods: GARD integrates multi-omics data from The Cancer Genome Atlas (TCGA), including copy number variation (CNV) and somatic mutations (SOM). The cohort was stratified by human papillomavirus (HPV) status. Risk-associated genes were identified and then expanded via high-confidence protein–protein interaction (PPI) networks. Top candidate genes were filtered through comprehensive analysis of publicly available literature data in PubMed using LLMs to validate the relationship between the identified genes and HNC. The top risk genes and their network-expanded neighbors were mapped against DrugBank, and through statistical significance testing and literature validation, established significant drug–gene associations. Results: Significant genes associated with HNC, inferred by genomics alteration, were identified across HPV-positive and HPV-negative subgroups, such as PIK3CA, SOX2, TP53, EIF4G1, TLR7, CLDN1, PRKCI, and EPHA2. Further expansion through the PPI network identified other targetable genes such as EGFR, ERBB2, and the FGFRs. Literature-based validation efforts ensured confidence in the gene–disease association. Drug–gene mapping revealed candidates spanning those already in clinical trials for HNC (e.g., Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, and Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing. Conclusions: The GARD pipeline demonstrates a genomics-driven, network-informed framework for systematic drug repurposing in HNC. HPV stratification enhances precision, literature-based validation strengthens confidence, and integrated drug mapping enables refinement of existing therapies and discovery of novel candidates for personalized treatment strategies. Code Availability: The full implementation of the GARD pipeline, including preprocessing scripts, statistical analysis modules, and visualization tools, is publicly available on GitHub. Full article

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors with significant biological diversity. Despite significant improvements in diagnostics and a growing range of available therapies, long-term disease control remains difficult in advanced cases. The tumor microenvironment, which in pNENs adopts a predominantly immunosuppressive profile and promotes tumor development, is attracting increasing attention. A complex network of interactions dominates the tumor tissue, including M2 macrophages, regulatory T cells, and numerous pathways that inhibit effector lymphocyte activity. M2 macrophages, through the secretion of anti-inflammatory cytokines and exosome-mediated signaling, support angiogenesis while simultaneously attenuating the cytotoxic response. Simultaneously, receptors and ligands associated with immune checkpoints are overexpressed. In addition to classic molecules such as PD-1/PD-L1 and CTLA-4, the role of B7x and CD276 is increasingly being emphasized, as their presence correlates with rapid disease progression and poor prognosis. To date, attempts to use checkpoint inhibitors as monotherapy have yielded modest clinical benefits. However, approaches based on combination strategies—both in the form of dual immune blockade and in combination with chemotherapy or angiogenesis-targeted therapy—have shown significantly greater activity. Therapies using tyrosine kinase inhibitors, such as sunitinib and newer drugs (lenvatinib, surufatinib, cabozantinib), may partially normalize the tumor’s disrupted vascular architecture and thus increase its susceptibility to immunological interventions. In the coming years, it will be crucial not only to overcome the immunosuppressive nature of the TME but also to identify predictive biomarkers that will allow for more precise patient selection. This approach may open the way to more effective, personalized therapies for pNENs. Full article

Background/Objectives: Preclinical models that accurately reflect Ewing sarcoma (ES) will enable the prioritisation of clinically active targeted agents from bench to clinic. To expedite this process, we have established and characterised patient-derived ES cultures (PDES) in vitro. Methods: Fluorescence in situ hybridisation, RT-PCR and western blotting were used to examine expression of the pathognomonic EWSR1 fusions. Activation or repression of EWSR1 fusion downstream targets and proliferation was examined by immunofluorescence and immunohistochemistry. Using next-generation sequencing, the DNA and transcriptomic profiles of PDES and cell lines were compared. The response of PDES and cell lines to standard-of-care chemotherapeutics, ionising radiation and investigational drugs was examined. Results: All PDES contain EWSR1 fusion DNA, consistent with a diagnosis of ES. EWSR1 fusion gene RNA and protein were detected in 70% and 21% of PDES, respectively. Markers of proliferation and expression of EWSR1 fusion target genes were consistent with the tumours from which PDES were derived (R² = 0.74, p < 0.0001) and the paediatric mesenchymal lineage (SBS5 and SBS1, ID1 and ID2). In contrast, the transcriptome of PDES was significantly different from that of cell lines. PDES had a significantly increased doubling time (p < 0.00001), decreased expression of Ki67 (p < 0.0001) and increased migration (p < 0.02) compared to cell lines. Consistent with the longer doubling time, PDES were more resistant to doxorubicin, etoposide and vincristine and ionising radiation (p < 0.0001) than cell lines. PDES were sensitive to mTKIs (cabozantinib, lenvatinib, and regorafenib), and trabectedin. The response of PDES to drugs in vitro reflects the clinical experience of patients. Conclusions: Models incorporating PDES cells may positively contribute to the preclinical pipeline. Full article

Background/Objectives: Standard treatment of multiply relapsed Ewing sarcoma remains to be established. Recent studies evaluating tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties have shown encouraging results. Therefore, we conducted a systematic review and meta-analysis to explore the efficacy and safety of TKIs in patients with Ewing sarcoma. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials (CTs) and cohort studies assessing TKIs in the treatment of advanced Ewing sarcoma patients who received at least one prior line of therapy. The main outcome was objective response rate (ORR). All analyses were conducted using R software (v.4.2.2), employing random effects models with 95% confidence intervals (CIs). Results: We included 14 studies (seven phase II CT and seven retrospective cohorts), comprising 257 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib, sorafenib, lenvatinib, sunitinib, fruquintinib, and imatinib. In a pooled analysis of all Ewing sarcoma patients treated with TKIs, the ORR was 23% (95% CI, 11.2–37.1%) and the DCR was 61.1% (95% CI, 47.3–74.2%). Responses were numerically higher but statistically nonsignificant between clinical trials and real-world studies. The analysis including only single-agent TKIs showed better responses for anlotinib and apatinib, yet these drugs are not available in Western countries. Among the FDA-approved TKIs, superior outcomes were noted with single-agent cabozantinib. (ORR: 21.6%) and regorafenib (ORR: 11.3%). Several studies did not report toxicity data exclusively for Ewing sarcoma patients; thus, conclusions about toxicity are mostly based on the general population of studies and may not be fully representative of Ewing sarcoma patients. Conclusions: Anti-angiogenic TKIs have shown important anti-tumoral activity in patients with Ewing sarcoma. Efficacy was consistently seen in both clinical trials and real-world studies. Nonetheless, there are important differences in study design and population that may limit our interpretation of efficacy and toxicity findings. Full article

Background/Objectives: Lenvatinib combined with anti-PD-1 therapy has shown promise in the treatment of hepatocellular carcinoma (HCC). The study evaluates changes in gut microbiota (GM) and metabolites during HCC treatment with lenvatinib combined with anti-PD-1. Methods: An HCC mouse model was established via diethylnitrosamine (DEN) injection, and the mice were then treated with lenvatinib, anti-PD-1, or their combination. GM composition and structural changes were assessed by 16S rDNA sequencing, and metabolite abundance by liquid chromatography–mass spectrometry (LC–MS). Results: Significant alterations in GM and metabolites were observed in the HCC group compared to the control group, and compared with the HCC group, both monotherapy and combination therapy resulted in varying degrees of GM and metabolites rebalancing. Specifically, compared to the HCC group, lenvatinib combined with anti-PD-1 therapy decreased the abundance of GM, including p_Patescibacteria, g_Lactobacillus, g_Clostridium_sensu_stricto_1, g_Eubacterium_siraeum_group, and g_Desulfovibrio, while the abundance of g_Prevotella_7 increased. Metabolite changes included increased 4-pyridoxic acid, deoxycholic acid, and taurochenodesoxycholic acid, and decreased myristic acid, oleic acid, riboflavin, and uric acid. Conclusions: HCC induces substantial alterations in the GM and metabolic profile of mice. Lenvatinib combined with anti-PD-1 treatment partially modulates these dysregulations. The relevant GM and metabolites may be associated with the efficacy of combined therapy and could serve as potential markers for further investigation. Full article

Background: Tyrosine kinase inhibitors (TKIs) are crucial to treating endocrine-related malignancies, including advanced thyroid cancers and neuroendocrine tumors, but their benefit is tempered by cutaneous adverse events (CAEs) that impair adherence and quality of life. Objective: To summarize the dermatologic toxicities of TKIs used in endocrine oncology and provide practical, multidisciplinary guidance for prevention and management. Methods: Narrative synthesis of clinical trial reports, post-marketing studies, and specialty guidelines pertinent to lenvatinib, vandetanib, cabozantinib, and other commonly used TKIs, integrating dermatologic and endocrine perspectives on mechanisms and care pathways. Results: VEGFR-targeted TKIs frequently cause hand–foot skin reaction, xerosis, fissuring, paronychia, and impaired wound healing; multikinase inhibition also produces alopecia, pigmentary changes, and mucositis. Epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) inhibition with vandetanib is associated with acneiform eruption, photosensitivity, and nail fragility. Pathogenesis reflects on-target inhibition of VEGF/EGFR signaling leading to keratinocyte dysfunction, vascular fragility, and altered eccrine mechanics. Early risk stratification, patient education, and bundle-based prophylaxis (emollients, keratolytics, urea-based creams, sun protection) reduce incidence and severity. Grade-based algorithms combining topical corticosteroids/antibiotics, dose interruptions or reductions, and short systemic courses (e.g., doxycycline, antihistamines) enable symptom control while maintaining anticancer intensity. Close coordination around procedures minimizes wound-healing complications. Conclusions: Dermatologic toxicities are predictable, mechanism-linked, and manageable with proactive, multidisciplinary care. Standardized prevention and treatment pathways tailored to specific TKIs—particularly lenvatinib, vandetanib, and cabozantinib—can preserve dose intensity, optimize quality of life, and sustain antineoplastic efficacy. Full article

Hepatocellular carcinoma (HCC) remains a prevalent form of cancer with a poor prognosis and requires systemic therapies for most advanced cases. In this review, we summarize considerations for selecting treatment options for HCC, particularly with regard to immune checkpoint inhibitors (ICIs). Traditional chemotherapy has been surpassed by molecular-targeted therapies and ICIs, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors, which enhance the immune response against tumors. The European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines recommend atezolizumab/bevacizumab (Atez/Bev) and tremelimumab/durvalumab (Dur/Tre) as first-line treatments for unresectable HCC, along with alternatives, such as sorafenib and lenvatinib. Atezolizumab and bevacizumab have demonstrated superior efficacy but require the monitoring of bleeding risk and adverse events, such as proteinuria. Tremelimumab and durvalumab offer alternatives for patients at high risk of anti-Vascular Endothelial Growth Factor (anti-VEGF)-related complications. In cases where ICIs are contraindicated, lenvatinib and sorafenib serve as additional options, with lenvatinib demonstrating longer progression free survival (PFS) in clinical trials. It is important to consider that each treatment has specific side effects or contraindications, and the choice of medication should be based not only on the therapeutic efficacy of the drug, but also on the patient’s health status, liver function, and tumor characteristics. Full article

The CABONEXT study is the first multicenter retrospective analysis evaluating subsequent systemic therapies after cabozantinib-based treatment in metastatic renal cell carcinoma (mRCC). This interim analysis includes 77 patients receiving subsequent treatments across two cohorts: after cabozantinib–nivolumab first-line treatment (Group A) and after ICI-based first-line treatment followed by cabozantinib (Group B). Time to subsequent treatment failure (TTF) and disease control rate (DCR) remain higher in Group A with a median TTF of 5 months (vs. 3.4 months in Group B) and a DCR of 86% (vs. 48%). Second-generation TKIs, mostly axitinib or lenvatinib, seemed to be the best option in Group B compared to other treatments including everolimus or first-generation TKIs (HR = 3.82, 95%CI [1.64; 8.93], p = 0.1). These findings already emphasize the need for innovative therapies targeting resistance mechanisms and optimal treatment sequences. Along with ongoing accrual, further analyses are expected. Full article