Search Results (98)

Background: Soft tissue sarcomas (STS) disproportionately affect older adults, yet patients aged ≥65 years remain markedly underrepresented in pivotal trials, limiting evidence on pazopanib in this population. We aimed to characterise the real-world efficacy and safety of pazopanib in elderly patients with advanced STS. Methods: This multicentre retrospective cohort study included consecutive patients aged ≥65 years with locally advanced unresectable or metastatic STS who received pazopanib between July 2010 and June 2022 at four tertiary Turkish oncology centres. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS) and the safety profile. Results: A total of 109 patients (median age, 70 years; 50.5% female; 48.6% with Eastern Cooperative Oncology Group [ECOG] performance status ≥ 2) were analysed. The objective response rate was 11.0% (95% CI, 5.8–18.4), and the disease control rate was 45.9%. Median PFS was 4.11 months (95% CI, 3.25–4.47), and median OS was 7.85 months (95% CI, 6.91–9.00) over a median follow-up of 17.6 months. PFS showed a borderline difference across age tertiles (log-rank p = 0.078), whereas a marked monotonic OS gradient was observed (9.00, 7.86, and 5.71 months for ages 65–69, 70–74, and ≥75 years, respectively; p < 0.001). In age-stratified multivariable Cox analysis, ECOG ≥ 2 (adjusted hazard ratio [aHR], 1.68; 95% CI, 1.01–2.80; p = 0.045) and female sex (aHR, 1.66; 95% CI, 1.02–2.72; p = 0.043) were independently associated with shorter OS. Grade ≥ 3 treatment-emergent adverse events occurred in 27.5% of patients, most commonly hypertension. Because only the single most clinically prominent treatment-emergent adverse event per patient was recorded, these figures represent a conservative, non-cumulative estimate of toxicity. No treatment-related deaths occurred. Conclusions: Pazopanib retains clinically meaningful activity in unselected patients aged ≥65 years with advanced STS. Performance status, rather than chronological age, is the dominant predictor of overall survival and should guide treatment decisions in this population. Full article

Background and Clinical Significance: Sarcomatoid renal cell carcinoma is a rare and highly aggressive variant of renal cell carcinoma, frequently associated with advanced-stage disease, early metastatic spread, and poor prognosis. Although immune checkpoint inhibitors have improved outcomes in metastatic renal cell carcinoma, particularly in tumors with sarcomatoid differentiation, they may also induce severe immune-related adverse events involving multiple organ systems. Case Presentation: We report the case of a 54-year-old woman with metastatic clear cell renal cell carcinoma with sarcomatoid differentiation, previously treated with nivolumab plus ipilimumab and subsequently with pazopanib, who was admitted with severe dehydration, repeated vomiting, marked asthenia, lower-limb-predominant muscle weakness, and inability to maintain orthostatism. Laboratory investigations revealed severe hyperkalemia, hyponatremia, hypoglycemia, anemia, thrombocytopenia, and prerenal acute kidney injury. The patient had a previous history of severe endocrine immune-related toxicity, including autoimmune hypophysitis and hypothyroidism, which had led to discontinuation of immunotherapy. Following fluid resuscitation, electrolyte correction, and supportive treatment, the metabolic abnormalities resolved and renal function improved significantly. Given the severity of the muscle weakness, a possible immune-mediated neuromuscular adverse event was also considered, although hyperkalemia remained a plausible contributing factor. Conclusions: This case highlights the complex interplay between prior immune checkpoint inhibitor exposure, endocrine dysfunction, metabolic decompensation, and possible neuromuscular involvement in metastatic sarcomatoid renal cell carcinoma. Early recognition, careful differential diagnosis, and multidisciplinary management are essential to prevent rapid clinical deterioration and optimize outcomes in patients with complex immune-related toxicities. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

Background: Accurate prognostic stratification is essential for clinical decision-making in metastatic renal cell carcinoma (mRCC). Although the International Metastatic RCC Database Consortium (IMDC) model is widely used, its discriminatory capacity may be limited in specific clinical subpopulations. The Royal Marsden Hospital (RMH) score, based on serum albumin, lactate dehydrogenase, and the number of metastatic sites, has not been evaluated as a prognostic tool in patients with de novo mRCC receiving first-line tyrosine kinase inhibitor (TKI) therapy. Methods: We retrospectively analyzed the data of 149 patients with de novo metastatic renal cell carcinoma who received first-line TKI therapy (pazopanib, sunitinib, or cabozantinib) at two tertiary oncology centers in Turkey. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The median OS and PFS were 23.1 months (95% CI: 19.4–26.8) and 9.4 months (95% CI: 7.0–11.8), respectively. The OS showed a stepwise decline across RMH risk groups, ranging from 40.7 months in patients with an RMH score of 0 to 8.6 months in those with an RMH score of 3. In the multivariate analysis, the RMH score (HR 1.29, 95% CI: 1.03–1.61; p = 0.026) and sarcomatoid differentiation (HR 2.01, 95% CI: 1.09–3.72; p = 0.025) were independently associated with worse OS. The IMDC score did not retain independent prognostic significance (p = 0.129). The RMH score was not significantly associated with PFS after multivariable adjustment, and the IMDC score was not significantly associated with PFS in univariate analysis and was therefore not entered into the multivariable PFS model. Conclusions: The RMH score independently predicted overall survival in patients with de novo mRCC receiving first-line TKI therapy, whereas the IMDC score did not retain independent prognostic significance in this cohort. Given its simplicity and reliance on objective parameters, the RMH score may provide complementary prognostic information in this patient population; however, external validation in independent cohorts is required before broader clinical implementation can be considered. Full article

Objectives: Limited intracellular exposure can reduce the in vitro activity of pazopanib (PAZ) and enzalutamide (ENZ). This study developed bovine serum albumin (BSA) particles co-encapsulating PAZ and ENZ (PE-BSA) and evaluated physicochemical properties, release kinetics, 4T1 cellular uptake, and in vitro cytotoxicity versus free drugs and single-drug particles. Methods: Drug-loaded BSA particles were prepared using a crosslinking-based method. Particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were determined. In vitro release was assessed over 48 h and fitted to kinetic models. 4T1 uptake was quantified after 2 and 4 h by intracellular drug levels. Cytotoxicity was measured by MTT at 24 and 72 h (1–100 µg/mL). Moreover, cell death analyses were conducted. Stability studies at +4 °C and serum were also carried out. Results: PE-BSA was nanoscale and monodisperse (PS 128.7 ± 2.6 nm; PDI 0.026 ± 0.01) with ZP −31.65 ± 1.13 mV and high EE (PAZ 98.59 ± 1.78%; ENZ 69.79 ± 0.02%). At 24/48 h, cumulative release from PE-BSA was 11.96/12.31% for PAZ and 52.26/85.95% for ENZ. The release kinetics were best described by the Korsmeyer–Peppas model for PAZ (r² = 0.9578) and the Higuchi model for ENZ (r² = 0.9605), indicating diffusion-controlled release. PE-BSA increased 4T1 uptake versus free drugs (2 h: 10.02% PAZ and 21.9% ENZ; 1.77-fold and 4.15-fold), with sustained enhancement at 4 h (2.2- and 4.69-fold, respectively). After 24 h, PE-BSA induced a markedly higher apoptotic response in 4T1 cells (32.5% early apoptosis and 0.8% late apoptosis/early necrosis) compared with free-PAZ (6.6% early apoptosis) and P-BSA (7.3% early apoptosis). Particles were stable. Conclusions: PE-BSA produced BSA particles with diffusion-governed release and enhanced 4T1 internalization, supporting albumin particles as a delivery platform to increase intracellular exposure of PAZ/ENZ in vitro. Full article

Identifying therapeutic target genes and their corresponding targeted drugs is of significant importance for the treatment of non-small cell lung cancer (NSCLC). This study proposes a multi-view graph auto-encoder model (MVGAE), which, together with the network-informed adaptive positive-unlabeled (NIAPU) and synthetic lethality multi-view graph auto-encoder (SLMGAE) model, constitutes an integrated computational framework. The framework integrates multi-source biological network data, including protein–protein interaction networks, disease-gene association information, and gene-drug bipartite graphs, for data mining. Through systematic analysis and computational screening, we ultimately predicted seven potential driver genes associated with NSCLC using the NIAPU model. The SLMGAE model predicted nine genes with synthetic lethality (SL) interactions to these driver genes as candidate therapeutic targets. Based on these SL targets, the MVGAE model further predicted corresponding targeted drugs. Notably, among the prioritized targets, existing studies indicate that ATR and RAD51 exhibit conditional SL effects in the context of functional impairment. Furthermore, several of the predicted candidate drugs (such as PAZOPANIB) have been previously reported to play a positive role in NSCLC treatment. This study highlights MVGAE as a novel computational framework for drug repurposing and demonstrates how its integration with complementary models can effectively prioritize potential therapeutic targets and candidate drugs, providing a robust computational basis for precision treatment strategies. Full article

Mesenchymal chondrosarcoma (MCS) is characterised by small round cell biology, frequent HEY1-NCOA2 fusion, and high vascularity. These features plausibly lessen extracellular matrix barriers and confer relative chemosensitivity. We synthesised peri-operative (preoperative/neoadjuvant; postoperative/adjuvant) and palliative chemotherapy outcomes separately across multiple cohorts and case reports as well as the summarised the guidelines (ESMO/NCCN) In localised disease, integrating multi-agent Ewing-type chemotherapy with complete resection is associated with improved disease control. Contemporary 5-year overall survival (OS) typically spans ~55–73% across studies, while event-free survival (EFS) gains are demonstrated more consistently than OS gains in pooled analyses. In advanced MCS, first-line polychemotherapy yields modest, non-curative activity, with objective response rates (ORRs) of ~25–35% in adults, median progression-free survival (PFS) of ~4.7–6.7 months, and median OS of ~18 months. Activity may be higher in younger patients and for platinum–anthracycline combinations. We also discussed emerging therapies. Trabectedin demonstrates low disease control rate in translocation-related sarcomas, including few MCS cases. Anti-angiogenic tyrosine kinase inhibitors, such as apatinib and pazopanib, demonstrate activity in chondrosarcoma, but MCS-specific data are lacking. IDH1 inhibition benefits conventional subtypes rather than MCS. Early immunotherapy experience is limited, but pathway-directed strategies targeting BCL2 and PI3K-mTOR warrant evaluation. Full article

Background/Objectives: Cutaneous angiosarcoma (CAS) is a rare and aggressive endothelial malignancy with a high rate of local recurrence and distant metastasis. In advanced cases, where surgical resection is not feasible, systemic therapy remains the cornerstone of treatment. This review aims to summarize the current landscape of systemic therapies for unresectable or metastatic CAS and discuss emerging strategies, particularly focusing on immune checkpoint inhibitors (ICIs). Methods: A comprehensive review of the literature was conducted, including clinical trials, retrospective studies, and case series focusing on systemic treatments for advanced CAS. Therapeutic approaches covered include cytotoxic chemotherapy, molecular targeted therapies, and ICIs, as well as combination strategies. Special attention was given to biomarker studies and ongoing clinical trials. Results: Taxane-based chemotherapy, particularly paclitaxel, has demonstrated clinical activity and remains a standard option. Molecular targeted agents such as pazopanib have yielded modest efficacy. Recent trials of ICIs, including the SWOG S1609 DART and AngioCheck studies, have shown encouraging results in select subgroups, especially tumors from sun-exposed regions associated with high tumor mutational burden (TMB). Although AngioCheck did not meet its predefined response criteria, a subset of patients achieved disease control. Biomarkers such as TMB, PD-L1 expression, and tumor-infiltrating lymphocytes are under investigation to guide patient selection. Combination therapies with ICIs and tyrosine kinase inhibitors (TKIs) are being actively explored. Conclusions: While systemic therapies for CAS remain limited in efficacy, ICIs—particularly in combination with TKIs—represent a promising avenue. Future trials should emphasize biomarker-driven, CAS-specific strategies to improve clinical outcomes in this challenging malignancy. 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

Background: The Meet-URO score combines the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria with neutrophil-to-lymphocyte ratio (NLR) and bone metastasis status. Although developed in immune checkpoint inhibitor (ICI) cohorts, its performance among patients receiving first-line tyrosine kinase inhibitor (TKI) monotherapy is uncertain. Methods: We performed a multicenter, retrospective cohort study of 301 adults with histologically confirmed metastatic renal cell carcinoma (mRCC) treated with first-line TKI monotherapy (sunitinib, pazopanib, or cabozantinib) between 2008 and 2025 across five tertiary centers in Turkey. The primary endpoint was overall survival (OS). Meet-URO was calculated at treatment start and analyzed as prespecified risk strata (0–4, 5–8, 9). Kaplan–Meier estimates, Cox models, and Harrell’s C-index assessed discrimination, with bootstrapped 95% CIs. Results: Median follow-up was 40 months; median OS (mOS) was 25 months (95% CI, 21–29) and median progression-free survival was 10 months (95% CI, 8–12). Meet-URO stratified OS: 41 months for scores 0–4, 21 months for 5–8, and 7 months for 9 (log-rank p < 0.001). In multivariable analysis, Meet-URO remained independently prognostic (HR 1.73 for 5–8 vs. 0–4; HR 3.57 for 9 vs. 0–4; both p < 0.001). Discrimination was modest (C-index 0.722) and slightly lower than IMDC (C-index 0.745). NLR ≥ 3.2 was associated with inferior OS (19 vs. 37 months; p < 0.001). Bone metastasis was not significantly associated with OS (p = 0.27). Conclusions: Meet-URO is a valid prognostic tool for mRCC patients treated with first-line TKIs and identifies an ultra-high-risk subgroup (score = 9) with poor survival. While not superior to IMDC, Meet-URO may offer complementary risk information to support clinical monitoring and trial referral, particularly in settings where ICI combinations are restricted. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors (TKIs), especially imatinib, has significantly transformed GIST treatment. However, the emergence of both primary and secondary resistance to imatinib presents ongoing therapeutic challenges. This review comprehensively explores the mechanisms underlying imatinib resistance and evaluates subsequent TKI therapies. Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents—such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib—have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs. Despite progress, long-term efficacy remains limited due to evolving resistance. Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options, especially for rare GIST subtypes. Full article

Cancer remains a major global health burden driven by complex biological mechanisms, and while targeted therapies like tyrosine kinase inhibitors (TKIs) have revolutionized treatment, their efficacy and safety are significantly influenced by drug–drug interactions (DDIs). Tyrosine-kinase receptors (RTKs) regulate critical cellular processes, and their dysregulation through mutations or overexpression drives oncogenesis, with TKIs designed to inhibit these aberrant signaling pathways by targeting RTK phosphorylation. Pharmacokinetic DDIs can critically impact the efficacy and safety of TKIs such as erlotinib, gefitinib, and pazopanib by affecting their absorption, distribution, and metabolism. The modification of pH can influence drug absorption; furthermore, the inhibition or induction of metabolizing enzymes may affect biotransformation, while distribution can be altered through the modulation of transmembrane transporters. Additionally, ensuring quality of life during TKI treatment requires vigilant monitoring and management of adverse events, which range from mild (e.g., rash, diarrhea, fatigue) to severe (e.g., hepatotoxicity, cardiotoxicity). Drug-specific toxicities, such as hyperlipidemia with lorlatinib or visual disturbances with crizotinib, must be assessed using specific criteria, with dose adjustments and supportive care tailored to individual patient responses. Thus, optimal TKI therapy relies on managing drug interactions through multidisciplinary care, monitoring, and patient education to ensure safety and treatment efficacy. Full article

Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for a significant proportion of all cancer cases in Korea. This case report presents a unique instance of spontaneous dramatic tumor regression in a 42-year-old Korean male diagnosed with clear cell RCC. The patient initially presented with right lower back pain, weight loss, and a loss of appetite. Following systemic immunotherapy with nivolumab and ipilimumab, and right radical nephrectomy, the patient was diagnosed with metastatic clear cell RCC, with new metastatic lesions detected in the liver, and on the chest wall on follow-up imaging. Second-line systemic treatment with pazopanib was initiated. Shortly thereafter, the patient developed severe systemic inflammatory syndrome, resulting in a mental stupor and acute kidney failure. Intensive care, including continuous renal replacement therapy and high-dose immunosuppressants, was administered. The patient’s condition improved significantly with the intensive care regimen, leading to unintended tumor regression. These potentially fatal side effects occurred without infection, as confirmed by negative blood and urine cultures, and were attributed to the recent introduction of pazopanib. Follow-up imaging showed a significant reduction in hepatic metastatic lesions and the disappearance of chest wall nodules. This is the first reported case of RCC tumor regression following the side effects of pazopanib, underscoring the need for further studies into the immune mechanisms involved in RCC treatment and highlighting potential therapeutic strategies that leverage innate immune responses. Full article

Pazopanib, a multi-targeted tyrosine kinase inhibitor, has been explored for its efficacy in treating various subtypes of thyroid cancer, including differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). This systematic review assesses the efficacy and safety of pazopanib, focusing on the progression-free survival (PFS), overall survival (OS), and response rates and adverse events. A comprehensive search was conducted in databases including PubMed, Scopus, and Web of Science up to October 2024 to identify randomized controlled trials and phase II clinical trials that investigated the use of pazopanib in thyroid cancer. The PRISMA guidelines were followed for data extraction and quality assessment. The review included six studies encompassing 289 patients, presenting a comprehensive overview of pazopanib’s application across different thyroid cancer subtypes. The studies reported median PFS rates ranging from 2.1 to 11.7 months and median OS rates ranging from 5.7 months to not reached. The partial response rates varied from 5% to 49%. Adverse events were common, with hypertension occurring in up to 71.7% of patients, and fatigue and diarrhea were also frequently reported. Grade 3–5 adverse events led to treatment discontinuations in up to 14% of patients. Pazopanib shows variable efficacy across thyroid cancer types, offering significant benefits in MTC and refractory DTC in terms of PFS and OS but limited impact in ATC. The adverse event profile necessitates careful management, particularly regarding hypertension and other treatment-related toxicities. Further studies are required to refine the therapeutic protocols for pazopanib, exploring combination therapies that may enhance its efficacy and reduce the adverse outcomes. Full article

Background: When companies are uncertain about the potential of a new formulation to be bioequivalent to a Reference product, it is common practice to carry out downsized pilot studies as a gatekeeping in vivo strategy to decide whether to move forward or not with a full-size pivotal study. However, due to the small study size, these studies are inarguably more sensitive to variability. Objectives: To address and mitigate the uncertainty of the conclusions of pilot studies concerning the maximum observed concentration (C_max), the f₂ factor was proposed as an alternative approach to the average bioequivalence statistical methodology. Methods: In this work, the alternative methodology is applied to pharmacokinetic data from pilot bioequivalence trials performed with pazopanib 200 mg and 400 mg. Results: Despite the small sample size, and very high intra-subject variability, the f₂ factor demonstrated the potential for predicting bioequivalence. The positive results were confirmed in the full sized pivotal studies. Conclusions: In conclusion, this alternate methodology shows promise in reducing uncertainty associated with pilot studies and aiding in decisions to go forward with pivotal bioequivalence studies. Full article