The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet. Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.

OBJECTIVE: Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension.
METHODS: In total, 47 patients who started pazopanib treatment for renal cell carcinoma or soft tissue sarcoma during hospitalization at Kurume University Hospital from November 2012 to February 2020 were included in the study. Patient background factors associated with pazopanib-induced hypertension were analyzed using a logistic regression model. Subsequently, a time-dependent receiver operating characteristic (ROC) analysis was performed to evaluate changes in the predictive performance of predictors of pazopanib-induced hypertension over time.
RESULTS: Logistic regression analysis showed that total bilirubin (t-bil) and sex are predictors of pazopanib-induced hypertension, along with systolic blood pressure (SBP) before pazopanib introduction. Additionally, evaluation of area under the curve (AUC) changes over time during the first 20 days of pazopanib treatment using time-dependent ROC showed that the AUC tended to be higher in the first half for SBP and in the second half for t-bil. Moreover, models including these two factors (SBP+t-bil and SBP+t-bil+sex) maintained a higher AUC from the early to late stages of the treatment period.
CONCLUSIONS: Total bilirubin and sex can serve as predictors of pazopanib-induced hypertension. Total bilirubin may contribute to the prediction of the development of hypertension after day 5.

Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.

Background Treatment of metastatic renal cell cancer (mRCC) has revolutionized with the introduction of anti-VEGF tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). There is limited data in the literature on the outcomes of Indian patients treated with TKI. Here, we report the outcome of mRCC treated with first-line TKI in a resource-poor setting. Material and methods This is a single-center retrospective study of clear cell mRCC treated with first-line TKI from June 2012 to December 2022. Demographic characteristics and treatment details, including outcome data, were captured from electronic medical records. Patients who received at least one week of therapy were eligible for survival analysis. Results A total of 345 patients with metastatic clear cell histology were analyzed, with a median age of 61 years (range: 20-84 years). One hundred and eighty patients (52%) underwent nephrectomy before systemic therapy. The majority received pazopanib (257 patients, 75%), followed by sunitinib (36 patients, 10%) and cabozantinib (21 patients, 6%); 145 (45%) patients required dose interruption, and 143 (43%) required dose modification of TKI for adverse events. After a median follow-up of 44 months, the median progression-free survival (PFS) was 20.3 months (95% CI: 17.8-24.8), and the median overall survival (OS) was 22.7 months (95% CI: 18.8-28.3). In the poor-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) group, no prior nephrectomy emerged as an independent poor-risk factor for both PFS and OS in multivariate analysis. Conclusion This is the largest single-center cohort of clear cell mRCC from Asia. Median PFS was 20.3 months with predominantly TKI monotherapy. In the poor-risk IMDC group, no prior nephrectomy emerged as an independent poor-risk factor for both PFS and OS.

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs.
METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests.
RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders.
CONCLUSIONS: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.

UNASSIGNED: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a tyrosine kinase inhibitor, is clinically used to treat pulmonary fibrosis. At present, only nintedanib is on the market for the treatment of pulmonary fibrosis. Pazopanib is a drug for the treatment of renal cell carcinoma and advanced soft tissue sarcoma.
UNASSIGNED: In this study, we explored whether pazopanib can attenuate bleomycin (BLM)-induced pulmonary fibrosis and explored its antifibrotic mechanism. In vivo and in vitro investigations were carried out to investigate the efficacy and mechanism of action of pazopanib in pulmonary fibrosis.
UNASSIGNED: In vivo experiments showed that pazopanib can alleviate pulmonary fibrosis caused by BLM, reduce the degree of collagen deposition and improve lung function. In vitro experiments showed that pazopanib suppressed transforming growth factor-β1 (TGF-β1)-induced myofibroblast activation and promoted apoptosis and autophagy in myofibroblasts. Further mechanistic studies demonstrated that pazopanib inhibited the TGF-β1/Smad and non-Smad signaling pathways during fibroblast activation.
UNASSIGNED: In conclusion, pazopanib attenuated BLM-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway. Pazopanib inhibits myofibroblast activation, migration, autophagy, apoptosis, and extracellular matrix (ECM) buildup by downregulating the TGF-β1/Smad signal route and the TGF-β1/non-Smad signal pathway. It has the same target as nintedanib and is a tyrosine kinase inhibitor.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800 mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7 nm and 182.0 nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selected due to its potential synthetic lethality with the CDH1 alteration. In addition, the CDK4/6 inhibitor palbociclib was administered to address the CDKN2A/B alterations. The patient exhibited a remarkable and sustained response to this innovative combination. This case not only underscores the potential of tyrosine kinase inhibitors, exemplified by pazopanib, as a viable alternative for patients without access to pan-FGFR inhibitors, but it also emphasizes their efficacy beyond commonly detected point mutations and rearrangements. Notably, the outstanding response to combination therapy, including crizotinib, in a patient with a CDH1 alteration, further substantiates the preclinical evidence of synthetic lethality between crizotinib and CDH1 alterations. To our knowledge, this represents the first clinical evidence demonstrating the efficacy of crizotinib in a patient with a CDH1 alteration. Through careful dosage adjustments and consideration of individualized genomic information, this case exemplifies the power of personalized medicine in achieving favorable treatment outcomes.

OBJECTIVE: This study aimed to construct a prognostic model for papillary renal cell carcinoma (pRCC) utilizing disulfidptosis-associated long non-coding RNAs (lncRNAs). Additionally, it investigated the potential of these lncRNAs in predicting immune responses and drug sensitivity in pRCC.
BACKGROUND: LncRNAs have been implicated in the progression and prognosis of pRCC. Recently, disulfidptosis, an emerging form of regulated cell death, has shown potential as a therapeutic approach for cancer. However, the potential association between disulfidptosis-related lncRNAs and pRCC remains unclear.
METHODS: We analyzed transcriptome profiling and clinical data of pRCC patients from The Cancer Genome Atlas database. Using Pearson correlation analysis, we identified lncRNAs associated with disulfidptosis. Based on the identified disulfidptosis-related lncRNAs that were correlated with overall survival (OS), we constructed a novel prediction model using the least absolute shrinkage and selection operator, univariable Cox regression, and multivariable Cox regression analyses. The model\'s utility was assessed through Kaplan-Meier survival, receiver operating characteristics, and principal component analyses. Moreover, functional analysis helped identify potential prognostic mechanisms, and the prediction of chemical drugs for pRCC was also performed. Finally, qRT-PCR validated the expression of prognostic lncRNAs in pRCC cells and patient samples.
RESULTS: Our prediction model was based on nine disulfidptosis-related lncRNAs. Evaluation and validation analyses demonstrated that the model had excellent, consistent, and independent prognostic value for pRCC patients, with area under the curve (AUC) values of 0.954, 0.910, and 0.830 for 1-, 3-, and 5-year OS, respectively. Through functional analysis, we discovered a significant correlation between the identified prognostic signature and immunity. Additionally, in terms of chemotherapy sensitivity, our analysis indicated that the low-risk group exhibited higher sensitivity to sunitinib and pazopanib. Furthermore, the expression patterns of the identified lncRNAs were validated in samples obtained from pRCC cells and patients.
CONCLUSIONS: This study successfully established and validated a novel disulfidptosis-related prediction model. The findings suggest the potential involvement of immune-related pathways in lncRNA signature-associated survival. This model holds promise for differentiating prognosis and improving personalized therapeutic strategies for pRCC in clinical practice.

Pazopanib is a multi-kinase inhibitor used to treat advanced/metastatic renal cell carcinoma and advanced soft tissue tumors; however, side effects such as diarrhea and hypertension have been reported, and dosage adjustment based on drug concentration in the blood is necessary. However, measuring pazopanib concentrations in blood using the existing methods is time-consuming; and current dosage adjustments are made using the results of blood samples taken at the patient\'s previous hospital visit (approximately a month prior). If the concentration of pazopanib could be measured during the waiting period for a doctor\'s examination at the hospital (in approximately 30 min), the dosage could be adjusted according to the patient\'s condition on that day. Therefore, we aimed to develop a method for rapidly measuring blood pazopanib concentrations (in approximately 25 min) using common analytical devices (a tabletop centrifuge and a spectrometer). This method allowed for pazopanib quantification in the therapeutic concentration range (25-50 μg/mL). Additionally, eight popular concomitant medications taken simultaneously with pazopanib did not interfere with the measurements. We used the developed method to measure blood concentration in two patients and obtained similar results to those measured using the previously reported HPLC method. By integrating it with the point of care and sample collection by finger pick, this method can be used for measurements in pharmacies and patients\' homes. This method can maximize the therapeutic effects of pazopanib by dose adjustment to control adverse events.