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Aim: Renal cell carcinoma (RCC) is the seventh commonest cancer in the UK, where first-line (1L) sunitinib and second-line (2L) axitinib are treatment options. Methods: Retrospective, non-interventional data from the Christie NHS Foundation Trust (Manchester, UK). The primary end point was median progression-free survival (mPFS). Results: For 1L sunitinib (n = 622) and 2L axitinib (n = 121), mPFS (95% CI) was 8.4 (7.6, 9.9) and 6.2 (4.9, 9.3) months, respectively. In 1L, Karnofsky performance status, lactate dehydrogenase (LDH), neutrophils, hemoglobin, time from diagnosis to treatment and age were predictors (p < 0.05) of PFS. In 2L, LDH and platelets were predictors of PFS (p < 0.05). Conclusion: Sunitinib and axitinib were effective treatments for RCC. PFS predictors varied between 1L and 2L; LDH was a predictor for both. Clinical Trial Registration:NCT04033991 (ClinicalTrials.gov). Article highlights Renal cell carcinoma (RCC) is the seventh most common type of cancer in the UK. In the UK, axitinib plus avelumab, lenvatinib plus pembrolizumab and nivolumab plus ipilimumab are approved for reimbursement within the NHS. Other approved 1L treatment options include axitinib plus pembrolizumab and cabozantinib plus nivolumab. Previous RCC first-line (1L) mainstay, sunitinib may be a treatment option when ICIs are not appropriate, or single-agent therapy is preferred. Axitinib is recommended as a 2L treatment when not administered in 1L. This study aimed to understand the clinical outcomes of patients with advanced RCC treated with 1L sunitinib and second-line (2L) axitinib in a real-world, UK-based setting, utilizing data extracted from a clinical database held by the Christie NHS Foundation Trust (Manchester, UK). For 1L sunitinib (n = 622), median progression-free survival (PFS) and overall survival (OS) (95% CI) were 8.4 (7.6, 9.9) and 18.3 (15.8, 20.4) months, respectively. For 2L axitinib (n = 121), median PFS and OS (95% CI) were for 6.2 (4.9, 9.3) and 15.8 (12.0, 20.4) months, respectively. Karnofsky performance status, lactate dehydrogenase (LDH), neutrophils, hemoglobin, time from diagnosis to treatment initiation and age were significant (p < 0.05) predictors of PFS for 1L sunitinib. For 2L axitinib, LDH and platelets were significant predictors for PFS. 59 patients received both 1L sunitinib and 2L axitinib. Of the 13 (22.0%) patients who were of favorable IMDC risk at 1L, four (30.8%) remained of favorable risk, eight (61.5%) progressed to intermediate risk and one (7.7%) progressed to poor risk when receiving 2L. Of the 28 (47.5%) patients who were of intermediate risk at 1L, 20 (71.4%) remained of intermediate risk, four (14.3%) progressed to poor risk, but four (14.3%) transitioned to favorable risk during 2L. In a real-world UK setting, 1L sunitinib and 2L axitinib were effective treatments for RCC. Predictors of PFS varied between the 1L and 2L cohorts, with only LDH as a significant predictor for both lines of treatment. 1L sunitinib and 2L axitinib were effective when given in sequence. [ABSTRACT FROM AUTHOR]

Background: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune‐checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. Methods: The number of patients expected to be enrolled was 15–25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression‐free survival (PFS), overall survival (OS), and safety. Results: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7–8.6 months) and the median OS was 15.8 months (95% CI, 8.2–not reached). Conclusions: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS. This study evaluated the efficacy and safety of nivolumab monotherapy for patients with clear cell sarcoma and alveolar soft part sarcoma in a single‐arm phase 2 trial. The results showed no clinical efficacy among patients with clear cell sarcoma, whereas further investigation was considered necessary among patients with alveolar soft part sarcoma. [ABSTRACT FROM AUTHOR]

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA. Clinical Trial Registration:NCT05734105 (ClinicalTrials.gov) Plain Language Summary Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in KIT exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in KIT exon 11 and KIT exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes. Tweetable Abstract This article describes the rationale and design for the INSIGHT Phase III trial evaluating patients with second-line advanced GIST who harbor primary KIT exon 11 mutations and secondary resistance mutations restricted to the activation loop (KIT exons 17/18). Executive summary Disease overview & management Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by activating mutations in KIT. Sunitinib is a multitargeted tyrosine kinase inhibitor (TKI) approved as a second-line therapy for advanced GIST after disease progression on or intolerance to imatinib. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA TKI approved as a fourth-line therapy for advanced GIST. Differential activity of ripretinib & sunitinib against secondary KIT mutations Exploratory baseline circulating tumor DNA (ctDNA) analysis from INTRIGUE determined that patients with KIT exon 11 + 13/14 mutations had improved progression-free survival (PFS) and objective response rate (ORR) with sunitinib versus ripretinib, while those with KIT exon 11 + 17/18 mutations had improved PFS, ORR and overall survival (OS) and a better safety profile with ripretinib versus sunitinib. Design INSIGHT is an international, Phase III, randomized, multicenter, open-label study evaluating the efficacy of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib and who have KIT exon 11 mutations and co-occurring mutations exclusively in KIT exons 17/18, as identified by ctDNA. Approximately 54 patients will be randomized 2:1 to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. Eligible patients must have a histologic diagnosis of advanced GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by central laboratory ctDNA analysis, as well as radiologic progression on imatinib. The primary outcome measure is PFS based on blinded independent radiologic review (IRR) using modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1), while key secondary outcome measures are ORR based on blinded IRR using mRECIST v1.1 and OS. Infographic [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive. Methods: By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays. Results: Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth. Conclusion: Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Many patients diagnosed with gastroenteropancreatic neuroendocrine tumors present with metastatic disease at the time of diagnosis. As many as 20% of patients with this diagnosis will present with metastasis to the peritoneal cavity which portends a significantly worse prognosis than solid organ metastasis alone. There is little to no evidence to guide treatment algorithms given the rarity of this disease. Surgical cytoreduction has been found to improve symptoms related to disease burden, though an understanding of the optimal cytoreductive strategies to offer the greatest benefit to most patients is lacking. While the current body of literature pertaining to the systemic treatment of the solid organ metastasis of this disease is more robust, it largely excludes patients with peritoneal metastasis. We provide a review of the current literature which is used to guide these management strategies and offer insight into the knowledge gaps that exist. Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival—particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed. [ABSTRACT FROM AUTHOR]

The document titled "Supplementary Materials" from the journal "Frontiers in Endocrinology" provides information on the linear correlation between bone mineral density and body mass index, as well as primer sequences for hub genes and potential drugs predicted based on these genes. The data includes a list of drugs and their associated odds ratios and scores, offering insights into potential pharmacological interventions related to bone health. This supplementary material can be valuable for researchers exploring the relationship between BMI, bone health, and pharmacological treatments. [Extracted from the article]

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Background: Hepatic ischemia reperfusion injury (IRI) is a common liver surgery complication. This study aims to explore the effect and potential mechanism of Sunitinib – a multi-target tyrosine kinase inhibitor – on hepatic IRI. Methods: We established a hepatic IRI model using C57BL/6 mice, and integrated 40 mg/kg of Sunitinib, solely or combined with 100 μg/kg of coumermycin A1 (C-A1), in the treatment strategy. H&E staining, TUNEL assay, and detection of serum ALT and AST activities were used to assess liver damage. Further, ELISA kits and Western Blots were utilized to determine IL-1β, TNF-α, IL-6, CXCL10, and CXCL2 levels. Primary macrophages, once isolated, were cultured in vitro with either 2 nM of Sunitinib, or Sunitinib in conjunction with 1 μM of C-A1, to gauge their influence on macrophage polarization. qPCR and Western blot were conducted to examine the level of p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2, and M1/M2 polarization markers. To quantify immune cell infiltration, we applied Immunofluorescence. Results: Sunitinib pretreatment significantly alleviated liver injury and reduced p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2 levels. In vitro, Sunitinib treatment curbed M1 polarization induced by LPS + IFN-γ and bolstered M2 polarization triggered by IL-4. C-A1 application upregulated JAK2/STAT pathway phosphorylation and promoted LPS + IFN-γ-induced M1 polarization, which was reversed by Sunitinib treatment. In IL-4-stimulated macrophages, application of C-A1 activated the JAK2/STAT pathway and decreased M2-type macrophages, which was reversed by Sunitinib treatment either. Conclusion: Sunitinib is capable of guiding the polarization of macrophages toward an M2-type phenotype via the inhibition of the JAK2/STAT pathway, thereby exerting a protective effect on hepatic IRI. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. Methods: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression‐free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. Results: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. Conclusions: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. Patient summary: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. Methods: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. Results: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1–36.8) and 63.8% (95% CI, 48.0–75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. Conclusion: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo Zuzhi Gongcheng Yanjiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Drug resistance after long‐term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome‐wide CRISPR‐based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF‐2α and enhance the transcriptional activity of the ETS1/HIF‐2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up‐regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF‐2α by impeded acetylation at ETS1‐K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8‐in‐PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC‐targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. Methods: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. Results: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. Conclusions: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib. [ABSTRACT FROM AUTHOR]

In this work, new pH‐sensitive and antibacterial drug carrier systems based on silver nanoparticles (AgNPs) embedded in the interlayer of laponite (Lap) in the presence of chitosan (CTS) for the controllable release of sunitinib maleate (STM) were developed. Silver ions and sunitinib maleate were first loaded into Lap, and the CTS‐based hybrid bionanocomposite carrier (Lap@CTS@AgNPs@STM) was obtained in the presence of citric acid as a cross‐linker agent. The successful preparation of nanocarrier and Ag NPs formation was thoroughly confirmed using techniques such as FTIR, XRD, TGA, SEM, and TEM. TEM images illustrated the excellent distribution of Ag NPs in the structure of Lap@CTS@AgNPs. The as‐prepared samples showed a pH‐sensitive anticancer drug release behavior. The STM release mechanism was studied using Korsmeyer–Peppas and Higuchi kinetic models. Furthermore, the in vitro cytotoxicity and antibacterial tests were carried out against both bacteria S. aureus and E. coli and MCF‐7 cell lines, respectively, to prove the effectiveness of synthesized samples as multifunctional carrier systems for biomedical applications. [ABSTRACT FROM AUTHOR]

Copyright of Namık Kemal Tıp Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco‐hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure‐response relationship), and safety (maximum tolerated dose, and exposure‐safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco‐hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A sophisticated electrochemical sensor is presented employing a glassy carbon electrode (GCE) modified with a novel composite of synthesized graphitic carbon nitride (g-C3N4) and CoNiO2 bimetallic oxide nanoparticles (g-C3N4/CoNiO2). The sensor's electrocatalytic capabilities for Sunitinib (SUNI) oxidation were demonstrated exceptional performance with a calculated detection limit (LOD) of 52.0 nM. The successful synthesis and integrity of the composite were confirmed through meticulous characterization using various techniques. FT-IR analysis affirmed the successful synthesis of g-C3N4/CoNiO2 by providing insights into its molecular structure. XRD, FE-SEM, SEM–EDX, and BET analyses collectively validated the material's structural integrity, surface morphology, and electrocatalytic performance. Optimization of key analytical parameters, such as loading volume, concentration, electrolyte solution type, and pH, enhanced the electrocatalytic sensing capabilities of g-C3N4/CoNiO2. The synergistic interaction between g-C3N4 and CoNiO2 bimetallic oxide nanoparticles executed the sensor highly effective in the electrical oxidation of SUNI. Across a concentration range of 0.1–83.8 µM SUNI, the anodic peak current exhibited a linear increase with good precision. Application of the newly developed g-C3N4/CoNiO2 system to detect SUNI in a variety of samples, including urine, human serum, and capsule dosage forms, obtained satisfactory recoveries ranging from 97.1 to 103.0%. This methodology offers a novel approach to underscore the potential of the developed sensor for applications in biological and pharmaceutical monitoring. [ABSTRACT FROM AUTHOR]

The treatment landscape for metastatic renal cell carcinoma (RCC) has advanced significantly with first-line immunotargeted therapy combinations. However, no statistically significant differences were observed in the cohort of patients with favorable risk and some oncologists continue to use sunitinib in these patients. PD-L1 expression has emerged as a negative prognostic factor in RCC, particularly in sunitinib-treated patients, where higher PD-L1 levels are linked to worse outcomes. This article discusses the potential risks associated with the use of sunitinib in PD-L1-positive patients. [ABSTRACT FROM AUTHOR]

This study investigated a novel radioimmunotherapy strategy for targeting tumor angiogenesis. We developed a radiopharmaceutical complex by labeling an anti-adenosine triphosphate synthase (ATPS) monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in serum. MKN-45 cancer cells exhibited the highest cellular uptake, which could be specifically blocked by unlabeled ATPS mAb. In mice, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 16.0 ± 1.5%ID/g on day 7. 177Lu-DOTA-ATPS mAb treatment significantly reduced the viability of MKN-45 cells in a dose-dependent manner. In a xenograft tumor model, this radioimmunotherapy strategy led to substantial tumor growth inhibition (82.8%). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, enhanced the therapeutic efficacy of sunitinib in the mouse model. Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This approach demonstrates significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Background: Sunitinib, a multi-targeted tyrosine kinase inhibitor, is used as a second-line therapy for gastrointestinal stromal tumors (GIST) resistant to imatinib. However, its impact on the vascular endothelial growth factor (VEGF) pathway can lead to significant toxicities, including hypertension and thrombotic microangiopathy (TMA). Case presentation: This case report describes a unique instance of a patient with metastatic GIST who developed endocapillary proliferative glomerulonephritis (EPGN) with IgA2 deposits and TMA following sunitinib treatment. The patient presented with severe hypertension, nephrotic syndrome, and acute kidney injury. Renal biopsy confirmed the diagnosis, revealing IgA2 deposits, which are not commonly associated with TMA. Discontinuation of sunitinib led to a rapid improvement in renal function and proteinuria. The potential mechanisms underlying sunitinib-induced glomerular injury may involve the blockade of VEGFR-1, affecting immune cell recruitment and function, and the disruption of the nitric oxide and endothelin systems, leading to endothelial damage and immune dysregulation. Management of these toxicities requires a personalized approach, with options ranging from symptomatic relief to drug discontinuation. The use of endothelin receptor antagonists and other therapeutic alternatives for GIST management is discussed. Conclusions: This case highlights the complex interplay between the therapeutic effects of sunitinib and its potential renal and cardiovascular toxicities, emphasizing the need for close monitoring and effective management strategies to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Regorafenib is an oral multi-targeted tyrosine kinase inhibitor (TKI) indicated for the treatment of various tumor types, including metastatic gastrointestinal stromal tumors (GIST), as a third-line systemic therapy. Erythrocytosis, which is characterized by an increase in erythrocyte count, hemoglobin, and hematocrit levels, has been described as a side effect of some antiangiogenic TKIs but has never been associatedwith regorafenib administration. Case presentation: An extra-GIST was diagnosed in a 58-year-old woman after she underwent surgery to remove a pelvic mass. Three years later, systemic therapy with imatinib was started due to pelvic disease recurrence. However, after six months, due to disease progression, we prescribed sunitinib, which the patient received for four years. Regorafenib was initiated in June 2019, and after six months, we noted an increase in the erythrocytes' count and hemoglobin (Hb) levels. Given that the patient had clinical benefit and hematocrit was within normal range, we only monitored the blood cell count and continued to give regorafenib at the same dose. The drug was then stopped for over six weeks due to hospitalization for severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection, and Hb levels returned to normal. Therefore, we decided to restart regorafenib at a lower dose. However, Hb levels rose again in conjunction with increased hematocrit, resulting in the need for multiple phlebotomies. We attempted to restart regorafenib every other day, but it was unsuccessful, so we stopped it permanently in May 2023, and all values returned to normal. Conclusion: Regorafenib may cause secondary erythrocytosis that could not be dose-related, as this case report suggests. Secondary erythrocytosis might be a marker of TKI efficacy, given the patient's prolonged clinical benefit during regorafenib treatment (48 months). In patients receiving regorafenib, monitoring blood count as well as any symptoms associated with erythrocytosis may be suggested. [ABSTRACT FROM AUTHOR]

Background. This study aims to assess and explore the different effects of national centralized drug procurement (NCDP) on three targeted antitumor drugs' use in clinical practice. Materials and Methods. Clinical drug volume data were collected covering 18 months before, during, and after the seventh round of the NCDP in Inner Mongolia. The interrupted time‐series method was employed to estimate the net effect of policy impact. Results. The volume of generic afatinib (30 mg) increased by 25.78 DDDs, the expenditures decreased by 3641.14 yuan (p = 0.001), and the DDDc decreased by 124.35 yuan (p < 0.001). The volume of generic afatinib (40 mg) increased by 65.19 DDDs (p < 0.001), the expenditures increased by 1304.93 yuan (p < 0.001), and the DDDc decreased by 120.2 yuan (p < 0.001). The volume of generic sunitinib increased by 75.79 DDDs (p < 0.001), the expenditures decreased by 15869.78 yuan (p < 0.001), and the DDDc decreased by 243.28 yuan. There was no significant change trend in volume, expenditures, and DDDc of the three original‐targeted drugs after NCDP intervention. Conclusions. After the policy intervention, generic afatinib (40 mg) successfully aligned with the objectives of NCDP by reducing drug costs and enhancing patient affordability; however, the desired outcomes were not achieved for generic afatinib (30 mg) and generic sunitinib. This discrepancy may be attributed to the inherent clinical efficacy and safety profiles of these drugs. Therefore, in implementing NCDP, it is necessary to enhance the clinical efficacy and safety of generic‐targeted antitumor drugs while considering economic efficiency. [ABSTRACT FROM AUTHOR]

Background: Sunitinib is approved for the treatment of metastatic renal cell carcinoma (mRCC), imatinib-resistant gastrointestinal stromal tumors (GIST), and advanced pancreatic neuroendocrine tumors (PNET). This study aims to investigate the safety profiles of sunitinib through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: The individual case safety reports (ICSRs) on sunitinib from 2006 Q1 to 2024 Q1 were collected from the ASCII data packages in the Food and Drug Administration Adverse Event Reporting System (FAERS). After standardizing the data, a variety of disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed to identify the potential safety signals of sunitinib-associated AEs. Results: A total of 35,923 ICSRs of sunitinib as the “primary suspected” drug were identified within the reporting period. The search detected 276 disproportionate preferred terms (PTs). The most common AEs, including diarrhea, asthenia, decreased appetite, hypertension, and dysgeusia, were consistent with the drug label and clinical trials. Unexpected significant AEs, such as uveal melanocytic proliferation, salivary gland fistula, yellow skin, eyelash discoloration, scrotal inflammation, were detected. The median onset time of sunitinib-related AEs was 57 days (interquartile range [IQR]16–170 days), with most of the ICSRs developing within the first month (n = 4,582, 39.73%) after sunitinib therapy as initiated. Conclusion: The results of our study were consistent with routine clinical observations, and some unexpected AEs signals were also identified for sunitinib, providing valuable evidence for the safe use of sunitinib in the realworld and contributing to the clinical monitoring and risk identification of sunitinib. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 430,000 new cases of renal cell carcinoma (RCC) occurred worldwide in 2022, and about one-third of RCC cases are diagnosed at an advanced stage of disease (aRCC). When patients with aRCC fail first-line treatment, they commonly receive one of the recommended second-line treatments, i.e., axitinib, cabozantinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib. Axitinib is a second-generation tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor tyrosine kinases 1, 2, and 3. It has been available since 2011 for the treatment of aRCC after the failure of prior therapy with sunitinib or cytokines. The aim of our research was to understand how axitinib compares with other treatment options considering data from clinical trials and observational studies that reflect real-world clinical practice. Therefore, we conducted a systematic literature review to summarise evidence on commonly used and recommended treatments in aRCC after the failure of prior therapy with sunitinib or cytokines. Background: We conducted a systematic literature review (SLR) to identify clinical evidence on treatments in advanced renal cell carcinoma (aRCC) after the failure of prior therapy with cytokines, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Herein, we summarise the evidence for axitinib in aRCC after the failure of prior therapy with cytokines or sunitinib. Methods: This SLR was registered with PROSPERO (CRD42023492931) and followed the 2020 PRISMA statement and the Cochrane guidelines. Comprehensive searches were conducted in MEDLINE and Embase as well as for conference proceedings. Study eligibility was defined according to population, intervention, comparator, outcome, and study design. Results: Of 1252 titles/abstracts screened, 266 peer-reviewed publications were reviewed, of which 182 were included. In addition, 28 conference abstracts were eligible. Data on axitinib were reported in 55 publications, of which 16 provided efficacy and/or safety outcomes on axitinib after therapy with sunitinib or cytokines. In these patients, median progression-free and overall survival ranged between 5.5 and 8.7 months and 11.0 and 69.5 months, respectively. Conclusions: Axitinib is commonly used in clinical practice and has a well-characterised safety and efficacy profile in the treatment of patients with aRCC after the failure of prior therapy with sunitinib or cytokines. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST. [ABSTRACT FROM AUTHOR]

The number of recognized sarcoma types harboring targetable molecular alterations continues to increase. Here we present 25 examples of a distinctive myofibroblastic tumor, provisionally termed "myxoid inflammatory myofibroblastic sarcoma," which might be related to inflammatory myofibroblastic tumor, and which occurred in 13 males (52%) and 12 females at a median age of 37 years (range: 7 to 79 years). Primary tumor sites were peritoneum (18 patients; 72%), paratesticular (2; 8%), chest wall (1), upper extremity (1), esophagus (1), retroperitoneum (1), and uterus (1). Nine peritoneal tumors (50%) were multifocal at presentation; all other tumors were unifocal. Tumors showed bland-to-mildly-atypical neoplastic myofibroblasts in a myxoid stroma, with prominent inflammatory infiltrates in 22 cases (88%). Most tumors showed delicate branching stromal vessels like those of myxoid liposarcoma, and most showed infiltrative growth through nonneoplastic tissue. Immunohistochemistry demonstrated expression of SMA (19/25 tumors; 76%), desmin (13/22; 59%), and CD30 (5/11; 45%), while ALK was expressed in 1 tumor (of 25; 4%) that was negative for ALK rearrangement. Sequencing of 11 tumors showed seven to harbor tyrosine kinase fusions (4 PDGFRB, 2 PML::JAK1, 1 SEC31A::PDGFRA). Two instead harbored hot spot KRAS mutations (G12V and Q61H), and 2 were negative for known driving alterations. Clinical follow-up was available for 18 patients (72%; median: 2.7 years; range: 4 mo-12.3 years). Nine patients (50%) were alive with no evidence of disease, 5 (28%) died of disease, and 4 (22%) were alive with disease. Seven patients (39%) experienced peritoneal relapse or distant metastasis. Two patients showed disease progression on conventional, nontargeted chemotherapy. The patient whose tumor harbored SEC31A::PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progressionfree periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease. [ABSTRACT FROM AUTHOR]

Purpose: Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application. Methods: We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. Results: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect. Conclusion: Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically. [ABSTRACT FROM AUTHOR]

Purpose: Model-based methods can predict pediatric exposure and support initial dose selection. The aim of this study was to evaluate the performance of allometric scaling of population pharmacokinetic (popPK) versus physiologically based pharmacokinetic (PBPK) models in predicting the exposure of tyrosine kinase inhibitors (TKIs) for pediatric patients (≥ 2 years), based on adult data. The drugs imatinib, sunitinib and pazopanib were selected as case studies due to their complex PK profiles including high inter-patient variability, active metabolites, time-varying clearances and non-linear absorption. Methods: Pediatric concentration measurements and adult popPK models were derived from the literature. Adult PBPK models were generated in PK-Sim® using available physicochemical properties, calibrated to adult data when needed. PBPK and popPK models for the pediatric populations were translated from the models for adults and were used to simulate concentration-time profiles that were compared to the observed values. Results: Ten pediatric datasets were collected from the literature. While both types of models captured the concentration-time profiles of imatinib, its active metabolite, sunitinib and pazopanib, the PBPK models underestimated sunitinib metabolite concentrations. In contrast, allometrically scaled popPK simulations accurately predicted all concentration-time profiles. Trough concentration (Ctrough) predictions from the popPK model fell within a 2-fold range for all compounds, while 3 out of 5 PBPK predictions exceeded this range for the imatinib and sunitinib metabolite concentrations. Conclusion: Based on the identified case studies it appears that allometric scaling of popPK models is better suited to predict exposure of TKIs in pediatric patients ≥ 2 years. This advantage may be attributed to the stable enzyme expression patterns from 2 years old onwards, which can be easily related to adult levels through allometric scaling. In some instances, both methods performed comparably. Understanding where discrepancies between the model methods arise, can further inform model development and ultimately support pediatric dose selection. [ABSTRACT FROM AUTHOR]

Background: Sunitinib is a multikinase inhibitor used to treat patients with advanced renal cell carcinoma (RCC). However, sunitinib toxicity makes it a double-edged sword. Potent immune modulation by sunitinib extends to nuclear interactions. To address these issues, there is an urgent need for delivery vectors suitable for sunitinib treatment. Methods: We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models. Results: The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment. Conclusion: Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. Methods: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. Results: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2–14.3) and 10.3 months (2.7–13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2–44.1] and sunitinib/pazopanib (29.2% [18.6–41.8]). Grade 3–5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. Conclusions: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. Clinical trial registration: ClinicalTrials.gov; NCT03260894. [ABSTRACT FROM AUTHOR]

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Purpose: Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs. Methods: A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs. Results: Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs. Conclusions: Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD. [ABSTRACT FROM AUTHOR]

The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system perspective. The partitioned survival model was developed to simulate 3-week patients' transition in 20-year time horizon to evaluate the cost-effectiveness of toripalimab plus axitinib compared with sunitinib for advanced RCC. Survival data were gathered from the RENOTORCH trial, and cost and utility inputs were obtained from the database and published literature. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. Subgroup analyses and sensitivity analyses were conducted to increase the comprehensiveness and estimate the robustness of the model results. In the base-case analysis, compared with sunitinib, toripalimab plus axitinib could bring additional 1.19 LYs and 0.65 QALYs, with the marginal cost of $41,499.23, resulting in the ICER of $64,337.49/QALY, which is higher than the WTP threshold. And ICERs were always beyond the WTP threshold of all subgroups. Sensitivity analyses demonstrated the model results were robust. Toripalimab plus axitinib was unlikely to be the cost-effective first-line therapy for patients with previously untreated advanced RCC compared with sunitinib from the Chinese healthcare system perspective. [ABSTRACT FROM AUTHOR]

Purpose: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. Methods: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. Result: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0–65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9–27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5–40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9–16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). Conclusion: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival. [ABSTRACT FROM AUTHOR]

Objectives: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. Material and methods: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. Results: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). Conclusion: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. Clinical relevance statement: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. Key Points: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions. [ABSTRACT FROM AUTHOR]

Background In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. Patients and Methods CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N  = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n  = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. Results Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P  < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P  < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P  < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. Conclusion In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. Clinicaltrials.gov Identifier NCT02231749 ; https://clinicaltrials.gov/ct2/show/NCT02231749. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the effect of CD276 expression on the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cell and animal models and the potential mechanisms involved. Methods: CD276 expression levels of ccRCC and normal samples were analyzed via online databases and real-time quantitative PCR (RT-qPCR). CD276 was knocked down in ccRCC cell models (sunitinib-resistant 786-O/R cells and sunitinib-sensitive 786-O cells) using shRNA transfection, and the cells were exposed to a sunitinib (2 µM) environment. Cells proliferation was then analyzed using MTT assay and colony formation experiment. Alkaline comet assay, immunofluorescent staining, and western blot experiments were conducted to assess the DNA damage repair ability of the cells. Western blot was also used to observe the activation of FAK-MAPK pathway within the cells. Finally, a nude mouse xenograft model was established and the nude mice were orally administered sunitinib (40 mg/kg/d) to evaluate the in vivo effects of CD276 knockdown on the therapeutic efficacy of sunitinib against ccRCC. Results: CD276 was significantly upregulated in both ccRCC clinical tissue samples and cell models. In vitro experiments showed that knocking down CD276 reduced the survival rate, IC50 value, and colony-forming ability of ccRCC cells. Knocking down CD276 increased the comet tail moment (TM) values and γH2AX foci number, and reduced BRCA1 and RAD51 protein levels. Knocking down CD276 also decreased the levels of p-FAK, p-MEK, and p-ERK proteins. Conclusion: Knocking down CD276 effectively improved the sensitivity of ccRCC cell and animal models to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Background: This research strived to construct a new signature utilizing disulfidptosis-related ferroptosis (SRF) genes to anticipate response to immunotherapy, prognosis, and drug sensitivity in individuals with colorectal cancer (CRC). Methods: The data for RNA sequencing as well as corresponding clinical information of individuals with CRC, were extracted from The Cancer Genome Atlas (TCGA) dataset. SRF were constructed with the help of the random forest (RF), least absolute shrinkage and selection operator (LASSO), and stepwise regression algorithms. To validate the SRF model, we applied it to an external cohort, GSE38832. Prognosis, immunotherapy response, drug sensitivity, molecular functions of genes, and somatic mutations of genes were compared across the high- and low-risk groups (categories). Following this, all statistical analyses were conducted with the aid of the R (version 4.23) software and various packages of the Cytoscape (version 3.8.0) tool. Results: SRF was developed based on five genes (ATG7, USP7, MMD, PLIN4, and THDC2). Both univariate and multivariate Cox regression analyses established SRF as an independent, prognosis-related risk factor. Individuals from the high-risk category had a more unfavorable prognosis, elevated tumor mutational burden (TMB), and significant immunosuppressive status. Hence, they might have better outcomes post-immunotherapy and might benefit from the administration of pazopanib, lapatinib, and sunitinib. Conclusion: In conclusion, SRF can act as a new biomarker for prognosis assessment. Moreover, it is also a good predictor of drug sensitivity and immunotherapy response in CRC but should undergo optimization before implementation in clinical settings. [ABSTRACT FROM AUTHOR]

Prostate cancers represent a significant health problem, and their etiology is complex and multifaceted. It is estimated that in 2018, 1.3 million new cases and 359,000 deaths due to prostate cancer were diagnosed. They constitute the second most common group of cancers and the fifth most common cause of cancer-related deaths in men worldwide. The present study encompasses a literature review aimed at conducting an analysis of the potential of combined anticancer therapy as a prospective method for enhancing treatment efficacy, minimizing side effects, and improving long-term survival outcomes for prostate cancer patients. Combinations of compounds such as sunitinib with docetaxel, carboplatin with paclitaxel, estramustine or flutamide with luteinizing hormone-releasing hormone agonists, as well as docetaxel in conjunction with dexamethasone and octreotide, have demonstrated synergistic effects and an augmentation of therapeutic effectiveness. It is noteworthy to emphasize the potential enhancement of docetaxel's anticancer activity with concurrent administration of dexamethasone and octreotide, as well as combined therapy involving docetaxel, prednisone, and curcumin. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a significant cause of death, particularly in the elderly, and makes accounting for about 3% of all cancer cases. In kidney cancer, as in many other malignancies, treatment response and strategy are largely dependent on the prognosis at the time of diagnosis. Targeted therapies have been the subject of many studies in kidney cancer treatment in recent years. We looked into the objective response rate (ORR), overall survival (OS), progression-free survival (PFS), treatment options, adverse effects, and demographics of patients with kidney cancer in our study. Patients having a diagnosis of kidney cancer were included in the study, received tyrosine kinase inhibitor treatment, and were treated and followed up in our center between January 2005 and September 2017 at the Medical Oncology Clinic of Internal Medicine, Faculty of Medicine, Ondokuz Mayıs University. The files of these patients were analyzed retrospectively. 160 RCC patients in all who had treatment and followed up in our center were evaluated. The study included 62 patients who received tyrosine kinase inhibitors after first-line interferon in the metastatic period. The age range was 24-79 years old 24 to 79 years, with a median age of 62.7 years at the time of diagnosis. Forty-four (70.9%) patients were treated with sunitinib and 18 (29.1%) patients were treated with pazopanib in the first-line setting after metastatic interferon. PFS was 10.8 months for pazopanib and 11.4 months for sunitinib. OS was 23.6 months with for pazopanib and 25 months with for sunitinib therapy. ORR was 19% with sunitinib. Anemia was the most common hematologic adverse effect and fatigue was the most frequent non-hematologic side effect after sunitinib treatment, according to evaluations of side effects both hematological and non-hematological. according to evaluations of both hematological and non-hematological side effects. Individuals treated with sunitinib with pazopanib exhibited prolonged progression-free survival and overall survival. The results suggest that created treatments for m-RCC are successful. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 2% of all pancreatic malignancies. Several systemic treatment options have been developed over the last four decades, ranging from cytotoxic chemotherapy and octreotide to newer targeted therapies like sunitinib, cabozantinib, and lenvatinib. Although surgery or liver-directed therapy remains cornerstone for management of metastatic PanNETs, however, they remain unfeasible in majority of cases. PanNETs behave differently than SI-NETs (small intestinal NET); the former is more aggressive and less responsive to somatostatin-based therapies. The optimal sequence of the systemic therapies for the advanced PanNETs depends mainly on the tumor burden, Ki-67 index, and the tempo of the disease. In the end, drawing from ENETS (European Neuroendocrine Tumor Society) and ESMO (European Society for Medical Oncology) guidelines, we propose a working algorithm for the management of advanced PanNETs, not amenable to surgery or liver-directed therapies. [ABSTRACT FROM AUTHOR]

Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non‐mutagenic drug‐tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib‐tolerant 786‐O/S and Caki‐2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib‐tolerance developed via dynamic processes, including (i) engagement of c‐MET and AXL pathways, (ii) alteration of stress‐induced p38 kinase and pro‐survival BCL‐2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib‐tolerant cell lines led to dramatic fine‐tuning of the actin‐cytoskeleton and boosted cellular migration and invasion, indicating that the drug‐response might depend on cell state transition rather than pre‐existing mutations. The drug‐tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib‐tolerance, providing possible novel therapeutic opportunities in RCC. [ABSTRACT FROM AUTHOR]

Background: Cell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain. Methods: Immunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC–MS/MS were performed to investigate the underlying mechanisms. Results: We found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression. Conclusions: Taken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients. [ABSTRACT FROM AUTHOR]

Background: Adenocarcinoma of the rete testis (AORT) is an extremely rare and aggressive tumor with a poor prognosis. Its etiology and pathological characteristics have not been extensively studied, making accurate diagnosis and appropriate management challenging. AORT, an invasive testicular tumor with a mortality rate of 46%, treatment typically involves radical orchiectomy, retroperitoneal pelvic lymph node dissection (RPLND), adjuvant chemotherapy, and/or ongoing monitoring, but the response to conventional radiation and chemotherapy is limited. At present, no effective targeted therapy for AORT has been found. Case description: In this case report, we present the clinical scenario of a 50-year-old male patient initially diagnosed with a right testicular hydrocele, who subsequently underwent eversion of the parietal tunica vaginalis. Postoperative pathological analysis revealed metastatic clear cell renal cell carcinoma (ccRCC). PET/CT demonstrated findings suggestive of left renal upper pole carcinoma with involvement of the right scrotum, para-aortic region, bilateral iliac vessels, bilateral inguinal region, and multiple metastases. Sunitinib, a tyrosine kinase inhibitor, is commonly employed in the treatment of ccRCC. The patient underwent treatment with sunitinib for a duration of 20 months, resulting in the inactivation of multiple metastases. Following this, a radical orchiectomy was performed, and the postoperative pathology confirmed the presence of AORT. This article provides a comprehensive account of the patient's medical history, diagnostic process, treatment modalities, and subsequent follow-up observations. Conclusions: This case report highlights the successful use of targeted therapy with sunitinib in a patient with AORT. The patient showed a positive response to targeted therapy. This study not only provides a novel foundation for the treatment of AORT, but also offers valuable insights for future treatment strategies in managing this particular form of testicular cancer. [ABSTRACT FROM AUTHOR]

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients' overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes' expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function. Glucose concentration, lactate secretion, and ATP production were measured. Glycolysis-Immune Related Prognostic Index (GIRPI) was constructed and combined analyzed with single-cell RNA-seq. High-GIRPI signature predicted significantly poorer outcomes and relevant clinical features of pRCC patients. Moreover, GIRPI also participated in several pathways, which affected tumor immune microenvironment and provided potential therapeutic strategy. As a key glycolysis regulator, PFKFB3 could promote renal cancer cell proliferation and migration in vitro. Blocking of PFKFB3 by selective inhibitor PFK-015 or glycolytic inhibitor 2-DG significantly restrained renal cancer cells' neoplastic potential. PFK-015 and sunitinib could synergistically inhibit pRCC cells proliferation. Glycolysis-Immune Risk Signature is closely associated with pRCC prognosis, progression, immune infiltration, and therapeutic response. PFKFB3 may serve as a pivotal glycolysis regulator and mediates Sunitinib resistance in pRCC patients. [ABSTRACT FROM AUTHOR]

Hemangiopericytoma (HPC) is a rare tumor originating from Zimmerman pericytes. It constitutes less than 1% of all intracranial tumors. Because of the high recurrence rates, radiotherapy (RT) is a vital step in the treatment, but the timing and dose remain uncertain. We presented a 39-year-old patient with a high-grade hemangiopericytoma located at the skull base. The patient presented with a severe headache. Cranial magnetic resonance imaging (MRI) revealed a mass of size of 60 × 50 mm. A subtotal resection was performed that confirmed the diagnosis of HPC. The patient received 66 Gy postoperative RT. Adjuvant sunitinib treatment was initiated after RT. The complete regression was achieved in the third month after RT. The patient has a complete response for 25 months. To our knowledge, this case is one of the rare cases in the literature in which immediate RT and adjuvant chemotherapy were used in combination with surgery. Although HPC is a radio- and chemo-resistant disease, a trimodality treatment approach can provide the patients with a complete response. In particular, patients with high-grade and inoperable tumors and patients who undergo subtotal resection should be evaluated for trimodal therapy. [ABSTRACT FROM AUTHOR]

In this retrospective study, among 107 mRCC patients with favorable risk receiving TKIs, those with 1 metastatic site had significantly longer overall survival and a trend of better progression-free survival compared to patients with > 1 site. Liver involvement was identified as independent poor prognostic factor for PFS. The site of metastases should be considered when choosing therapies for these patients. Background: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. Material and Methods: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. Results: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. Conclusion: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites. [ABSTRACT FROM AUTHOR]

The limited treatment options for metastatic pheochromocytomas and paragangliomas (PPGLs) pose a significant challenge. This study examined treatment outcomes and the impact of germline mutations in 33 patients with metastatic PPGLs. Cyclophosphamide, vincristine, dacarbazine (CVD), and sunitinib were effective treatments. The results suggest that CVD treatment may hold potential benefits, particularly for patients with SDHB and SDHD mutations. Introduction: Metastatic disease affects approximately 15% to 17% of patients with pheochromocytomas and paragangliomas (PPGLs). Unfortunately, treatment options for metastatic PPGLs are limited and rely on small, nonrandomized clinical trials. The impact of germline mutation status on systemic treatment outcomes remains unclear. To address these gaps, we retrospectively evaluated treatment outcomes in patients with PPGL. Patients and Methods: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. Results: The median age of the patients was 49. Germline mutations were revealed in nine patients (39.1%) out of 23 who underwent germline testing, with SDHB mutation being the most frequent in 5 patients. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was administered to 18 patients, with an objective response rate (ORR) of 22% and a disease control rate (DCR) of 67%. The median progression-free survival (PFS) was 7.9 and the median overall survival (OS) was 36.2 months. Sunitinib was given to 6 patients, which had an ORR of 33%, a DCR of 83%, and a median PFS of 14.6 months. Notably, patients with SDHB/SDHD mutation (4 patients and one patient, respectively) who received CVD treatment had a significantly better OS than those without (median OS 94.0 months vs. 13.7 months, P = .01). Conclusion: Our study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment. [ABSTRACT FROM AUTHOR]

Given the treatment landscape evolution for aRCC, real-world data are needed. All French patients newly treated for aRCC initiated in 2016 were included. In first-line, patients were mainly treated with sunitinib, and in secondline half were treated with nivolumab. The highest OS was observed for patients treated with sunitinib in firstline and for patients treated with nivolumab in second-line. Background: Treatment landscape for advanced renal cell carcinoma (aRCC) has evolved quickly and few data about the real-world treatment patterns are available. This study aimed at describing the real-world treatment patterns and effectiveness of all systemic treatments available for aRCC in first and second-line treatment. Materials and Methods: A cohort of patients initiating a first-line systemic treatment for aRCC in 2016 was extracted from the French nationwide healthcare insurance system database (SNDS). The first-line treatment initiation date constituted the index date and patients were followed until death, loss to follow-up, or December 31, 2019, whichever occurred first. aRCC was identified using hospital diagnosis, long-term disease, or renal biopsy before index date. All analyses were performed for first and second-line treatment. Overall survival (OS) and time-to-next treatment or death (TNT-D) were estimated using Kaplan-Meier approach. Results: In 2016, 1629 patients initiated a first-line treatment for aRCC. Most of them were male (75.9%) and the median age was 67 years. Most of patients (91.7%) had received a tyrosine kinase inhibitor as first-line treatment, mainly sunitinib (64.4%), and 53.5% received a second-line, among which 43.7% nivolumab. Median OS (95% confidence interval [CI]) was 20.7 (95% CI:18.2-22.4) months from first-line treatment initiation and 15.4 (13.9-17.5) months from second-line treatment initiation. Median TNT-D were respectively 9.3 (9.7-12.1) months and 6.9 (5.9-7.7) months. Conclusion: This study highlights the limited survival of aRCC patients These results provide a valuable baseline and highlight the need for innovation, such as immune checkpoint inhibitor-based combinations that have recently became first-line standard of care. [ABSTRACT FROM AUTHOR]