Renal Cancer Patients Research Articles

Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients

PurposePazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care.MethodsA retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated.ResultsLiver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment.ConclusionOur study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.

A novel prognostic predictor of immune microenvironment and therapeutic response in clear cell renal cell carcinoma based on angiogenesis–immune-related gene signature

BackgroundClear cell renal cell carcinoma (ccRCC), the most common type of RCC, typically produces no symptoms initially. Patients with ccRCC are at increased risk of developing advanced metastatic disease due to the absence of dependable and effective prognostic biomarkers. Therefore, it is particularly urgent to find optimal stratification of patients with ccRCC to distinguish the clinical benefits of different malignant degrees. Angiogenesis has a profound impact on the malignant behavior of renal cancer cells, and anti-angiogenic drugs have been applied to metastatic renal cancer patients. Moreover, immune function dysregulation is also a significant factor in tumorigenesis. We aim to construct a predictive model that combines angiogenesis and immune-related genes (AIRGs) to aid clinicians in predicting ccRCC prognosis. MethodsWe gathered transcriptome and clinicopathology data from two datasets, the E-MTAB-1980 dataset and the Cancer Genome Atlas (TCGA). We utilized consensus clustering to find new molecular subgroups. A predictive model for the prognosis of angiogenesis-immune-associated genes (AIRGs) was conducted by the lasso and multivariate Cox regression analysis. The signature's predictive ability was then tested in different datasets. Meticulous scrutiny and comprehensive assessment were undertaken, both internally and externally, to establish the prognostic model. Analyses of immunogenomics were carried out to examine the relationship between risk scores and clinical/immune features, including immune cell infiltration, genomic alterations, and response to targeted and immunotherapy therapy. ResultsOur prognostic signature, comprising 4 AIRGs, stood as an independent prognostic factor for ccRCC, while risk scores emerged as a novel indicator for forecasting overall survival. Risk scores exhibited significant associations with various immunophenotypic factors, such as oncogenic pathways, antitumor response, different immune cell infiltration, antitumor immunity, and response to targeted and immunotherapy therapy. ConclusionsAIRGs-based prognostic prediction model could effectively predict immunotherapy responses and survival outcomes of ccRCC.

Construction of the prognostic model in non-metastatic renal cancer patients with venous tumor thrombus.

Venous system invasion is a prominent characteristic of local progression in renal cancer and treatment-naïve renal cancer patients with venous tumor thrombus (VTT) gained short natural course and poor prognosis. This study aimed to investigate the efficacy of the surgery and prognostic factors in non-metastatic renal cancer patients with VTT and to construct a nomogram prognostic model. Clinical data of 114 non-metastatic renal cancer patients with VTT who underwent surgical treatment from January 2011 to September 2022 were retrospectively analyzed. In order to find independent risk factors of prognosis, survival analysis was performed via univariate and multivariate Cox regression models and Kaplan-Meier method. Nomogram prognostic model was established to calculate patients' risk scores. Receiver operating characteristic curve and decision curve analysis were conducted to evaluate the efficacy of the prognostic model. A total of 114 patients were included in this study and there were 48, 12, 25, 23, and 6 cases of grade 0-IV VTT. No perioperative death occurred. The 3-year probabilities of overall survival (OS) and 5-year probabilities of OS were 67% and 43.8%, respectively. Multivariate Cox regression analysis revealed that kidney tumor diameter, preoperative lactate dehydrogenase (LDH), and preoperative neutrophils were independent risk factors. Nomogram was constructed to predict prognosis in renal cancer patients with VTT based on above indicators and Mayo VTT grading. The area under the ROC curve of 1-, 2-, 3-, and 5-year OS of the patients were 0.82, 0.67, 0.57, and 0.55 respectively. Surgical treatment enables renal cancer patients with VTT to gain a better prognosis. Kidney tumor diameter, preoperative LDH, and preoperative neutrophils were independent risk factors. The nomogram perfects the Mayo grading, and provides a reliable reference for evaluation of prognosis of renal cancer patients with VTT.

Clinical significance of clinicopathological features in predicting surgical treatment and risk of complications in renal cancer with venous tumor thrombosis

Aim. To study and analyze the surgical results and prognostic factors accompanying radical nephrectomy combined with venous thrombectomy in renal cancer patients with venous tumor thrombosis.Materials and methods. Retrospective analysis of clinical data of patients with renal cancer and venous tumor thrombosis who underwent surgical treatment at the Clinic of Cardiovascular Surgery and the Clinic of Urology of the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University) from May 2010 to February 2023. Kaplan–Meier analysis was used to obtain overall survival curves and log-rank tests were used for statistical comparisons; Cox regression models were used for multivariate analysis of survival and complications to find independent risk factors affecting prognosis.Results. A total of 42 patients were included, 15 patients with grade 0–II tumor thrombosis and 27 patients with grade III–IV thrombosis. There were 3 perioperative deaths. The 5-year postoperative survival rate of patients was 68 %. Cox regression analysis: stage Т: HR = 0.515, 95 % confidential interval (CI) 0.111–2.393, p = 0.397; stage N: HR = 1.430, 95 % CI 0.380–5.457, p = 0.592; stage М: HR = 3.312, 95 % CI 0.811–4.561, p = 0,138; time of operation: HR = 1.001, 95 % CI 0.997–1.004, p = 0.771.Conclusion. Kidney cancer patients with venous tumor thrombosis have better surgical treatment results, which may significantly improve their prognosis compared with non-operated patients. Stage N and stage M were important factors directly affecting patients’ survival (HR >1), but the level of tumor thrombosis could not be a factor affecting patients’ survival (HR = 1), but p >0.05, so it was not statistically significant. The level of tumor thrombosis and the duration of surgery affect the intraoperative blood loss, and the greater the intraoperative blood loss, the higher the stage of early postoperative complications and the worse the patient’s prognosis.

SIOG2023-5-P-340 - Using the Senior Adult Oncology Programme Questionnaire to Screen Skin and Renal Cancer Patients

SIOG2023-5-P-340 - Using the Senior Adult Oncology Programme Questionnaire to Screen Skin and Renal Cancer Patients

Treatment of Metastatic Renal Cell Carcinoma with Checkpoint Inhibitors in Clinical Practice in the Volga-Ural Region of the Eurasian Continent.

Renal cancer ranks 10th in the mortality structure of the Russian Federation. The introduction of checkpoint inhibitors has changed the paradigm of treatment of patients with malignant neoplasms. Data from clinical trials have shown good progression-free median and median overall survival. Each cancer center has been accumulating its own experience in treating patients with renal cell cancer by applying modern target drugs and immunotherapy. In routine clinical practice, oncologists do not get the results that have been demonstrated in clinical trials when evaluating the effectiveness of the therapy. In this single-center clinical study, we discuss the results of using nivolumab as mono-therapy and the combination of nivolumab with ipilimumab in metastatic renal parenchyma cancer patients.

Polarization-sensitive optical coherence tomography for renal tumor detection in ex vivo human kidneys

Kidney cancer is a kind of high mortality cancer because of the difficulty in early diagnosis and the high metastatic dissemination in treatments. The surgical resection of tumors is the most effective treatment for renal cancer patients. However, precise assessment of tumor margins is a challenge during surgical resection. The objective of this study is to demonstrate an optical imaging tool in precisely distinguishing kidney tumor borders and identifying tumor zones from normal tissues to assist surgeons in accurately resecting tumors from kidneys during the surgery. 30 samples from six human kidneys were imaged using polarization-sensitive optical coherence tomography (PS-OCT). Cross-sectional, enface, and spatial information of kidney samples were obtained for microenvironment reconstruction. Polarization parameters (phase retardation, optic axis direction, and degree of polarization uniformity (DOPU) and Stokes parameters (Q, U, and V) were utilized for multi-parameter analysis. To verify the detection accuracy of PS-OCT, H&E histology staining and dice-coefficient were utilized to quantify the performance of PS-OCT in identifying tumor borders and regions. In this study, tumor borders were clearly identified by PS-OCT imaging, which outperformed the conventional intensity-based OCT. With H&E histological staining as golden standard, PS-OCT precisely identified the tumor regions and tissue distributions at different locations and different depths based on polarization and Stokes parameters. Compared to the traditional attenuation coefficient quantification method, PS-OCT demonstrated enhanced contrast of tissue characteristics between normal and cancerous tissues due to the birefringence effects. Our results demonstrated that PS-OCT was promising to provide imaging guidance for the surgical resection of kidney tumors and had the potential to be used for other human kidney surgeries in clinics such as renal biopsy.

Outcomes of Targeted Therapy Plus Immunotherapy and High-Dose Stereotactic Ablative Body Radiotherapy (SABR) for Metastatic Renal Cell Cancer Patients.

Stereotactic ablative body radiotherapy (SABR) is one of the treatment options for metastatic renal cell carcinoma (mRCC) but is limited by a lack of data to evaluate targeted therapy plus immunotherapy concurrently with high-dose SABR to multiple sites. We evaluated the safety and disease control for mRCC patients who concurrently received the above tri-modality treatment. Patients were treated with SABR (40-70 Gy/5-10 fractions) for small lesions or partial-SABR (tumor center boosted with 6-8 Gy/3-5 fractions with 50-60 Gy/20-25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs. When SABR/partial-SABR was not feasible, a moderate fractionated radiotherapy plan, usually 60Gy/20 fractions were applied. of Targeted therapy plus immunotherapy (PD-1 inhibitor) was not interrupted during or after radiotherapy (RT). Adverse events (AEs) were evaluated. Disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were calculated. The PFS1 was defined as the first progression since the start of RT. The PFS2 was defined as the second progression after the second RT course, if new metastases occurred after first RT were all re-irradiated, and the systemic therapy was not changed. The Kaplan-Meier method was used for time-to-event endpoints. A total of 51 patients, with a median age of 57 yr, were enrolled. The median follow-up was 12 months. There were 75% of patients with intermediate-risk and 18% with favorable-risk disease. 61% of the patients were oligometastatic. 71% had clear cell renal cancer. There were 241 metastases while 161 (67%) were irradiated. 80% of the lesions received SABRP/partial SABR. 1 patient with 14 lesions irradiated received proton therapy. All the surviving patients are continuing using targeted therapy while 81% patients complete at least 1-year PD-1 therapy. 10 patients (20%) had grade 3 drug-related AEs: pneumonitis (n = 2), elevated alanine transaminase (n = 4), myositis (n = 1), hand-foot syndrome myositis (n = 1), enteritis (n = 1), fatigue (n = 1). There were 1 grade 4 AEs of upper gastrointestinal bleeding. No grade 3-5 RT-related AEs was found. ORR and DCR for irradiated lesion were 51% and 98%. Median OS and PFS2 was not reached. Median PFS1 was 14(6-22) months. Estimated 1- and 2-yr OS, PFS1 and PFS2 were 90% and 90%, 56% and 38%, 74% and 51% respectively. Univariate analysis showed that an PFS1 benefit was found in patients who received radiation before systemic therapy failure (p = 0.038). We investigated the high-dose RT in combination of concurrent targeted and immunotherapy in patients with metastatic RCC. We found that this treatment regimen was well tolerated, with good cancer control. Early use of high-dose RT to multi-lesions may improve PFS. Partial-SABR for bulky lesions close to critical organs could be safely and effectively applied under certain circumstances. These encouraging findings warrant further investigation.

SDPS-32 A CLINICALLY COMPATIBLE IN VITRO DRUG-SCREENING PLATFORM IDENTIFIES THERAPEUTIC VULNERABILITIES IN PRIMARY CULTURES OF BRAIN METASTASES

Abstract Approximately 20% of cancer patients (including lung, melanoma, breast, renal, and colorectal cancer patients) develop brain metastases. Current systemic therapies often show limited efficacy for brain metastasis treatment and support palliative care only. In this preclinical study, short-term cultured primary cancer cells from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to identify pharmacological treatment sensitivities. Next-generation sequencing identified matched genetic alterations between brain metastasis tissues and corresponding patient-derived cultured cancer cells. Mutant allele frequencies indicated that short-term cultures of cancer cells reflect the existence of distinct subpopulations of cancer cells within brain metastases. This indicates that our short-term cultured primary brain metastasis cells are suitable models for recapitulating heterogeneity in the sensitivity of tumor cells to anti-cancer drugs. Employing our in-house high-throughput in vitro drug screening platform, we screened the primary cultures from the brain metastasis patients for response to 267 anticancer compounds, and integrated the molecular and high-throughput drug screening data sets. Our preclinical study provides proof-of-concept for combining molecular profiling with in vitro drug screening for improved prediction of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.

Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study

Background & AimsCheckpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI). MethodsPrescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI. ResultsOut of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2–15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have ‘life-threatening’ grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases. ConclusionsThe real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care. Impact and implicationsUsing prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.

Point of care parenchymal volume analyses to estimate split renal function and predict functional outcomes after radical nephrectomy

Accurate prediction of new baseline GFR (NBGFR) after radical nephrectomy (RN) can inform clinical management and patient counseling whenever RN is a strong consideration. Preoperative global GFR, split renal function (SRF), and renal functional compensation (RFC) are fundamentally important for the accurate prediction of NBGFR post-RN. While SRF has traditionally been obtained from nuclear renal scans (NRS), differential parenchymal volume analysis (PVA) via software analysis may be more accurate. A simplified approach to estimate parenchymal volumes and SRF based on length/width/height measurements (LWH) has also been proposed. We compare the accuracies of these three methods for determining SRF, and, by extension, predicting NBGFR after RN. All 235 renal cancer patients managed with RN (2006–2021) with available preoperative CT/MRI and NRS, and relevant functional data were analyzed. PVA was performed on CT/MRI using semi-automated software, and LWH measurements were obtained from CT/MRI images. RFC was presumed to be 25%, and thus: Predicted NBGFR = 1.25 × Global GFRPre-RN × SRFContralateral. Predictive accuracies were assessed by mean squared error (MSE) and correlation coefficients (r). The r values for the LWH/NRS/software-derived PVA approaches were 0.72/0.71/0.86, respectively (p < 0.05). The PVA-based approach also had the most favorable MSE, which were 120/126/65, respectively (p < 0.05). Our data show that software-derived PVA provides more accurate and precise SRF estimations and predictions of NBGFR post-RN than NRS/LWH methods. Furthermore, the LWH approach is equivalent to NRS, precluding the need for NRS in most patients.

Incidence, Prognostic Factors, and Survival of Patients with Renal Cancer: A Population-Based Study

Background The main objective of this article is to understand trends in the incidence of renal cancer and to construct a nomogram to predict the prognosis of patients with renal cancer by analyzing clinical parameters. Methods We extracted data from the Surveillance, Epidemiology and End Results (SEER) database for patients with renal cancer from 2010 to 2015. The incidence rate was calculated to understand the trend of renal cancer in recent years, and the Kaplan–Meier method was used to analyze the relationship between patients’ clinical variables and overall survival. Nomogram and calibration curves were constructed based on factors predicted by multivariate Cox regression. Results Data from 68,496 eligible renal cancer patients were included in the study. The incidence of renal cancer was higher in men than women and tended to stabilize over time. We further found that age, gender, marital status, AJCC stage, histological type, metastatic disease, and surgery were independent parameters for prognosis in renal cancer patients. Finally, a nomogram was constructed based on the above parameters, and its validity was verified with the agreement index and calibration curve. Conclusion Renal cancer incidence trend gradually stabilized. Seven independent parameters for renal cancer patients were obtained by analysis and utilized to construct a nomogram that could provide guidance for clinical practice.

Abstract 3866: Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer

Abstract Advanced stage renal cell carcinoma (RCC) often becomes resistant to the currently available therapeutic options. Receptor Tyrosine Kinase (RTK), c-Met, is overexpressed and hyperactivated in renal cancer; and it promotes tumor-promoting pathways following binding with its ligand, Hepatocyte Growth Factor (HGF). Cabozantinib (Cabo), an inhibitor of c-Met/few other RTKs (like, AXL and KDR), is being used for the treatment of RCC. However, acquired therapeutic resistance is a major hurdle in its clinical use. Mechanism(s) of drug resistance against c-Met inhibition is largely unknown. Although Cabo (XL184) can effectively inhibit c-Met/RTK phosphorylation, very interestingly, we found that, prolonged treatment of Cabozantinib (24 hours, in vitro) increased the expression of total c-Met and AXL in renal cancer cells in a dose-dependent manner. AXL is also overexpressed in RCC and has a novel cross-talk with c-Met. We found that silencing AXL (either by gene knock-down approach or using a specific inhibitor (TP-0903)) markedly down-regulates Cabo-mediated total c-Met expression and enhances apoptosis of human RCC cells. We have also utilized murine model(s) of renal cancer growth (both xenograft and syngeneic), and found that Cabo treatment increases the levels of c-Met and AXL in tumor tissues, and the inhibition of AXL using TP-0903 can markedly inhibit the expression levels of total c-Met and AXL. We observed that HGF-mediated c-Met phosphorylation is short-lived when AXL is silenced. We also found that a lower concentration of Cabo can mediate cancer cell survival; and either the knock-down of AXL or using AXL inhibitor in combination with Cabo can reverse these effects. We have studied the downstream signaling pathways (Akt, ERK1/2 and STAT3) of c-Met, and found that AXL inhibition is crucial to down-regulate c-Met-induced signaling molecules following Cabo treatment. Our observations indicate that Cabo-mediated increase in total c-Met in RCC cells is not regulated at the transcriptional level; however, Cabo can interfere with the receptor degradation pathway leading to increased accumulation of c-Met. We have also studied the levels of c-Met and AXL in renal tumor tissues (archived specimens) from renal cancer patients before and after Cabozantinib treatment. Interestingly, we found increased levels of total c-Met and AXL in tumor tissues following Cabo treatment. Together our data suggest that AXL plays a critical role in mediating therapeutic resistance against c-Met inhibitor; and a combination of Cabo and an AXL/other RTK inhibitor can effectively block the resistance. Citation Format: Akash Sabarwal, Laxminarayan Rawat, Johannes Wedel, Yuzuru Sasamoto, Sabina Signoretti, Toni K. Choueiri, Murugabaskar Balan, Soumitro Pal. Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3866.

Abstract 701: Evaluation of an AKT-1 antisense oligonucleotide in combination with Lenvatinib and Everolimus in Renca-luciferase syngeneic orthotopic murine tumor model

Abstract Background: The combination of 18mg Lenvatinib and 5mg Everolimus per day is used in the clinic for advanced renal cancer patients. However, due to the severe side effects of Lenvatinib, the dose is often reduced to 12mg. Archexin, a fully phosphorothioated 20-mer antisense oligonucleotide, inhibits AKT-1 mRNA translation and inhibits tumor growth. Combination of Archexin with reduced-dosed Lenvatinib and Everolimus may reduce adverse reactions while enhancing therapeutic efficacy. Methods: First, Lenvatinib and Everolimus monotherapies were evaluated for antitumor efficacy in an orthotopic Renca-luciferase syngeneic model. 45 mice were randomly divided into 9 groups (5 in each group), vehicle control, Lenvatinib (5, 10, 20, and 30 mg/kg) and Everolimus (0.2, 0.5, 1, 2, and 4 mg/kg) via daily oral administration for 20 days. Next, we investigated the anti-tumor effect of the two- and three-drug combination. 35 mice were randomly divided into 7 groups (5 in each group), including vehicle control, Lenvatinib/Everolimus combinations (5+0.2, 10+0.2 and 10+0.5 mg/kg) and Archexin/Lenvatinib/Everolimus combinations (60+5+0.2, 60+10+0.2 and 60+10+0.5 mg/kg) via tail vein injection (vehicle/Archexin, Q3D*6 times) or oral administration (Lenvatinib and Everolimus, QD*18 days). Body weight was monitored daily. Tumor burden was measured by bioluminescence through whole-body fluorescence images, performed twice a week. Results: The results showed that Everolimus inhibited tumor growth in a dose-dependent manner. Partial response was observed in mice treated with varying doses of Lenvatinib(TGIs: 57.94%,76.65% and 60.22%), and no significant dose-effect correlation was found. The dose of Lenvatinib and Everolimus that partially inhibited the orthotopic tumor growth had also been identified and selected for subsequent study investigating drug combinations. The drugs combination study showed that three drug combinations (Archexin/Lenvatinib/Everolimus) had superior efficacy compared to the Lenvatinib and Everolimus combination. The fluorescence signal intensities (Lg10) of the three-drug combination were significantly lower than that of the two-drug combination group with P value &amp;lt;0.05. No severe adverse effects were observed in the three drug combinations group. Conclusion: Three drugs combination of Archexin, Lenvatinib and Everolimus, demonstrated superior anti-tumor efficacy compared to the two-drug combination currently used in the clinic. This finding suggests the three-drug combination warrant investigation in the clinical trial in the patients with advanced renal cancer. Citation Format: Fengyang Xie, Jia Wei, Lan Deng, Chao Wang, Ben Zhao, Robert J. Lee, Yuxin Angela Men. Evaluation of an AKT-1 antisense oligonucleotide in combination with Lenvatinib and Everolimus in Renca-luciferase syngeneic orthotopic murine tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 701.

MP04-07 VOLATILOME ANALYSIS IN RENAL CANCER BY ELECTRONIC NOSE: A PILOT MONOCENTRIC STUDY

You have accessJournal of UrologyCME1 Apr 2023MP04-07 VOLATILOME ANALYSIS IN RENAL CANCER BY ELECTRONIC NOSE: A PILOT MONOCENTRIC STUDY Manuela Costantini, Alessio Filianoti, Alfredo Maria Bove, Umberto Anceschi, Aldo Brassetti, Mariaconsiglia Ferriero, Riccardo Mastroianni, Leonardo Misuraca, Gabriele Tuderti, Simone D'annunzio, Gennaro Ciliberto, and Giuseppe Simone Manuela CostantiniManuela Costantini More articles by this author , Alessio FilianotiAlessio Filianoti More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Riccardo MastroianniRiccardo Mastroianni More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Simone D'annunzioSimone D'annunzio More articles by this author , Gennaro CilibertoGennaro Ciliberto More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003215.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although challenging and highly expensive for health systems worldwide, no useful markers are available in clinical practice that aim to anticipate renal cancer diagnosis in the early stages in the context of wide population screening. Urine analysis by an electronic nose provides volatile organic compounds (VOCs) easily usable in the diagnosis of urological diseases. Some previous works suggested that dogs trained to smell urine could recognize lung, bladder, or breast cancer with various success rates, but no strong results have been reported in renal cancer (RCC) setting. In this study, we investigated the diagnostic potential of urinary VOCs profiling by enose in discriminating renal patients from healthy controls. METHODS: This prospective pilot study includes 252 individuals subdivided in two groups: 110 RCC patients, and 142 healthy controls. For each case, urine samples were collected, stabilized at 37°C, and twice analyzed using a commercially available electronic nose (Cyranose C320-32 sensors). Statistical analysis of the sensor responses was performed off-line using principal component (PCA) analyses and discriminant analysis (CDA). The best discriminating principal component groups were identified with univariable ANOVA analysis. We used the “leave-one-out method” to calculate the Cross Validated Accuracy (CVA), an estimate of accuracy of a predictive model in clinical practice. The discrimination accuracy of the built model was evaluated by ROC curves. RESULTS: Based on PCA analysis, 79/110 and 127/142 cases were correctly identified in RCC and healthy control cohorts, respectively (sensitivity 71.8%, specificity 89.4%; positive predictive value 84.4%, negative predictive value 80.3%). Results obtained with CDA demonstrated a correct classification in 81.7% of cases (p<0.001). At ROC analysis, the discrimination accuracy of the model area under the curve (AUC) was 0.85. Repeated analysis of a second measurement of urine samples provided comparable findings. CONCLUSIONS: This study provides a first evaluation of urinary volatilome in RCC. Urine VOCs profiling by e-nose seems a promising, non-invasive diagnostic tool with high accuracy in discriminating patients from controls. Ease of use, low costs and non-invasive nature makes this test a potential molecular biomarker in early RCC diagnostic settings. Source of Funding: Italian Ricerca Corrente 2022 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e35 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Manuela Costantini More articles by this author Alessio Filianoti More articles by this author Alfredo Maria Bove More articles by this author Umberto Anceschi More articles by this author Aldo Brassetti More articles by this author Mariaconsiglia Ferriero More articles by this author Riccardo Mastroianni More articles by this author Leonardo Misuraca More articles by this author Gabriele Tuderti More articles by this author Simone D'annunzio More articles by this author Gennaro Ciliberto More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement PDF downloadLoading ...

SLC14A1 is a new biomarker in renal cancer.

Renal cancer is one of the common malignant tumors of the urinary tract, prone to distant metastasis and drug resistance, with a poor clinical prognosis. SLC14A1 belongs to the solute transporter family, which plays a role in urinary concentration and urea nitrogen recycling in the renal, and is closely associated with the development of a variety of tumors. Transcription data for renal clear cell carcinoma (KIRC) were obtained from the public databases Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA), and we investigated the differences in SLC14A1 expression in cancerous and normal tissues of renal cancer, its correlation with the clinicopathological features of renal cancer patients. Then, we verified the expression levels of SLC14A1 in renal cancer tissues and their Paracancerous tissues using RT-PCR, Western-blotting and immunohistochemistry. Finally, we used renal endothelial cell line HEK-293 and renal cancer cell lines 786-O and ACHN to explore the effects of SLC14A1 on the biological behaviors of renal cancer cell proliferation, invasion and metastasis using EDU, MTT proliferation assay, Transwell invasion assay and scratch healing assay. SLC14A1 was lowly expressed in renal cancer tissues and this was further validated by RT-PCR, Western blotting, and immunohistochemistry in our clinical samples. Analysis of KIRC single-cell data suggested that SLC14A1 was mainly expressed in endothelial cells. Survival analysis showed that low levels of SLC14A1 expression were associated with a better clinical prognosis. In biological behavioral studies, we found that upregulation of SLC14A1 expression levels inhibited the proliferation, invasion, and metastatic ability of renal cancer cells. SLC14A1 plays an important role in the progression of renal cancer and has the potential to become a new biomarker for renal cancer.

The novel putative methyltransferase METTL7A as one prognostic biomarker potentially associated with immune infiltration in human renal cancer

Among urological cancers, renal cancer has the highest fatality rate. In a previous pan-cancer study of the METTL family, we observed a stronger association between the METTL family members and the risk of renal cancer compared to other cancers. Among these members, METTL7A, a potential methyltransferase, was identified as a protective factor, although its role and mechanism in renal cancer remain unclear. In this study, we utilized public databases to examine the expression of METTL7A in renal cancer tissues and normal tissues and found that METTL7A expression was much lower in renal cancer tissues. We also noticed a link between low METTL7A expression and poor prognosis for patients. According to the results of our functional enrichment analysis, METTL7A may have a role in immunological functions in renal cancer. METTL7A expression was strongly linked with the degrees of immune cell infiltration and expression of numerous immunological components. METTL7A had significantly different effects on the survival times of renal cancer patients with high or low immune infiltration. Our findings suggest that METTL7A may be used as both a prognostic biomarker and an immunological target for kidney cancer. In conclusion, our study sheds light on the importance of METTL7A in renal cancer and emphasizes the potential of targeting METTL7A as a novel therapeutic strategy for kidney cancer.

The role of three-dimensional models in preoperative communication and postoperative management of partial nephrectomy

ObjectiveThis study aims to examine the significance of utilizing three-dimensional (3D) image reconstruction technique in preoperative communication prior to partial nephrectomy (PN) and its impact on postoperative follow-up. MethodsA retrospective study was performed with 158 renal cancer patients treated with PN at our center from May 1, 2017 to April 30, 2019. 81 patients (group A) had preoperative communication using the 3D reconstruction technique, while 77 patients (group B) did not. The surgeon explained the anatomical structure, tumor characteristics, and surgical approach in detail to the two groups of patients. Each patient completed a questionnaire. The loss to follow-up rate over a 3-year period was counted for both groups, and non-cancer-related serious complications such as renal failure and cardio-cerebrovascular disease were observed. This research did not include patients who returned for follow-up care owing to associated complications such as postoperative chronic kidney disease. Comparisons between two groups were performed using the Mann–Whitney U test and chi-square test. ResultsAll patients showed no statistically significant differences in basic clinical parameters, such as age, gender, body mass index, tumor size, and R.E.N.A.L. score (P ​> ​0.05). In group A, patients were significantly more likely to experience understanding of renal anatomy (P ​= ​0.001), characteristics of renal cell carcinoma (P ​= ​0.003), surgical approach (P ​= ​0.007), and relief of preoperative anxiety (P ​= ​0.013). The follow-up adherence at 3 years postoperatively in group A and group B was 21 cases and 10 cases, respectively (P ​= ​0.041). In addition, glomerular filtration rate < 60 ​mL/min/1.73 ​m2 or serum creatinine > 186 ​μmol/L at 3 years after surgery occurred in 5 patients in group A and 13 in group B (P ​= ​0.034), and a systolic blood pressure rise greater than 20 ​mmHg occurred in 9 patients in group A and 18 in group B (P ​= ​0.041). ConclusionsThe findings of this study suggest that the integration of 3D reconstruction techniques in preoperative communication effectively enhances patients’ understanding and perception of kidney tumors and PN. Moreover, the utilization of these techniques can contribute to the prevention of significant non-cancer-related complications during the postoperative phase.

Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients

BackgroundRenal carcinoma is a common malignant tumor of the urinary system. Advanced renal carcinoma has a low 5-year survival rate and a poor prognosis. More and more studies have confirmed that chromatin regulators (CRs) can regulate the occurrence and development of cancer. This article investigates the functional and prognostic value of CRs in renal carcinoma patients.MethodsmRNA expression and clinical information were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and LASSO regression analysis were used to select prognostic chromatin-regulated genes and use them to construct a risk model for predicting the prognosis of renal cancer. Differences in prognosis between high-risk and low-risk groups were compared using Kaplan–Meier analysis. In addition, we analyzed the relationship between chromatin regulators and tumor immune infiltration, and explored differences in drug sensitivity between risk groups.ResultsWe constructed a model consisting of 11 CRs to predict the prognosis of renal cancer patients. We not only successfully validated its feasibility, but also found that the 11 CR-based model was an independent prognostic factor. Functional analysis showed that CRs were mainly enriched in cancer development-related signalling pathways. We also found through the TIMER database that CR-based models were also associated with immune cell infiltration and immune checkpoints. At the same time, the genomics of drug sensitivity in cancer database was used to analyze the commonly used drugs of renal clear cell carcinoma patients. It was found that patients in the low-risk group were sensitive to medicines such as axitinib, pazopanib, sorafenib, and gemcitabine. In contrast, those in the high-risk group may be sensitive to sunitinib.ConclusionThe chromatin regulator-related prognostic model we constructed can be used to assess the prognostic risk of patients with clear cell renal cell carcinoma. The results of this study can bring new ideas for targeted therapy of clear cell renal carcinoma, helping doctors to take corresponding measures in advance for patients with different risks.

Accumulated cholesterol protects tumours from elevated lipid peroxidation in the microenvironment

Elevated lipid peroxidation (LPO), usually present in the tumour microenvironment (TME), is profoundly implicated in antitumour immunity and may be targeted for the development of new antitumour therapies. However, tumour cells may also rewire their metabolism to survive elevated LPO. Here, we report a novel and nonantioxidant mechanism by which tumour cells benefit from accumulated cholesterol to restrain LPO and ferroptosis, a nonapoptotic form of cell death characterized by accumulated LPO. Modulating cholesterol metabolism, especially LDLR-mediated cholesterol uptake, shifted the susceptibility of tumour cells to ferroptosis. Elevation of cellular cholesterol content specifically restrained LPO triggered by GSH-GPX4 inhibition or oxidizing factors in the TME. Furthermore, depletion of TME cholesterol by MβCD efficiently enhanced the antitumour efficacy of ferroptosis in a mouse xenograft model. Distinct from the antioxidant effect of its metabolic intermediates, the protective role of cholesterol was ascribed to its ability to decrease membrane fluidity and promote lipid raft formation, which affects the diffusion of LPO substrates. A correlation between LPO and lipid rafts was also found in tumour tissues from renal cancer patients. Together, our findings have identified a general and nonsacrificial mechanism by which cholesterol suppresses LPO, which can be exploited to enhance the efficacy of ferroptosis-based antitumour strategies.