Impact of diabetes mellitus and hypertension on renal function during first-line targeted therapy for metastatic renal cell carcinoma: a retrospective multicenter study.

Background: Renal function deterioration during systemic therapy in patients with metastatic renal cell carcinoma (mRCC) is a long-term concern in treatment planning. Although hypertension (HTN) and diabetes mellitus (DM) are the most common factors that affect chronic kidney disease (CKD) development and progression, their impact on renal function during targeted therapy is unclear. This study investigated whether DM and HTN were associated with a decline in renal function during first-line targeted therapy for mRCC. Methods: This retrospective multicenter study analyzed patients receiving first-line targeted therapy for mRCC. They were classified as follows: group 1: HTN-, DM-; group 2: HTN+, DM-; group 3: HTN-, DM+; and group 4: HTN+, DM+. Changes in renal function and factors affecting progression to stage 4 CKD after targeted therapy were analyzed. Results: Among the 424 enrolled patients, 303 (71.5%) and 121 (28.5%) were treated with sunitinib and pazopanib, respectively [median duration: 10.3 months, interquartile range (IQR), 3.1-37.0 months]. Although all groups showed a decreased mean estimated glomerular filtration rate (eGFR) after treatment (P<0.001 for group 1, group 2, and group 4, P=0.02 for group 3, respectively), there were no significant differences in changes in eGFR (∆eGFR) between groups (P=0.10). However, actual renal function change calculated using percent ∆eGFR (%∆eGFR) showed differences between groups (P=0.02); the %∆eGFR of group 4 was significantly lower compared with group 1 (P=0.008). The mean progression time to stage 4 CKD in group 4 (38.6 months) was significantly shorter compared to the other groups (P<0.001). Multivariate analysis identified increased age (P=0.008), increased number of metastatic sites (P=0.047), and DM and HTN coexistence (P<0.001) as predictors of progression to stage 4 CKD. Conclusions: Patients with DM and HTN experienced further decline in renal function and had a higher risk of progression to stage 4 CKD after targeted therapy compared to patients without these risk factors. Recognition and proactive management of DM and HTN are necessary to facilitate the proper administration of life-prolonging oncological treatments.

Phospholipase C-ß3 is dispensable for vascular constriction but indispensable for vascular hyperplasia.

Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-ß (PLC-ß), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-ß3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-ß3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-ß3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-ß3∆SMC, NOX1-/-, NOX4-/- and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-ß3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1-/- and PLC-ß3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1-/- and PLC-ß3∆SMC mice. These results suggest that PLC-ß3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.

Alix-normalized exosomal programmed death-ligand 1 analysis in urine enables precision monitoring of urothelial cancer.

Anti-programmed death-ligand 1 (PD-L1) Ab-based therapies have demonstrated potential for treating metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers for liquid biopsy, but urine's high variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio to normalize exosomal PD-L1 signal intensity with Alix, an internal exosomal protein less susceptible to heterogeneity concerns than surface protein markers. Extracellular vesicles were isolated using ExoDisc and characterized using various methods, including ExoView to analyze tetraspanins, PD-L1, and Alix on individual exosomes. On-disc ELISA was used to evaluate PD-L1 and Alix-normalized PD-L1 in 15 urothelial cancer patients during the initial treatment cycle with Tecentriq. Results showed that Alix signal range was relatively uniform, whereas tetraspanin marker intensity varied for individual exosome particles. On-disc ELISA was more reliable for detecting exosomal PD-L1 expression than standard plate ELISA-based measurement. Using exosomal Alix expression for normalization is a more reliable approach than conventional methods for monitoring patient status. Overall, the study provides a practical and reliable method for detecting exosomal PD-L1 in urine samples from patients with urothelial cancer.

Rate of benign histology after resection of suspected renal cell carcinoma: multicenter comparison between Korea and the United States.

BACKGROUND: In the United States, the rate of benign histology among resected renal tumors suspected to be malignant is increasing. We evaluated the rates in the Republic of Korea and assessed the racial effect using recent multi-institutional Korean-United States data. METHODS: We conducted a multi-institutional retrospective study of 11,529 patients (8,812 from The Republic of Korea and 2,717 from the United States) and compared the rates of benign histology between the two countries. To evaluate the racial effect, we divided the patients into Korean, Asian in the US, and Non-Asian in the US. RESULTS: The rates of benign histology and small renal masses in Korean patients were significantly lower than that in United States patients (6.3% vs. 14.3%, p < 0.001) and (≤ 4 cm, 7.6% vs. 19.5%, p < 0.001), respectively. Women, incidentaloma, partial nephrectomy, minimally invasive surgery, and recent surgery were associated with a higher rate of benign histology than others. CONCLUSIONS: In Korea, the rate of benign histology among resected renal tumors was significantly lower than that in the United States. This disparity could be caused by environmental or cultural differences rather than racial differences. Our findings suggest that re-evaluating current context-specific standards of care is necessary to avoid overtreatment.

Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). MATERIALS AND METHODS: A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups. RESULTS: No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% vs. 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% vs. 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups. CONCLUSIONS: ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.

Perioperative systemic therapy in muscle invasive bladder cancer: Current standard method, biomarkers and emerging strategies.

Bladder cancer ranks as the 10th most common cancer type globally, and muscle-invasive disease accounts for approximately 25% of newly diagnosed bladder cancers. Despite definitive treatment, 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastasis within 2 years, leading to death. Perioperative systemic therapy is generally recommended to control local relapse or distant metastasis after surgical resection for patients with MIBC. Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard treatment to improve oncologic control and survival outcomes. Adjuvant chemotherapy is recommended for patients with pathological T3-4 or positive lymph nodes after radical cystectomy if no neoadjuvant chemotherapy was given. Nonetheless, perioperative systemic therapy is not applied widely because of its toxicity, and less than 25% of patients receive cisplatin-based neoadjuvant chemotherapy. Therefore, the development of predictive biomarkers for neoadjuvant chemotherapy efficacy and alternative effective regimens for cisplatin-ineligible patients are important. Furthermore, recently, novel anticancer agents such as immune checkpoint inhibitors and antibody-drug conjugates have proven survival benefits in the metastatic setting, thereby expanding their therapeutic applications to the perioperative setting for non-metastatic MIBC. Herein, we discuss the current status and future perspectives of perioperative systemic strategies for MIBC.

Patients' self-management of adverse events and patient-reported outcomes in advanced renal cell carcinoma treated with targeted therapies: A prospective, longitudinal, observational study.

BACKGROUND: Early intervention to reduce the impact of adverse events (AEs) may improve patients' quality of life and enable optimal treatment duration. METHODS: This nationwide, multicenter, prospective, longitudinal, 1-year observational study investigated patients' self-management of AEs associated with targeted therapy for advanced renal cell carcinoma (RCC) and explored corresponding outcomes, including treatment duration and patient-reported outcomes (PROs). RESULTS: We enrolled 77 advanced RCC patients (mean age 62 years) treated with a first targeted therapy. 210 cases of seven AEs of interest (fatigue, hand-foot syndrome, oral mucosal inflammation, diarrhea, gastrointestinal symptoms, hypertension, and anorexia) were observed. Most AEs were mild to moderate. Overall, 63.4% of patients were identified as managing their AEs well, reporting numerically longer treatment duration and significantly higher PRO scores than patients identified as poor managers. CONCLUSIONS: Longer treatment duration and improved PROs were observed when advanced RCC patients managed targeted therapy-associated AEs well. Repeated education for consolidating AE self-management could be considered to enhance overall treatment outcomes.

Prognostic value of the endothelial activation and stress index in patients with upper tract urothelial cancer undergoing radical nephroureterectomy.

PURPOSE: The relationship with endothelial activation and stress index (EASIX), which represents the degree of endothelial dysfunction, is unwell known in upper tract urothelial carcinoma (UTUC). The present study aims to assess the prognostic value of the EASIX for recurrence-free survival (RFS) and overall survival (OS) in patients with UTUC who underwent radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively reviewed the clinical data of 627 patients with UTUC who underwent RNU without neoadjuvant chemotherapy at three hospitals between 2002 and 2019. EASIX scores were calculated using the formula "serum lactate dehydrogenase (U/L)×creatinine (mg/dL)/platelet count (109/L)" and evaluated based on log2-transformed values. We divided the patients according to the EASIX score (>1.27 vs. ≤1.27). RESULTS: Among 627 patients, 380 were finally analyzed. Using maximally selected log-rank statistics, the optimal EASIX cutoff value was 1.27 on the log2 scale. The baseline characteristics were similar between the two groups except for age. The high EASIX score group had worse RFS and OS than the low EASIX score group (log-rank p=0.001 and p=0.006, respectively). At 5 years, the mean RFS and OS difference between the low and high EASIX score groups was 11.1 and 7.35 months, respectively. High EASIX score remained a key prognosticator of RFS and OS after RNU in multivariable analysis. CONCLUSIONS: EASIX score may represent endothelial dysfunction in patients with UTUC and may serve as a readily available prognostic factor for oncologic outcomes.

Akt1-dependent expression of angiopoietin 1 and 2 in vascular smooth muscle cells leads to vascular stabilization.

Retinal angiogenesis was delayed in VSMC-specific Akt1-deficient mice (Akt1∆SMC) but not in Akt2∆SMC mice. The proliferation of ECs, recruitment of pericytes, and coverage of VSMCs to the endothelium were defective in Akt1∆SMC. The silencing of Akt1 in VSMCs led to the downregulation of angiopoietin 1 (Ang1) and the upregulation of Ang2. The activation of Notch3 in VSMCs was significantly reduced in the retinas of Akt1∆SMC mice. Silencing Akt1 suppressed the activation of Notch3. Moreover, the silencing of Notch3 downregulated Ang1, whereas the overexpression of Notch3 intracellular domain (NICD3) enhanced Ang1 expression. The nuclear localization and transcriptional activity of yes-associated protein (YAP) were affected by the expression level of Akt1. Silencing YAP downregulated Ang2 expression, whereas overexpression of YAP showed the opposite results. Ang1 antibody and Ang2 suppressed endothelial sprouting of wild-type aortic tissues, whereas the Ang2 antibody and Ang1 facilitated the endothelial sprouting of aortic tissues from Akt1∆SMC mice. Finally, severe hemorrhage was observed in Akt1∆SMC mice, which was further facilitated under streptozotocin (STZ)-induced diabetic conditions. Therefore, the Akt1-Notch3/YAP-Ang1/2 signaling cascade in VSMCs might play an essential role in the paracrine regulation of endothelial function.

Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.

Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

SEEDING to Enable Sensitive Electrochemical Detection of Biomarkers in Undiluted Biological Samples.

Electrochemical biosensors have shown great potential for simple, fast, and cost-effective point-of-care diagnostic tools. However, direct analysis of complex biological fluids such as plasma has been limited by the loss of sensitivity caused by biofouling. By increasing the surface area, the nanostructured electrode can improve detection sensitivity. However, like a double-edged sword, a large surface area increases the nonspecific adsorption of contaminating proteins. The use of nanoporous structures may prevent fouling proteins. However, there is no straightforward approach for creating nanostructured and nanoporous surfaces compatible with microfabricated thin-film electrodes. Herein, the preferential etching of chloride and surfactant-assisted anisotropic gold reduction to create homogeneous, nanostructured, and nanoporous gold electrodes is demonstrated, yielding a 190 ± 20 times larger surface area within a minute without using templates. This process, "surfactant-based electrochemical etch-deposit interplay for nanostructure/nanopore growth" (SEEDING), on electrodes enhances the sensitivity and antibiofouling capabilities of amperometric biosensors, enabling direct analysis of tumor-derived extracellular vesicles (tEVs) in complex biofluids with a limit of detection of 300 tEVs µL-1  from undiluted plasma and good discrimination between patients with prostate cancer from healthy ones with an area under the curve of 0.91 in urine and 0.90 in plasma samples.

Regulation of Epithelial-Mesenchymal Transition of A549 Cells by Prostaglandin D2.

BACKGROUND/AIMS: Despite significant advances in diagnostic and operative techniques, lung cancer remains one of the most lethal malignancies worldwide. Since prostaglandins such as prostaglandin D2 (PGD2) is involved in various pathophysiological process, including inflammation and tumorigenesis, this study aims to investigate the role of PGD2 during the process of epithelial-mesenchymal transition (EMT) in A549 cells. METHODS: A549 cells were stimulated with PGD2 and expression of EMT markers was analyzed by immunoblotting and immunofluorescence. EMT-related gene, Slug expression was evaluated using quantitative real-time polymerase chain reaction (qPCR). Migration and invasion abilities of A549 cells were determined in chemotaxis and Matrigel invasion assays, respectively. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor or silencing of TGF-ß1 and TGFß type I receptor (TGFßRI), and protein expression was assessed by immunoblotting and immunofluorescence. RESULTS: Here, we found that stimulation of A549 cells with PGD2 resulted in morphological changes into a mesenchymal-like phenotype under low serum conditions. Stimulation of A549 cells with PGD2 resulted in a significant reduction in proliferation, whereas invasion and migration were enhanced. The expression of E-cadherin was markedly downregulated, while Vimentin expression was upregulated after treatment of A549 cells with PGD2. Slug expression was markedly upregulated by stimulating A549 cells with PGD2, and stimulation of A549 cells with PGD2 significantly enhanced TGF-ß1 expression, and silencing of TGF-ß1 significantly blocked PGD2-induced EMT and Smad2 phosphorylation. In addition, PGD2-induced Smad2 phosphorylation and EMT were significantly abrogated by either pharmacological inhibition or silencing of TGFßRI. PGD2-induced expression of Slug and EMT were significantly augmented in low nutrient and low serum conditions. Finally, the subsequent culture of mesenchymal type of A549 cells under normal culture conditions reverted the cell's phenotype to an epithelial type. CONCLUSION: Given these results, we suggest that tumor microenvironmental factors such as PGD2, nutrition, and growth factors could be possible therapeutic targets for treating metastatic cancers.

Comparative Analysis of Proteomes and Phosphoproteomes in Patients with Prostate Cancer Using Different Surgical Conditions.

PURPOSE: To establish the standard of procedure in preparing benign and cancerous prostate tissues and evaluate the quality of proteomics and phosphoproteomics during transurethral resection of the prostate (TUR-P) with different surgical conditions. MATERIALS AND METHODS: TUR-P tissue samples from three patients, two diagnosed with prostate cancer and one with benign prostatic hyperplasia, were each analyzed under three different conditions, based on differences in energy values, tissue locations, and surgical techniques. Global- and phosphorylated proteomic profiles of prostate tissues were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: A total of 6,019 global proteins and 4,280 phosphorylated peptides were identified in the nine tissues. The quantitative distributions of proteins and phosphorylation in tissues from the same patient were not affected by changes in the surgical conditions, but indirect relative comparisons differed among patients. Phosphorylation levels, especially of proteins involved in the androgen receptor pathway, important in prostate cancer, were preserved in each patient. CONCLUSIONS: Proteomic profiles of prostate tissue collected by TUR-P were not significantly affected by energy levels, tissue location, or surgical technique. In addition, since protein denaturation of samples through TUR-P is rarely confirmed in this study, we think that it will be an important guide for tissue samples in castration resistant prostate cancer patients, where it is difficult to obtain tissue. This result is the first report about proteomic and phosphoproteomic results with TUR-P samples in prostate cancer and will be theoretical basis in protein analysis research with prostate cancer tissues.

A Unique Urinary Metabolic Feature for the Determination of Bladder Cancer, Prostate Cancer, and Renal Cell Carcinoma.

Prostate cancer (PCa), bladder cancer (BCa), and renal cell carcinoma (RCC) are the most prevalent cancer among urological cancers. However, there are no cancer-specific symptoms that can differentiate them as well as early clinical signs of urological malignancy. Furthermore, many metabolic studies have been conducted to discover their biomarkers, but the metabolic profiling study to discriminate between these cancers have not yet been described. Therefore, in this study, we aimed to investigate the urinary metabolic differences in male patients with PCa (n = 24), BCa (n = 29), and RCC (n = 12) to find the prominent combination of metabolites between cancers. Based on 1H NMR analysis, orthogonal partial least-squares discriminant analysis was applied to find distinct metabolites among cancers. Moreover, the ranked analysis of covariance by adjusting a potential confounding as age revealed that 4-hydroxybenzoate, N-methylhydantoin, creatinine, glutamine, and acetate had significantly different metabolite levels among groups. The receiver operating characteristic analysis created by prominent five metabolites showed the great discriminatory accuracy with area under the curve (AUC) > 0.7 for BCa vs. RCC, PCa vs. BCa, and RCC vs. PCa. This preliminary study compares the metabolic profiles of BCa, PCa, and RCC, and reinforces the exploratory role of metabolomics in the investigation of human urine.

Polymer-dispersed reduced graphene oxide nanosheets and Prussian blue modified biosensor for amperometric detection of sarcosine.

A new disposable amperometric biosensor for sarcosine (Sar, a biomarker for prostate cancer) was designed based on screen-printed carbon electrodes, Prussian blue, polymer dispersed reduced graphene oxide (P-rGO) nanosheets, and sarcosine oxidase (SOx). Poly(sodium 4-styrenesulfonate-r-LAHEMA) denoted as PSSL was newly synthesized as dispersant for rGO. The P-rGO was utilized for SOx immobilization, the sulfonate and disulfide functionalities in PSSL enable physical adsorption of SOx and its bioactivity and stability properties were improved. The biosensor was optimized by various enzyme concentration, applied potential, and operating pH. Under the optimized conditions, the biosensor exhibited maximum current responses within 5 s at an applied potential of -0.1 V vs. integrated Ag/AgCl reference electrode. The biosensor had a dynamic linear range of 10-400 µM, with a sensitivity of 9.04 µA mM-1 cm-2 and a low detection limit of 0.66 µM (S/N = 3). Additionally, the biosensor possesses strong anti-interference capability, high reproducibility, and storage stability over 3 weeks. Furthermore, its clinical applicability was tested in urine samples from both prostate cancer patients and healthy control, and the analytical recoveries were satisfactory. Therefore, this biosensor has significant potential in the rapid and non-invasive point-of-care testing for prostate cancer diagnosis.

Modulation of Vascular Smooth Muscle Cell Phenotype by High Mobility Group AT-Hook 1.

OBJECTIVE: The purpose of this study is to examine the effect of high mobility group AT-hook 1 (HMGA1) on the phenotyptic change of vascular smooth muscle cells (VSMCs). METHODS: Gene silencing and overexpression of HMGA1 were introduced to evaluate the effect of HMGA1 expression on the phenotypic change of VSMCs. Marker gene expression of VSMCs was measured by promoter assay, quantitative polymerase chain reaction, and western blot analysis. Common left carotid artery ligation model was used to establish in vivo neointima formation. RESULTS: HMGA1 was expressed strongly in the synthetic type of VSMCs and significantly downregulated during the differentiation of VSMCs. Silencing of HMGA1 in the synthetic type of VSMCs enhanced the expression of contractile marker genes thereby enhanced angiotensin II (Ang II)-dependent contraction, however, significantly suppressed proliferation and migration. Stimulation of contractile VSMCs with platelet-derived growth factor (PDGF) enhanced HMGA1 expression concomitant with the downregulation of marker gene expression which was blocked significantly by the silencing of HMGA1. Silencing of HMGA1 retained the Ang II-dependent contractile function, which was curtailed by PDGF stimulation, however, overexpression of HMGA1 in the contractile type of VSMCs suppressed marker gene expression. Proliferation and migration were enhanced significantly by the overexpression of HMGA1. Furthermore, the Ang II-dependent contraction was reduced significantly by the overexpression of HMGA1. Finally, the expression of HMGA1 was enhanced significantly in the ligated artery, especially in the neointima area. CONCLUSION: HMGA1 plays an essential role in the phenotypic modulation of VSMCs. Therefore, paracrine factors such as PDGF may affect vascular remodeling through the regulation of HMGA1.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score-matched study using the Korean Renal Cancer Study Group database.

OBJECTIVES: To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5 years or ≥5 years after the surgical treatment for renal cell carcinoma. METHODS: Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5 years after surgery, and late recurrence was defined as occurring ≥5 years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. RESULTS: Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P < 0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56 months vs 36 months; P < 0.0001) and median first-line progression-free survival (12 months vs 8 months; P = 0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P = 0.007; and hazard ratio 1.76, P < 0.001, respectively). CONCLUSIONS: Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.

Clinical factors that influence the occurrence of symptomatic pseudoaneurysms and arteriovenous fistulas after partial nephrectomy: multi-institutional study of renal function outcomes after one year of selective arterial embolization

ABSTRACT Purpose: Renal artery pseudoaneurysms (RAPs) and arteriovenous fistulas (AVFs) are rare but potentially life-threatening complications after partial nephrectomy (PN). Selective arterial embolization (SAE) is an effective method for controlling RAPs/AVFs. We assessed the clinical factors affecting the occurrence of RAPs/AVFs after PN and the effects of SAE on postsurgical renal function. Materials and Methods: Four hundred ninety-three patients who underwent PN were retrospectively reviewed. They were placed in either the SAE or the non-SAE group. The effects of clinical factors, including R.E.N.A.L. scores, on the occurrence of RAPs/AVFs were analyzed. The influence of SAE on the estimated glomerular filtration rate (eGFR) during the first postoperative year was evaluated. Results: Thirty-three (6.7%) patients experienced RAPs/AVFs within 8 days of the median interval between PN and SAE. The SAE group had significantly higher R.E.N.A.L. scores, higher N component scores, and higher L component scores (all, p <0.05). In the multivariate analysis, higher N component scores were associated with the occurrence of RAPs/AVFs (Odds ratio: 1.96, p=0.039). In the SAE group, the mean 3-day postembolization eGFR was significantly lower than the mean 3-day postoperative eGFR (p <0.01). This difference in the eGFRs was still present 1 year later. Conclusions: Renal tumors located near the renal sinus and collecting system were associated with a higher risk for RAPs/AVFs after PN. Although SAE was an effective method for controlling symptomatic RAPs/AVFs after PN, a procedure-related impairment of renal function after SAE could occur and still be present at the end of the first postoperative year.

Prognostic significance of sarcopenia and decreased relative dose intensity during the initial two cycles of first-line sunitinib for metastatic renal cell carcinoma.

Targeted therapy for metastatic renal cell carcinoma (mRCC) treatment requires the identification of clinically important factors that can predict the therapeutic effect. We retrospectively investigated the prognostic roles of pre-treatment sarcopenia and relative dose intensity during the initial two cycles (2c-RDI) of sunitinib treatment in patients with mRCC. In total, 41 (52.6%) patients were classified as having sarcopenia and 16 (20.5%) patients were classified with low 2c-RDI at <75%. The mean dose reduction during sunitinib treatment was higher for sarcopenic than for non-sarcopenic patients. The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in sarcopenic patients with low 2c-RDI (n = 14, 17.9%) than in non-sarcopenic patients with high 2c-RDI (n = 35, 44.9%). Multivariate analysis identified sarcopenia and low 2c-RDI as poor prognostic factors for PFS and OS. Our findings provide new insights into the prognostic role of sarcopenia and 2c-RDI for targeted therapy in mRCC.

Clinical factors that influence the occurrence of symptomatic pseudoaneurysms and arteriovenous fistulas after partial nephrectomy: multi-institutional study of renal function outcomes after one year of selective arterial embolization.

PURPOSE: Renal artery pseudoaneurysms (RAPs) and arteriovenous fistulas (AVFs) are rare but potentially life-threatening complications after partial nephrectomy (PN). Selective arterial embolization (SAE) is an effective method for controlling RAPs/AVFs. We assessed the clinical factors affecting the occurrence of RAPs/AVFs after PN and the effects of SAE on postsurgical renal function. MATERIALS AND METHODS: Four hundred ninety-three patients who underwent PN were retrospectively reviewed. They were placed in either the SAE or the non-SAE group. The effects of clinical factors, including R.E.N.A.L. scores, on the occurrence of RAPs/AVFs were analyzed. The influence of SAE on the estimated glomerular filtration rate (eGFR) during the first postoperative year was evaluated. RESULTS: Thirty-three (6.7%) patients experienced RAPs/AVFs within 8 days of the median interval between PN and SAE. The SAE group had significantly higher R.E.N.A.L. scores, higher N component scores, and higher L component scores (all, p <0.05). In the multivariate analysis, higher N component scores were associated with the occurrence of RAPs/AVFs (Odds ratio: 1.96, p=0.039). In the SAE group, the mean 3-day postembolization eGFR was significantly lower than the mean 3-day postoperative eGFR (p <0.01). This difference in the eGFRs was still present 1 year later. CONCLUSIONS: Renal tumors located near the renal sinus and collecting system were associated with a higher risk for RAPs/AVFs after PN. Although SAE was an effective method for controlling symptomatic RAPs/AVFs after PN, a procedure-related impairment of renal function after SAE could occur and still be present at the end of the first postoperative year.