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Rolf von Knobloch

Publications and source records attributed to Rolf von Knobloch.

17 recordsLinked to original sources
PubMed2005

Cellular retinoic acid binding protein I: expression and functional influence in renal cell carcinoma.

Despite the known anti-proliferative and tumor-suppressive effects seen with retinoic acid (RA), treatment of metastatic renal cell carcinoma (RCC) failed to meet the initial expectations. As the exact mechanisms of action of RA and especially the role of the cellular RA binding proteins (CRABP) have not been elucidated yet, we investigated the expression of CRABP-I and its potential influence on RA response in RCC. Real-time RT-PCR analysis disclosed a significant lack of CRABP-I expression in four RCC cell lines and 12 primary RCC samples; in contrast, high expression levels were found in the respective adjacent normal kidney tissue. To further investigate the impact of CRABP-I on RA response in RCC, A-498 RCC cells were employed as a cellular model system. CRABP-I was stably transfected into A-498 cells which consequently displayed substantial resistance to all-trans (ATRA) and 9-cis RA compared to vector controls lacking CRABP-I. Comparison of gene expression profiles of ATRA-treated CRABP-I-expressing A-498 cells and vector controls revealed specific regulation of 54 of approximately 20,000 genes tested on a selected human CodeLink UniSet Bioarray, with a prominent modulation of genes involved in transcriptional control, signaling, apoptosis, cell cycle regulation and metabolism. The genetic changes reported here contribute to a better understanding of the role of RA in RCC. They also provide new insights into CRABP-I-mediated signaling and gene expression.

Aged↗
PubMed2005

Application of thalidomide/interleukin-2 in immunochemotherapy-refractory metastatic renal cell carcinoma.

Thalidomide has been reported to yield anti-tumor activity in advanced renal cell carcinoma (RCC). We evaluated safety and efficacy of a combination therapy comprising interleukin (IL)-2 and thalidomide in patients with metastatic RCC refractory to both immuno- and chemotherapy. Twelve patients with progressive metastatic RCC who had failed prior treatment with immunochemotherapy and desired further active therapy were enrolled in this study. Oral thalidomide was started at 200 mg/day and escalated after 2 days to 400 mg/day at week 0. IL-2 at 7 MIU/m was given by s.c. injection, starting at week 1, days 1-5, weeks 1-4, with rest from IL-2 at weeks 5 and 6. Response was assessed every two therapy cycles. Ten patients were evaluable for response. There was no objective response; four patients showed stable disease for 14+, 11+, 10+ and 9 months, respectively. Toxicities were predominantly grade I-II, and included somnolence and constipation, as well as flu-like symptoms associated with IL-2. However, one patient developed serious constipation which led to a paralytic ileus and discontinuation of treatment. Another patient left the study after 7 weeks due to increasing disorientation/confusion. Eight patients required IL-2 dose reduction. Time on therapy ranged from 3 to 44 weeks (median 20 weeks). Median overall survival was 12+ months. At present, all patients have discontinued treatment. We conclude that outpatient administration of thalidomide/IL-2 is feasible in patients with heavily pretreated and progressive RCC who desire further active treatment. However, toxicity and costs are considerable, and clinical benefit is uncertain. Therefore, thalidomide/IL-2 might not represent a promising therapeutic approach for this subgroup of patients.

Adult↗
PubMed2005

Expression and functional influence of cellular retinoic acid-binding protein II in renal cell carcinoma.

INTRODUCTION: Retinoic acid (RA) and its derivates possess antiproliferative and tumor-suppressive abilities and are successfully used in the treatment of various malignancies. However, in metastatic renal cell carcinoma (RCC), its application did not meet first expectations. As the exact mechanisms of RA action and especially the role of the cellular retinoic acid-binding proteins (CRABP) still remain unclear, we studied the expression of CRABP-II and its potential influence on RA response in RCC. MATERIALS AND METHODS: We used the real-time RT-PCR methodology to investigate CRABP-II expression in 12 RCC samples and corresponding normal kidney tissue. Moreover, CRABP-II was cloned and overexpressed in CAKI-2 RCC cells. CRABP-II (un)transfected CAKI-2 cells were stimulated with all-trans RA (ATRA) and 9-cis RA, and their antiproliferative effects were evaluated using 3H-thymidine-proliferation assays. RESULTS: Using RPS9 and RPLP0 to normalize its expression, the median tumor/kidney ratio for CRABP-II expression was 0.16 and 0.12, respectively. Using proliferation assays, CRABP-II overexpressing CAKI-2 cells did not exhibit a significant change in RA sensitivity, but appeared to be less sensitive toward RA-stimulation compared to CAKI-2 cells expressing naturally low levels of CRABP-II (maximum difference, 59% at 3 microM ATRA). CONCLUSIONS: We were able to demonstrate a downregulation of CRABP-II expression in primary RCC tumor samples compared to the corresponding normal kidney tissue. However, CRABP-II overexpression in CAKI-2 RCC cells did not significantly influence RA associated antiproliferative actions. Further experiments are necessary to define the exact role of CRABP-II and its downregulation in RCC including its influence and dependence on other molecules involved in RA signalling and metabolism.

Aged↗
PubMed2004

Genetic pathways and new progression markers for prostate cancer suggested by microsatellite allelotyping.

PURPOSE: At diagnosis, the biological behavior of prostate cancer is uncertain, making the choice of an adequate therapy option difficult. Performing microsatellite allelotyping on a large series of consecutive prostate cancers procured during radical prostatectomy at our institution, we sought to identify molecular markers associated with disease progression. EXPERIMENTAL DESIGN: A total of 156 consecutive fresh tumor samples was prospectively collected and macroscopically dissected from the whole prostatectomy specimen immediately after operation. Histologically 100 samples contained >75% tumor cells and were therefore enrolled in the microsatellite allelotyping, using a total of 24 polymorphic markers for the chromosomal regions 5p, 5q, 7q, 8p, 9p, 9q, 13q, 17p, 17q, and 18q. Fresh paired normal and tumor DNA was investigated in fluorescent microsatellite analysis with automated laser product detection. RESULTS: The incidence of tumor-DNA alterations [loss of heterozygosity or allelic imbalance (AI)] was highest for chromosomal regions 13q and 8p with 72 and 71%, respectively, followed by chromosomes 7q, 18q, 5q, and 17p with 57, 53, 41, and 39%, respectively. Alterations at chromosomes 8p, 9p, 13q, and 17p were significantly (P < 0.05) associated with advanced tumor stage, whereas AI at 8p and 17p was also associated with high Gleason score (P < 0.05). AI at 5q and 9p was associated with regional lymph node metastasis (P < 0.05). The combination of AI at 8p and 13q was strongly associated with advanced tumor stage (P < 0.0001). CONCLUSIONS: With the obtained results, we are able to postulate three distinct pathways in prostate carcinogenesis, and we identified microsatellite markers of prognostic value.

Alleles↗
PubMed2004

Molecular serological detection of DNA alterations in transitional cell carcinoma is highly sensitive and stage independent.

PURPOSE: To evaluate the efficacy of fluorescent microsatellite analysis (MSA) for the serological diagnosis of transitional cell carcinoma (TCC) of the urinary tract analyzing free tumor DNA in the serum of cancer patients. EXPERIMENTAL DESIGN: We applied fluorescent MSA to detect serum-DNA alterations in patients suffering from bladder and upper urinary tract TCC and prospectively collected fresh tumor, peripheral blood, and serum specimens from 61 consecutive patients to obtain the corresponding DNA. Fluorescent MSA was performed with a total of 17 polymorphic markers from the chromosomal regions 5q, 8p, 9p, 9q, 13q, 14q, 17p, 17q, and 20q in the 61 cancer patients, as well as in 20 healthy controls. RESULTS: Molecular serological analysis led to tumor-specific diagnosis of TCC in 80.3% (49 of 61) of cases. Four healthy controls displayed serum-DNA artifacts rendering a specificity of 80%. The highest frequency of serum-DNA alterations was detected for chromosomal region 8p with 36%. Chromosomes 5q, 9p, and 20q showed serum-DNA alterations in 18 to 21%. The identification of serum-DNA alterations was not statistically associated with underlying local tumor stage (P = 0.29) but was more frequent in high-grade tumors (P = 0.08). CONCLUSIONS: MSA offers a highly sensitive method for serological diagnosis of TCC. To optimize specificity, simultaneous analysis of tumor DNA is advised to rule out artifacts resembling allelic imbalance in MSA of serum DNA.

Biomarkers, Tumor↗
PubMed2004

Genetic pathways and new progression markers for prostate cancer defined by microsatellite allelotyping.

A prospective study was carried out on a large cohort of males undergoing radical retropubic prostatectomy in order to identify genetic marker regions significantly associated with tumor formation. By comprehensive allotyping of chromosomes known to be associated with prostate carcinogenesis, an algorithm could be formulated for the genetic pathway and a method of discrimination between aggressive and less aggressive forms could be identified.

Alleles↗
PubMed2004

Application of retinoids in the treatment of renal cell carcinoma--a futile effort?

The therapeutic benefit of adding retinoids such as all-trans retinoic acid (RA), 9-cis-RA or 13-cis-RA to established single-agent or combination immuno/chemotherapy regimens for the treatment of metastatic renal cell carcinoma (RCC) has been extensively investigated during the last decade. However, at present results are contradictory and their application controversial. Moreover, recent studies indicated a significantly higher incidence of toxic side-effects in patients treated with retinoids in addition to established bio/chemotherapy. This Commentary summarizes preclinical and clinical trials investigating efficacy and toxicity of retinoids in the treatment of RCC.

Animals↗
PubMed2004

Molecular serological diagnosis in transitional cell bladder cancer.

There are no reliable serological tumor markers for transitional cell carcinoma (TCC) of the urinary bladder. Fluorescent microsatellite analysis (MSA) was used to detect serum-DNA alterations in patients with bladder cancer. Prospectively, fresh tumor-, peripheral blood-, and serum-specimens were collected from 58 consecutive patients treated for TCC of the bladder to obtain the corresponding DNA. DNA was extracted by the phenol-chloroform method from tumors and blood lymphocytes. Serum DNA was isolated by a commercial kit. Fluorescent MSA was performed with a total of 17 polymorphic markers from chromosomal regions 5q, 8p, 9p, 9q, 13q, 14q, 17p, 17q, and 20q in the 58 cancer specimens as well as in specimens from 20 healthy controls. Detection of allelic imbalance and loss of heterozygosity in the tumor and serum specimens was carried out on an automated laser sequencer. Serum-DNA alterations were identified in 79.3% (46/58). Four healthy controls displayed serum-DNA artefacts rendering a specificity of 80%. The highest frequency of serum-DNA alterations (38%) was detected for chromosomal region 8p. Chromosomes 5q, 9p, and 20q showed serum-DNA alterations in 20% to 23%. Identification of tumor-specific serum-DNA alterations was stage independent (P >0.05), but was more frequent in high-grade tumors (P = 0.08). To optimize specificity, simultaneous analysis of tumor DNA is advised to rule out artefacts resembling allelic imbalance in MSA of serum DNA. The method then has potential for application as a "serological marker" in the follow-up of patients after radical surgical therapy for invasive TCC of the bladder.

Carcinoma, Transitional Cell↗
PubMed2003

Giant hydronephrosis mimicking progressive malignancy.

BACKGROUND: Cases of giant hydronephroses are rare and usually contain no more than 1-2 litres of fluid in the collecting system. We report a remarkable case of giant hydronephrosis mimicking a progressive malignant abdominal tumour. CASE PRESENTATION: A 78-year-old cachectic woman presented with an enormous abdominal tumour, which, according to the patient, had slowly increased in diameter. Medical history was unremarkable except for a hysterectomy >30 years before. A CT scan revealed a giant cystic tumour filling almost the entire abdominal cavity. It was analysed by two independent radiologists who suspected a tumour originating from the right kidney and additionally a cystic ovarian neoplasm. Subsequently, a diagnostic and therapeutic laparotomy was performed: the tumour presented as a cystic, 35 x 30 x 25 cm expansive structure adhesive to adjacent organs without definite signs of invasive growth. The right renal hilar vessels could finally be identified at its basis. After extirpation another tumourous structure emerged in the pelvis originating from the genital organs and was also resected. The histopathological examination revealed a >15 kg hydronephrotic right kidney, lacking hardly any residual renal cortex parenchyma. The second specimen was identified as an ovary with regressive changes and a large partially calcified cyst. There was no evidence of malignant growth. CONCLUSION: Although both clinical symptoms and the enormous size of the tumour indicated malignant growth, it turned out to be a giant hydronephrosis. Presumably, a chronic obstruction of the distal ureter had caused this extraordinary hydronephrosis. As demonstrated in our case, an accurate diagnosis of giant hydronephrosis remains challenging due to the atrophy of the renal parenchyma associated with chronic obstruction. Therefore, any abdominal cystic mass even in the absence of other evident pathologies should include the differential diagnosis of a possible hydronephrosis. Diagnostic accuracy might be increased by a combination of endourological techniques such as retrograde pyelography and modern imaging modalities.

Aged↗
PubMed2003

Magnetic resonance urography in pediatric urology.

OBJECTIVE: To evaluate the efficiency of magnetic resonance urography (MRU) in pediatric urology. MATERIAL AND METHODS: We report retrospectively on 12 children who underwent MRU between January 1999 and November 2001. MRU was performed to accurately evaluate the entire urinary tract because of megaureter, ectopic ureter, vesicoureteral reflux, Y-inverted duplication and hydronephrosis because of pyeloureteral stenosis. T1- and T2-weighted images were obtained in the coronal, sagittal and axial planes. The mean age of the children (8 females, 4 males) investigated was 36 months (range 2-140 months). RESULTS: An accurate anatomical picture of the entire urinary tract could be obtained in all children. The obstructive nature of megaureter could be differentiated. The distal orifice of ectopic ureter could be identified in the vagina. Vesicoureteral reflux into the blind-ending ureteral bud of a duplicated system was accurately identified. Hydronephrosis was demonstrated to be the result of pyeloureteral stenosis. The location of stenoses was easily identified in the sagittal and coronal planes. CONCLUSIONS: MRU is an excellent imaging modality for accurately depicting the urinary tract. MRU is superior to conventional intravenous urography because it does not use ionizing radiation, the gadolinium contrast medium used is not nephrotoxic and the imaging quality is excellent, reproducible and not interfered with by gas superposition. Considering the high costs and diagnostic benefit of MRU compared to intravenous urography, MRU should be performed in patients with impaired renal function, in those with an allergy to contrast medium and if anatomic relationships are not clear prior to reconstructive surgery.

Age Factors↗
PubMed2002

Cellular fibronectin in patients with transitional cell carcinoma of the bladder.

Various tumor markers for transitional cell carcinoma (TCC) of the bladder have been described, but none of them are used in clinical routine. Fibronectin, a glycoprotein, seems to play a very important role in both the progression and invasion of cancer. The aim of this study was to evaluate cellular fibronectin (cFN) in the urine and blood of patients with TCC of the bladder and to determine its possible role as a tumor marker and prognostic factor. Morning urine samples and blood were collected from 20 patients (8 women, 12 men, mean age 69.9 years) before they underwent transurethral resection of bladder tumors (TURB). Twenty patients (10 women, 10 men, mean age 63.4 years) with nonmalignant urological disorders were recruited as the control group. Determination of cFN in plasma and urine was performed by using a newly developed time-resolved fluorescence immunoassay (TRFIA). Patients with nonmalignant diseases had mean cFN plasma levels of 404 ng/ml (range 181-746 ng/ml). Patients with TCC of the bladder showed significantly higher cFN plasma levels of 686 ng/ml (range 274-1999 ng/ml, p<0.05). Subdivided according to the TNM system, muscle-invasive bladder tumors (n=5) demonstrated higher cFN plasma levels (mean 944 ng/ml) than superficial bladder tumors (n=15, mean 463 ng/ml). There were no differences of plasma cFN concentrations concerning tumor grade and also no differences in urine levels between the different groups. We found a significant difference (p<0.04) of cFN plasma levels between patients with TCC of the bladder and the control group. The difference in cFN plasma levels between pTa/pT1 and >or=pT2 tumors indicates a clinically useful potential of this tumor marker for preoperative staging and postoperative follow-up. Our data underline the important but still unclear role of cFN as a tumor marker in TCC, and this will be the focus of future studies.

Aged↗
PubMed2002

High frequency of serum DNA alterations in renal cell carcinoma detected by fluorescent microsatellite analysis.

To date there are no reliable serological markers for renal cell carcinoma (RCC). We applied fluorescent microsatellite analysis (MSA) to detect serum DNA alterations in patients with RCC. Fresh tumour, peripheral blood and serum specimens from 60 consecutive patients treated for malignant renal tumours (n= 53 RCC and n= 7 non-RCC) were prospectively collected. After DNA extraction, we performed MSA with a total of 9 markers from the chromosomal regions 3p, 5q, 7p, 7q, 9p, 13q, 17p and 17q to identify tumour specific serum DNA alterations in Group I (n= 53 RCC); 11 additional markers were used in the first 23 RCCs (Group II) in order to increase sensitivity; and 20 healthy controls were investigated with 10 markers. Besides the histomorphological diagnosis the RCCs were genetically stratified according to the "Heidelberg Classification" of renal tumours. Detection of allelic imbalance and loss of heterozygosity (LOH) was carried out on an automated laser sequencer. In Group I we identified serum DNA alterations in 74% (39/53) of cases. When applying 20 markers, the sensitivity was elevated to 87% (20/23) in Group II. Investigating 20 healthy controls with 10 markers, the method rendered 85% specificity. The highest incidence of alterations was detected for chromosomal regions 3p and 5q. The presence of serum DNA alteration was not associated with tumour nuclear grade but exhibited a trend towards advanced stages (p = 0,044). In RCC, the microsatellite analysis has a high sensitivity in the detection of serum DNA alterations when a sufficient number of markers from various chromosomal regions are used. Advanced tumours tend to express serum DNA alterations more frequently.

Adenoma, Chromophobe↗
PubMed2002

TGF-beta1 in patients with renal cell carcinoma.

Up to now, clinical tumor-markers for renal cell carcinoma (RCC) have been lacking. Increased plasma levels of transforming growth factor-beta1 (TGF-beta1) were described as a tumor-marker and prognostic factor in RCC. The aim of this study was to test the clinical suitability of plasma TGF-beta1 as a tumor-marker for RCC. The concentrations of active and latent TGF-beta1 were determined in plasma of patients with localized (n = 39) and metastasised (n = 17) RCC. A newly developed, highly sensitive ELISA, which is specific for the isoform beta1, was used. Active TGF was directly measured in the EDTA plasma. To determine the amount of latent TGF-beta1, which is bound predominantly at beta2-macroglobulin, an optimized activation procedure was applied. Patients with localized RCC showed median concentrations of 16,700 ng/l (6,200-54,800 ng/l) for latent TGF-beta1. A total of 94 patients with various nonmalignant urological diseases were recruited as a control group. In comparison, this group had median concentrations of 19,900 ng/l (2,640-52,300 ng/l) for latent TGF-beta1. There was no significant difference (nonparametric Kruskal-Wallis ANOVA) between these groups. Patients with metastatic RCC showed median concentrations of 34,500 ng/l (6,800-48,960 ng/l) for latent TGF-beta1. In comparison to the localized RCC group, a statistically significant difference was found. Plasma levels after operative therapy (days 1, 5 and 10) and during follow-up without evidence of disease (2-6 months) showed no significant differences. Contrary to other study groups, our results suggest that TGF-beta1 is not a suitable tumor-marker for the diagnosis of localized RCC. In the face of higher TGF-beta1 plasma levels in metastatic disease, TGF-beta1 may be useful in the early detection of RCC recurrence or to control the success of immunochemotherapy.

Biomarkers, Tumor↗
PubMed2002

Nephron-sparing surgery for renal angiomyolipoma.

INTRODUCTION: Renal angiomyolipoma (RAML) is a benign tumor composed of varying amounts of mature adipose tissue, smooth muscle and thick-walled blood vessels. RAML tend to grow over time requiring active intervention due to serious associated complications, such as hemorrhage and pain. Although RAML is an ideal tumor for organ preservation, data concerning efficacy of nephron-sparing surgery (NSS) are sparse. The aim of the study was to evaluate the efficacy of NSS in RAML with regard to renal function, tumor recurrence and surgical feasibility. PATIENTS AND METHODS: Charts of patients with pathologically confirmed RAML were reviewed and data recorded: tumor size, associated symptoms, intraoperative blood loss, serum creatinine, follow-up data with regard to tumor recurrence and long-term renal function. A total of 28 patients were identified with RAML who underwent NSS because of tumor size > 4 cm, pain and/or to rule out malignancy due to radiographic features of uncertain interpretation. RESULTS: The median follow-up of all patients is 58 (3-114) months; median age was 55.6 (34-78) years, 24 patients were women, 4 patients were men. None of the patients developed a local recurrence. Median size of enucleated tumors was 5.5 (2.5-15) cm; indication for NSS was symptomatic tumor with hemorrhage in 4 patients (16%), prophylaxis of hemorrhage in 5 patients (20%) and radiographic features suspicious for malignancy in 16 patients (64%). In those cases, unenhanced and enhanced CT scans exhibit a hyperdense and a hypodense lesion as compared to the adjacent normal renal cortex, respectively. There were no intraoperative complications, median blood loss was 320 (50-1200) ml, none of the patients required blood transfusions. Post-operative course was uneventful in 26 patients (96%), 2 patients (7.1%) developed a urinary fistula managed by an endoluminal stent. Pre-operative serum creatinine was 0.9 (0.7-1.3) mg/dl, post-operative creatinine was 1.23 (0.7-1.5) mg/dl and serum creatinine at last follow-up was 0.95 (0.7-1.2) mg/dl. CONCLUSIONS: NSS can be performed with a high success rate in RAML when surgical management is indicated. Long-term follow-up reveals no local tumor recurrences and stable renal function even in patients with a solitary kidney.

Angiomyolipoma↗
PubMed2002

Bilateral fine-needle administered local anaesthetic nerve block for pain control during TRUS-guided multi-core prostate biopsy: a prospective randomised trial.

INTRODUCTION: Transrectal multi-core biopsies of the prostate can cause substantial discomfort with the need for high dose systemic analgesics. In a prospective randomised trial we investigated the efficacy of fine-needle administered local anaesthesia for bilateral prostatic nerve block prior to transrectal ultrasound (TRUS) guided prostate biopsy. MATERIALS AND METHODS: One hundred and eight men suspected of having cancer of the prostate were randomised to receive TRUS-guided bilateral prostate nerve block prior to biopsy or not, when having no history of previous prostate biopsies (groups I and II, n=68). In group III (n=40) all patients with history of previous biopsies exclusively received local anaesthesia injection. Patients routinely underwent a 10-core biopsy regimen. For repeat biopsy 12 cores were taken. The consented patients documented pain on a visual analogue pain score. RESULTS: In the randomised groups I and II average pain score was 1.85 with versus 3.29 without periprostatic nerve block (p<0.0001). In group III the difference in pain stated for the present biopsy with local anaesthesia nerve block in comparison to the pain experienced with the previous biopsy solely under transrectal lidocaine gel was even higher (1.71 versus 4.59; p<0.0001). Pain relief was independent of the number of biopsy cores sampled. Overall cancer detection rate was 46% (50/108). CONCLUSION: Bilateral local anaesthesia nerve block prior to multi-core TRUS-guided prostate biopsy significantly reduces pain independent of the number of cores taken.

Biopsy, Needle↗
PubMedDate not supplied

Plasma levels of cellular fibronectin in patients with localized and metastatic renal cell carcinoma.

Clinical markers for renal cell carcinoma (RCC) are lacking. Fibronectin is a glycoprotein that plays an important role in cellular attachment and cell spread. The aim of this study was to test the clinical suitability of cellular fibronectin (cFN) in plasma as a tumor marker for RCC and to determine a possible relationship between cFN plasma levels and stage of disease. Therefore, cFN was determined in the plasma of patients with localized (n = 40) and metastatic (n = 20) RCC using a time-resolved fluorescence immunoassay. Fifty patients with different non-malignant urological disorders were recruited as a control group. In the control group, mean cFN plasma levels amounted to 553 ng/ml. In patients with localized RCC, plasma concentrations of cFN were increased (1,295 ng/ml; p < 0.01). Patients with metastatic disease had the highest concentrations (3,842 ng/ml). Statistical analysis demonstrated a significant difference between controls, and patients with localized and metastatic RCC (p < 0.01), with a sensitivity of 80%, a specificity of 78% and a positive predictive value of 81% using a cutoff value of 540 ng/ml (receiver-operating characteristic curve analysis). These data suggest that cFN is not a realistic marker for the detection of RCC. However, elevated plasma levels in more advanced disease and an acceptable predictive value could indicate that cFN is useful as a follow-up tool in the management of RCC patients.

Aged↗