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ABSTRACT: Adverse events during fetal development can predispose the individual for cardiovascular disease later in life, a correlation known as fetal programming of adult hypertension. The "programming" events are not known but might reside in the kidneys due to these organs significant role in extracellular volume control and long term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number has been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus on mechanisms of postnatal development the renal medulla and putting medullary developmental lesions into perspective with regard to the programming effect. Moreover, the renin-angiotensin system is critically involved in mammalian kidney development and signaling disorders give rise to developmental renal lesions that has been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given. Acta Physiologica © 2013 Scandinavian Physiological Society.
Acta Physiologica 02/2013; · 3.09 Impact Factor
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ABSTRACT: BACKGROUND: Chronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model. METHODS: Sprague--Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses. RESULTS: Compared to controls, CsA-treatment reduced relative tubular volume (0.73+/-0.03 vs. 0.85+/-0.01, p<0.05) and increased relative interstitial volume (0.080+/-0.004 vs. 0.045+/-0.003, p<0.05); EPL attenuated these changes (0.82+/-0.02, p<0.05, and 0.060+/-0.006, p<0.05, respectively). CsA-treated rats had more sclerotic glomeruli and a higher degree of vascular depositions in arterioles; both were significantly reduced in CsA+EPL-treated animals. CsA increased BP and reduced body weight gain and GFR. In CsA+EPL rats, weight gain, GFR and BP at rest (daytime) were normalized; however, BP during activity (night) remained elevated. Plasma sodium and potassium concentrations, kidney-to-body weight ratios and CsA whole blood concentration were similar in CsA and CsA+EPL rats. CONCLUSIONS: It is concluded that in the chronic cyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors.
BMC Nephrology 02/2013; 14(1):42. · 2.18 Impact Factor
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Mads H Poulsen,
Kirsten Bouchelouche,
Poul F Høilund-Carlsen,
Henrik Petersen,
Oke Gerke,
Signe Inglev Steffansen, Niels Marcussen,
Niels Svolgaard,
Werner Vach,
Ulla Geertsen,
Steen Walter
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ABSTRACT: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Staging of patients with prostate cancer is the cornerstone of treatment. However, after curative intended therapy a high portion of patients relapse with local and/or distant recurrence. Therefore, one may question whether surgical lymph node dissection (LND) is sufficiently reliable for staging of these patients. Several imaging methods for primary LN staging of patients with prostate cancer have been tested. Acceptable detection rates have not been achieved by CT or MRI or for that matter with PET/CT using the most common tracer fluoromethylcholine (FCH). Other more recent metabolic tracers like acetate and choline seem to be more sensitive for assessment of LNs in both primary staging and re-staging. However, previous studies were small. Therefore, we assessed the value of [(18) F]FCH PET/CT for primary LN staging in a prospective study of a larger sample and with a 'blinded' review. After a study period of 3 years and >200 included patients, we concluded that [(18) F]FCH PET/CT did not reach an optimal detection rate compared with LND, and, therefore, it cannot replace this procedure. However, we did detect several bone metastases with [(18) F]FCH PET/CT that the normal bone scans had missed, and this might be worth pursuing. OBJECTIVES: • To assess the value of [(18) F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging of prostate cancer. • To evaluate if FCH PET/CT can replace LN dissection (LND) for LN staging of prostate cancer, as about one-third of patients with prostate cancer who receive intended curative therapy will have recurrence, one reason being undetected LN involvement. PATIENTS AND METHODS: • From January 2008 to December 2010, 210 intermediate- or high-risk patients had a FCH PET/CT scan before regional LND. • After dissection, the result of histological examination of the LNs (gold standard) was compared with the result of FCH PET/CT obtained by 'blinded review'. • Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of FCH PET/CT were measured for detection of LNe metastases. RESULTS: • Of the 210 patients, 76 (36.2%) were in the intermediate-risk group and 134 (63.8%) were in the high-risk group. A medium (range) of 5 (1-28) LNs were removed per patient. • Histological examination of removed LNs showed metastases in 41 patients. Sensitivity, specificity, PPV, and NPV of FCH PET/CT for patient-based LN staging were 73.2%, 87.6%, 58.8% and 93.1%, respectively. • Corresponding values for LN-based analyses were 56.2%, 94.0%, 40.2%, and 96.8%, respectively. • The mean diameter of the true positive LN metastases was significantly larger than that of the false negative LNs (10.3 vs 4.6 mm; P < 0.001). • In addition, FCH PET/CT detected a high focal bone uptake, consistent with bone metastases, in 18 patients, 12 of which had histologically benign LNs. CONCLUSIONS: • Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer. • However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases.
BJU International 04/2012; · 2.84 Impact Factor
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Ying Liu,
Frank Echtermeyer,
Florian Thilo,
Gregor Theilmeier,
Antje Schmidt,
Ralf Schülein,
Boye L Jensen,
Christoph Loddenkemper,
Vera Jankowski, Niels Marcussen,
Maik Gollasch,
William J Arendshorst,
Martin Tepel
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ABSTRACT: Syndecan 4 (Sdc4) modulates signal transduction and regulates activity of protein channels. Sdc4 is essential for the regulation of cellular permeability. We hypothesized that Sdc4 may regulate transient receptor potential canonical 6 (TRPC6) channels, a determinant of glomerular permeability, in a RhoA/Rho-associated protein kinase-dependent manner.
Sdc4 knockout (Sdc4(-/-)) mice showed increased glomerular filtration rate and ameliorated albuminuria under baseline conditions and after bovine serum albumin overload (each P<0.05). Using reverse transcription-polymerase chain reaction and immunoblotting, Sdc4(-/-) mice showed reduced TRPC6 mRNA by 79% and TRPC6 protein by 82% (each P<0.05). Sdc4(-/-) mice showed an increased RhoA activity by 87% and increased phosphorylation of ezrin in glomeruli by 48% (each P<0.05). Sdc4 knockdown in cultured podocytes reduced TRPC6 gene expression and reduced the association of TRPC6 with plasma membrane and TRPC6-mediated calcium influx and currents. Sdc4 knockdown inactivated negative regulatory protein Rho GTPase activating protein by 33%, accompanied by a 41% increase in RhoA activity and increased phosphorylation of ezrin (P<0.05). Conversely, overexpression of Sdc4 reduced RhoA activity and increased TRPC6 protein and TRPC6-mediated calcium influx and currents.
Our results establish a previously unknown function of Sdc4 for regulation of TRPC6 channels and support the role of Sdc4 for the regulation of glomerular permeability.
Arteriosclerosis Thrombosis and Vascular Biology 12/2011; 32(2):378-85. · 6.37 Impact Factor
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ABSTRACT: It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3β (pGSK-3β) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7-28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3β-immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β-, and pGSK-3β-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3β, proliferation, and microcysts.
AJP Renal Physiology 11/2011; 302(4):F455-65. · 4.42 Impact Factor
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Histopathology 11/2011; 59(5):1012-3. · 3.08 Impact Factor
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Histopathology 11/2011; 59(5):1014. · 3.08 Impact Factor
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Histopathology 11/2011; 59(5):1010-1. · 3.08 Impact Factor
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ABSTRACT: Calcium channel blockers are widely used for treatment of hypertension, because they decrease peripheral vascular resistance through inhibition of voltage-gated calcium channels. Animal studies of renal vasculature have shown expression of several types of calcium channels that are involved in kidney function. It was hypothesized that human renal vascular excitation-contraction coupling involves different subtypes of channels. In human renal artery and dissected intrarenal blood vessels from nephrectomies, PCR analysis showed expression of L-type (Ca(v) 1.2), P/Q-type (Ca(v) 2.1), and T-type subtype (Ca(v) 3.1 and Ca(v) 3.2) voltage-gated calcium channels (Ca(v)s), and quantitative PCR showed highest expression of L-type channels in renal arteries and variable expression between patients of subtypes of calcium channels in intrarenal vessels. Immunohistochemical labeling of kidney sections revealed signals for Ca(v) 2.1 and Ca(v) 3.1 associated with smooth muscle cells of preglomerular and postglomerular vessels. In human intrarenal arteries, depolarization with potassium induced a contraction inhibited by the L-type antagonist nifedipine, EC(50) 1.2×10(-8) mol/L. The T-type antagonist mibefradil inhibited the potassium-induced constriction with large variations between patients. Interestingly, the P/Q-type antagonist, ω-agatoxin IVA, inhibited significantly the contraction with 24% at 10(-9) mol/L. In conclusion L-, P/Q, and T-type channels are expressed in human renal blood vessels, and L- and P/Q-type channels are of functional importance for the depolarization-induced vasoconstriction. The contribution of P/Q-type channels to contraction in the human vasculature is a novel mechanism for the regulation of renal blood flow and suggests that clinical treatment with calcium blockers might affect vascular reactivity also through P/Q-type channel inhibition.
Hypertension 09/2011; 58(3):464-70. · 6.21 Impact Factor
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ABSTRACT: •To compare the bladder tumour recurrence rate in stage Ta and T1 tumours after conventional transurethral resection of the bladder in white light (WL TURB) and after fluorescence-guided TURB (HAL TURB) using hexaminolaevulinate (HAL: Hexvix®, Photocure, Norway) for photodynamic diagnosis during 12 months of follow-up. •As secondary objectives, to relate the tumour recurrence rate to fluorescence-detected residual tumour after WL TURB and to assess the false positive rate.
•This was a prospective, comparative, randomized, open-label study carried out in hospital outpatient urology clinics and the operating theatre. A total of 233 patients presenting with suspected superficial bladder tumour were recruited. Both patients with new tumours and patients with recurrent tumours were included. •The study duration was 2.5 years with follow-up cystoscopic investigations at 4, 8 and 12 months. •Patients were randomized to cystoscopy and WL TURB (118 patients) or WL TURB followed immediately by HAL TURB (115 patients). Cystoscopy/TURB and bladder biopsies were performed under general anaesthesia. No patients had intravesical chemotherapy immediately after TURB. •Recurrences were verified histologically.
•The two groups were similar regarding age and previous bladder cancer history. •In all, 90 patients from the HAL TURB group had bladder tumour. Fluorescence-guided cystoscopy after complete WL TURB identified residual tumour tissue in 44 of 90 patients (49%). In 37 of 83 (45%) residual Ta tumour was found; in three of seven residual T1 was found and in four cases carcinoma in situ. •True (and false) positive detection rate of photodynamic diagnosis was 64% (25%) and of white light 83% (16%). •In all, 145 patients were eligible for analysis of tumour recurrence. Twelve patients had their last follow-up after 4 months. The recurrence rate in patients followed for 12 months was 47.3% (35/74) after WL TURB and 30.5% (18/59) after HAL TURB (P= 0.05). •Kaplan-Meier analyses comprising data from all 145 patients showed that the recurrence-free period was significantly longer in the HAL TURB group than in the WL TURB group (P= 0.02).
•WL TURB often leaves residual tumour in the bladder. HAL TURB improves the detection of Ta/T1 tumours of the bladder resulting in more complete TURB procedures and thus a reduced recurrence rate.
BJU International 03/2011; 108(8 Pt 2):E297-303. · 2.84 Impact Factor
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ABSTRACT: OBJECTIVE: The treatment and prognosis of bladder cancer are based on the depth of primary tumour invasion and the presence of metastases. A highly accurate preoperative tumour, node, metastasis (TNM) staging is critical to proper patient management and treatment. This study retrospectively investigated the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed axial tomography (¹⁸F-FDG PET/CT) and magnetic resonance imaging (MRI) for preoperative N staging of bladder cancer. Material and methods. From June 2006 to January 2008, 48 consecutive patients diagnosed with bladder cancer were referred to preoperative staging including MRI and ¹⁸F-FDG PET/CT. Eighteen out of 48 patients underwent radical cystoprostatectomy including removal of lymph nodes for histology, and were included in the study. Values of ¹⁸F-FDG PET/CT and MRI for regional N staging were compared to histopathology findings, the gold standard. Results. ¹⁸F-FDG PET/CT and MRI were performed in 18 patients. The specificities for detection of lymph-node metastases for MRI and ¹⁸F-FDG PET/CT were 80% (n = 15) and 93.33% (n = 15), respectively. The negative predictive values were 80% (n = 15) and 87.5% (n = 16) for MRI and ¹⁸F-FDG PET/CT, respectively. The differences in specificity and negative predictive values were not statistically significant. Conclusions. No significant statistical difference between ¹⁸F-FDG PET/CT and MRI for preoperative N staging of urothelial bladder cancer was found in the study. However, the trend of the data indicates an advantage of ¹⁸F-FDG PET/CT over MRI. Larger prospective studies are needed to elucidate the role of ¹⁸F-FDG PET/CT in N staging of bladder cancer.
Scandinavian Journal of Urology and Nephrology 03/2011; 45(2):122-8. · 0.99 Impact Factor
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ABSTRACT: Proper examination and accurate reporting of radical prostatectomy specimens (RPS) is essential in determining post-surgical treatment and predicting patient outcome. Surveys have demonstrated the absence of consensus on handling of RPS. The aim of this study was to determine whether significant information is lost when only half the horizontal tissue sections are examined.
During a 1-year period, 238 RPS were sectioned into horizontal slices. Apex and basis was cut sagittally, and remaining slices were embedded in quadrants. Glass slides from every second horizontal slice were withheld. The remaining slides were evaluated microscopically, and essential pathological parameters were recorded. Subsequently, a full report was compiled, including the withheld slides. A median of 12 slides (30%) were withheld during initial assessment. In eight RPS (3.2%) the pTNM stage had to be changed; in six cases (2.6%) from pT2b to pT2c and in two cases (0.8%) from pT2c to pT3a. In one RPS (0.4%) the surgical margin status was changed.
Only little information is lost with systematic partial embedding, overlooking features significant for the postoperative treatment in only 1.2%. Partial embedding as suggested, decreasing the laboratory workload by 30%, is concluded to be acceptable for valid histopathological assessment.
Histopathology 01/2011; 58(2):211-6. · 3.08 Impact Factor
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Mads H Poulsen,
Kirsten Bouchelouche,
Oke Gerke,
Henrik Petersen,
Birgitte Svolgaard, Niels Marcussen,
Niels Svolgaard,
Mattias Ogren,
Werner Vach,
Poul F Høilund-Carlsen,
Ulla Geertsen,
Steen Walter
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ABSTRACT: To evaluate prospectively [(18)F]-fluorocholine positron-emission/computed tomography (FCH PET/CT) for lymph node staging of prostate cancer before intended curative therapy, and to determine whether imaging 15 or 60 min after radiotracer injection is preferable.
In all, 25 consecutive patients with newly diagnosed prostate cancer (Gleason score >6, and/or a prostate-specific antigen level of >10 ng/mL, and/or T3 cancer) were scanned before lymphadenectomy. Each patient was assessed twice with imaging, at 15 and 60 min after the injection with FCH. Images were compared with the results of histopathological examination of the surgically removed lymph nodes. Maximum standardized uptake values (SUV(max) ) at 15 and 60 min were also compared.
Histopathologically, metastases were present in removed lymph nodes from three patients. FCH PET/CT showed a high radiotracer uptake in four patients, the former three and a fourth. The sensitivity, specificity, positive and negative predictive value of FCH PET/CT for patient based lymph node staging of prostate cancer were 100%, 95%, 75% and 100%, respectively; the corresponding 95% confidence intervals were 29.2-100%, 77.2-99.9%, 19.4-99.4% and 83.9-100%, respectively. Values of SUV(max) at early and late imaging were not significantly different.
This small series supports the use of FCH PET/CT as a tool for lymph node staging of patients with prostate cancer. Values of SUV(max) at early and late imaging did not differ. However, larger prospective studies are needed to validate these findings.
BJU International 09/2010; 106(5):639-43; discussion 644. · 2.84 Impact Factor
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ABSTRACT: Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantified CD31(+) postglomerular microvessels, performed quantitative PCR analysis of vascular growth factor expression, and measured renal blood flow by magnetic resonance. Treating rats with the angiotensin II type 1 receptor antagonist candesartan for 2 weeks after birth reduced the total length, volume, and surface area of capillaries in both the cortex and the medulla and inhibited the organization of vasa recta bundles. In addition, angiotensin II type 1 antagonism inhibited the transcription of angiogenic growth factors vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, and the angiopoietin receptor Tie-2 in cortex and medulla. Similarly, Agtr1a(-/-);Agtr1b(-/-) mouse kidneys had decreased angiopoietin-1, angiopoietin-2, and Tie-2 mRNAs at postnatal day 14. To test whether increased urinary flow leads to microvascular injury, we induced postnatal polyuria with either lithium or adrenalectomy, but these did not alter vascular endothelial growth factor expression or vasa recta organization. Compared with vehicle-treated rats, renal blood flow was significantly (approximately 20%) lower in candesartan-treated rats even 14 days after candesartan withdrawal. Taken together, these data demonstrate that angiotensin II promotes postnatal expansion of postglomerular capillaries and organization of vasa recta bundles, which are necessary for development of normal renal blood flow.
Journal of the American Society of Nephrology 03/2010; 21(3):448-59. · 9.66 Impact Factor
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ABSTRACT: We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell renal cell carcinoma (RCC).
The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX [CA IX]) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.
The intratumoral neutrophils ranged from zero to 289 cells/mm(2) tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX < or = 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio [HR], 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.
The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
Journal of Clinical Oncology 08/2009; 27(28):4709-17. · 18.37 Impact Factor
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ABSTRACT: Bladder cancer develops through different pathways, provisionally entitled "papillary" and "invasive." Carcinoma in situ (CIS) is thought to be the precursor of invasive bladder cancer. However, little is known about chromosomal alterations of these clinically important lesions, and the relationship between chromosomal alterations and the different pathways. We laser-microdissected 12 CIS and 4 dysplasia samples concomitant to invasive bladder cancer. We determined genome-wide chromosome copy number changes and loss of heterozygosity (LOH) using Mapping 10K SNP microarrays. We further examined 48 high-risk non-muscle-invasive bladder cancers using SNP microarrays to reveal characteristic changes correlated with the CIS-phenotype. DNA copy-number changes were further validated using QPCR in 77 independent tumor samples. CIS was found to be chromosomal unstable in 8 of 12 cases. Characteristic chromosomal changes were copy number gains of chromosomes 5p, 6p22.3, 10p15.1 and losses/LOH of chromosome 5q and 13q13-q14. Tumor samples with these alterations were significantly associated with CIS. Using FGFR3 mutations as markers of the opposing papillary phenotype, we found 5p gains and FGFR3 mutations mutually exclusive. No FGFR3 mutations were found in 23 CIS and dysplasia samples. Based on this, we classified high-risk non-muscle-invasive bladder tumors according to FGFR3 mutations and chromosomal changes into papillary and CIS-type tumors with high correlation to CIS status (p = 0.001). Furthermore, we found significant correlation to the results of molecular classifiers based on gene-expression. We concluded that chromosomal changes may be used to characterize different pathways in bladder cancer development.
International Journal of Cancer 07/2009; 125(9):2095-103. · 5.44 Impact Factor
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ABSTRACT: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown.
Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival.
A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells.
Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.
Clinical Cancer Research 02/2009; 15(3):1052-8. · 7.74 Impact Factor
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BJU International 07/2008; 101 Suppl 4:41-4. · 2.84 Impact Factor
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ABSTRACT: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats.
Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats.
CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality.
MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.
Nephrology Dialysis Transplantation 05/2008; 23(9):2777-83. · 3.40 Impact Factor
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Lars Dyrskjøt,
Karsten Zieger,
Francisco X Real,
Núria Malats,
Alfredo Carrato,
Carolyn Hurst,
Sanjeev Kotwal,
Margaret Knowles,
Per-Uno Malmström,
Manuel de la Torre,
Kenneth Wester,
Yves Allory,
Dimitri Vordos,
Aurélie Caillault,
François Radvanyi,
Anne-Mette K Hein,
Jens L Jensen,
Klaus M E Jensen, Niels Marcussen,
Torben F Orntoft
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ABSTRACT: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non-muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression.
We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome.
Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of T(a) or T(1) tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis.
This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non-muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
Clinical Cancer Research 07/2007; 13(12):3545-51. · 7.74 Impact Factor
