| 61. |
- Figueroa, Jonine D., et al.
(författare)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Tidskriftsartikel (refereegranskat)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 62. |
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| 63. |
- Fritz, Helena, et al.
(författare)
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The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.
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| 64. |
- Fritz, Helena, et al.
(författare)
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The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:10, s. 1758-1765
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. Experimental design: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n = 152) and 50 normal kidney samples. Results: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b),) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P = 0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P = 0.016; confidence interval (CI) 1.201-5.736). Conclusions: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance.
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| 65. |
- Fu, Yi-Ping, et al.
(författare)
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The 19q12 Bladder Cancer GWAS Signal : Association with Cyclin E Function and Aggressive Disease
- 2014
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:20, s. 5808-5818
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
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| 66. |
- Gaziano, Liam, et al.
(författare)
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Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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| 67. |
- Granfors, Torvald, et al.
(författare)
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Downstaging and survival benefits of neoadjuvant radiotherapy before cystectomy for patients with invasive bladder carcinoma.
- 2009
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 43:4, s. 293-299
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To compare the long-term outcomes of a series of patients treated with neoadjuvant radiotherapy combined with cystectomy against a later series of patients treated with immediate cystectomy. MATERIAL AND METHODS: A total of 187 consecutive patients, surgically treated with cystectomy due to cT1-3 transitional cell bladder carcinoma with (n=90) or without (n=97) neoadjuvant radiotherapy, was included in a retrospective analysis. The clinical stage at the primary bladder resection and the pathological reports after the cystectomy were re-evaluated and progression-free, disease-specific and overall survival were calculated. RESULTS: Seven of 97 (7%) patients treated without any neoadjuvant therapy had pT0 in the bladder specimen. In contrast, 51 of 90 patients (57%) treated with neoadjuvant radiotherapy downstaged to pT0. Among cT3 tumours none of 16 patients (0%) treated without radiotherapy downstaged to pT0, while 19 (56%) of 34 patients treated with radiotherapy did so. The progression-free survival was significantly longer for patients with pT0 than for those with a remaining tumour (pT1-4) in the cystectomy specimen (p<0.001). A high T stage correlated with adverse overall survival. Patients with cT3 tumours treated with neoadjuvant radiotherapy followed by cystectomy had significantly longer disease-specific survival time (p=0.007) than those undergoing cystectomy only. In a Cox regression analysis, cT stage as well as pT stage and occurrence of carcinoma in situ in the cystectomy specimens remained as independent prognostic factors. CONCLUSIONS: In this retrospective study neoadjuvant radiotherapy before the cystectomy resulted in significant downstaging of invasive bladder transitional cell carcinoma. This downstaging was most significant for patients with cT3 tumours leading to prolonged survival.
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| 68. |
- Gref, Margareta, 1950-
(författare)
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Glomerular filtration rate in adults : a single sample plasma clearance method based on the mean sojurn time
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glomerular filtration rate (GFR) is a key parameter in evaluating kidney function. After a bolus injection of an exogenous GFR marker in plasma an accurate determination of GFR can be made by measuring the marker concentration in plasma during the excretion. Simplified methods have been developed to reduce the number of plasma samples needed and yet still maintain a high accuracy in the GFR determination. Groth previously developed a single sample GFR method based on the mean sojourn time of a GFR marker in its distribution volume. This method applied in adults using the marker 99m Tc-DTPA is recommended for use when GFR is estimated to be ≥ 30 mL/min. The aim of the present study was to further develop the single plasma sample GFR method by Groth including patients with severely reduced renal function and different GFR markers. Three different GFR markers 51Cr-EDTA, 99mTc-DTPA and iohexol were investigated. Formulas were derived for the markers 51Cr-EDTA and iohexol when GFR is estimated to be ≥ 30 mL/min. For patients with an estimated GFR < 30 mL/min a special low clearance formula with a single sample obtained about 24 h after marker injection was developed. The low clearance formula was proven valid for use with all three markers. The sources of errors and their influence on the calculated single sample clearance were investigated. The estimated distribution volume is the major source of error but its influence can be reduced by choosing a suitable sampling time. The optimal time depends on the level of GFR; the lower GFR the later the single sample should be obtained. For practical purpose a 270 min sample is recommended when estimated GFR ≥ 30 mL/min and a 24 h sample when estimated GFR < 30 mL/min. Sampling at 180 min after marker injection may be considered if GFR is estimated to be essentially normal.
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| 69. |
- Grimm, Marc-Oliver, et al.
(författare)
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Safe Use of Immune Checkpoint Inhibitors in the Multidisciplinary Management of Urological Cancer : The European Association of Urology Position in 2019
- 2019
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 76:3, s. 368-380
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitors (ICIs) are now used routinely to treat advanced or metastatic urothelial and renal cell carcinoma, among other cancers. Furthermore, multiple trials are currently exploring their role in adjuvant, neoadjuvant, and noninvasive (eg, high-grade non-muscle-invasive bladder cancer) settings. Consequently, urologists are increasingly confronted with patients who are on, have recently received, or will be treated with ICI therapy. The care of these patients is likely to be shared between urologists and medical oncologists, with additional occasional support of other medical specialties. Therefore, it is important that urologists have good knowledge of immune-related side effects. Here, we provide advice on prevention, early diagnosis, and clinical management of the most relevant toxicities to strengthen urologists' insight and, thus, role in the multidisciplinary management in the new immunotherapy era. Patient summary: Immune therapy is a common treatment for many patients with advanced cancer. We describe common side effects of this treatment, and advise how they are best prevented and managed.
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| 70. |
- Guðmundsson, Eirikur, et al.
(författare)
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Metastatic potential in renal cell carcinomas <= 7 cm : swedish kidney cancer quality register data
- 2011
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Ingår i: European Urology. - Basel : Karger. - 0302-2838 .- 1873-7560. ; 60:5, s. 975-982
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Tidskriftsartikel (refereegranskat)abstract
- Background: Renal cell carcinoma(RCC) represents 2-3% of all malignancies and accounts for approximately 90% of all kidney malignancies. An increasing proportion of RCCs are discovered incidentally, and the average tumor diameter at diagnosis has decreased over the last few decades. Small RCCs have often been regarded by many as relatively harmless. Objective: The objective was to evaluate the incidence of local T-category distribution and lymph node and distant metastases in relation to tumor size in RCCs <= 7 cm in a nationally based patient population. Design, setting, and participants: Data were extracted from the National Swedish Kidney Cancer Register containing 3489 RCCs diagnosed between 2005 and 2008. This is a population-based registry including 99% of all RCCs diagnosed nationwide. The study included 2033 patients having a tumor <= 7 cm in diameter. Measurements: The size of the tumors was compared with sex, age, cause of diagnosis, Fuhrman grade, RCC type, and TNM category. Results and limitations: Most RCCs were discovered incidentally and incidence correlated inversely to tumor size. There were 887 (43%) patients with category T1a tumors, 836 (40%) with category T1b, 174 (8%) with T3a, 131 (6%) with T3b/c, and 12 (1%) patients had invasion of adjacent organs (T4). A total of 309 (15%) patients had lymph node and/or distant metastases. Of the 177 1- to 2-cm RCCs, category T3 tumors were identified in three patients and lymph node and/or distant metastases were identified in 8 (5%). Only for tumors <= 1 cm was there neither advanced stage nor metastasis. The occurrence of locally advanced growth, lymph node and distant metastases, and high tumor grade correlated to tumor size. Patients with Fuhrman grade III or IV had a fourfold greater risk of metastases than grades I or II. Conclusions: Lymph node and distant metastases occur even in small RCCs. Risk of metastases increases with tumor size. The data clearly show that small RCCs also have a malignant potential and should be properly evaluated and adequately treated. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.
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