Comparison of peak wall stress and peak wall rupture index in ruptured and asymptomatic intact abdominal aortic aneurysms.

BACKGROUND: Previous studies have suggested that finite element analysis (FEA) can estimate the rupture risk of an abdominal aortic aneurysm (AAA); however, the value of biomechanical estimates over measurement of AAA diameter alone remains unclear. This study aimed to compare peak wall stress (PWS) and peak wall rupture index (PWRI) in participants with ruptured and asymptomatic intact AAAs. METHODS: The reproducibility of semiautomated methods for estimating aortic PWS and PWRI from CT images was assessed. PWS and PWRI were estimated in people with ruptured AAAs and those with asymptomatic intact AAAs matched by orthogonal diameter on a 1 : 2 basis. Spearman's correlation coefficient was used to assess the association between PWS or PWRI and AAA diameter. Independent associations between PWS or PWRI and AAA rupture were identified by means of logistic regression analyses. RESULTS: Twenty individuals were included in the analysis of reproducibility. The main analysis included 50 patients with an intact AAA and 25 with a ruptured AAA. Median orthogonal diameter was similar in ruptured and intact AAAs (82·3 (i.q.r. 73·5-92·0) versus 81·0 (73·2-92·4) mm respectively; P = 0·906). Median PWS values were 286·8 (220·2-329·6) and 245·8 (215·2-302·3) kPa respectively (P = 0·192). There was no significant difference in PWRI between the two groups (P = 0·982). PWS and PWRI correlated positively with orthogonal diameter (both P < 0·001). Participants with high PWS, but not PWRI, were more likely to have a ruptured AAA after adjusting for potential confounders (odds ratio 5·84, 95 per cent c.i. 1·22 to 27·95; P = 0·027). This association was not maintained in all sensitivity analyses. CONCLUSION: High aortic PWS had an inconsistent association with greater odds of aneurysm rupture in patients with a large AAA.

Finite element analysis in asymptomatic, symptomatic, and ruptured abdominal aortic aneurysms: in search of new rupture risk predictors.

OBJECTIVES: To compare biomechanical rupture risk parameters of asymptomatic, symptomatic and ruptured abdominal aortic aneurysms (AAA) using finite element analysis (FEA). STUDY DESIGN: Retrospective biomechanical single center analysis of asymptomatic, symptomatic, and ruptured AAAs. Comparison of biomechanical parameters from FEA. MATERIALS AND METHODS: From 2011 to 2013 computed tomography angiography (CTA) data from 30 asymptomatic, 15 symptomatic, and 15 ruptured AAAs were collected consecutively. FEA was performed according to the successive steps of AAA vessel reconstruction, segmentation and finite element computation. Biomechanical parameters Peak Wall Rupture Risk Index (PWRI), Peak Wall Stress (PWS), and Rupture Risk Equivalent Diameter (RRED) were compared among the three subgroups. RESULTS: PWRI differentiated between asymptomatic and symptomatic AAAs (p < .0004) better than PWS (p < .1453). PWRI-dependent RRED was higher in the symptomatic subgroup compared with the asymptomatic subgroup (p < .0004). Maximum AAA external diameters were comparable between the two groups (p < .1355). Ruptured AAAs showed the highest values for external diameter, total intraluminal thrombus volume, PWS, RRED, and PWRI compared with asymptomatic and symptomatic AAAs. In contrast with symptomatic and ruptured AAAs, none of the asymptomatic patients had a PWRI value >1.0. This threshold value might identify patients at imminent risk of rupture. CONCLUSIONS: From different FEA derived parameters, PWRI distinguishes most precisely between asymptomatic and symptomatic AAAs. If elevated, this value may represent a negative prognostic factor for asymptomatic AAAs.

Meta-analysis of peak wall stress in ruptured, symptomatic and intact abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of sudden death; however, there are currently incomplete means to predict the risk of AAA rupture. AAA peak wall stress (PWS) can be estimated using finite element analysis (FEA) methods from computed tomography (CT) scans. The question is whether AAA PWS can predict AAA rupture. The aim of this systematic review was to compare PWS in patients with ruptured and intact AAA. METHODS: The MEDLINE database was searched on 25 May 2013. Case-control studies assessing PWS in asymptomatic intact, and acutely symptomatic or ruptured AAA from CT scans using FEA were included. Data were extracted independently. A random-effects model was used to calculate standard mean differences (SMDs) for PWS measurements. RESULTS: Nine studies assessing 348 individuals were identified and used in the meta-analysis. Results from 204 asymptomatic intact and 144 symptomatic or ruptured AAAs showed that PWS was significantly greater in the symptomatic/ ruptured AAAs compared with the asymptomatic intact AAAs (SMD 0·95, 95 per cent confidence interval 0·71 to 1·18; P < 0·001). The findings remained significant after adjustment for mean systolic blood pressure, standardized at 120 mmHg (SMD 0·68, 0·39 to 0·96; P < 0·001). Minimal heterogeneity between studies was noted (I(2) = 0 per cent). CONCLUSION: This study suggests that PWS is greater in symptomatic or ruptured AAA than in asymptomatic intact AAA.

A novel strategy to translate the biomechanical rupture risk of abdominal aortic aneurysms to their equivalent diameter risk: method and retrospective validation.

OBJECTIVE: To translate the individual abdominal aortic aneurysm (AAA) patient's biomechanical rupture risk profile to risk-equivalent diameters, and to retrospectively test their predictability in ruptured and non-ruptured aneurysms. METHODS: Biomechanical parameters of ruptured and non-ruptured AAAs were retrospectively evaluated in a multicenter study. General patient data and high resolution computer tomography angiography (CTA) images from 203 non-ruptured and 40 ruptured aneurysmal infrarenal aortas. Three-dimensional AAA geometries were semi-automatically derived from CTA images. Finite element (FE) models were used to predict peak wall stress (PWS) and peak wall rupture index (PWRI) according to the individual anatomy, gender, blood pressure, intra-luminal thrombus (ILT) morphology, and relative aneurysm expansion. Average PWS diameter and PWRI diameter responses were evaluated, which allowed for the PWS equivalent and PWRI equivalent diameters for any individual aneurysm to be defined. RESULTS: PWS increased linearly and PWRI exponentially with respect to maximum AAA diameter. A size-adjusted analysis showed that PWS equivalent and PWRI equivalent diameters were increased by 7.5 mm (p = .013) and 14.0 mm (p < .001) in ruptured cases when compared to non-ruptured controls, respectively. In non-ruptured cases the PWRI equivalent diameters were increased by 13.2 mm (p < .001) in females when compared with males. CONCLUSIONS: Biomechanical parameters like PWS and PWRI allow for a highly individualized analysis by integrating factors that influence the risk of AAA rupture like geometry (degree of asymmetry, ILT morphology, etc.) and patient characteristics (gender, family history, blood pressure, etc.). PWRI and the reported annual risk of rupture increase similarly with the diameter. PWRI equivalent diameter expresses the PWRI through the diameter of the average AAA that has the same PWRI, i.e. is at the same biomechanical risk of rupture. Consequently, PWRI equivalent diameter facilitates a straightforward interpretation of biomechanical analysis and connects to diameter-based guidelines for AAA repair indication. PWRI equivalent diameter reflects an additional diagnostic parameter that may provide more accurate clinical data for AAA repair indication.

Increasing prevalence of ciprofloxacin resistance in extended-spectrum-ß-lactamase-producing Escherichia coli urinary isolates.

PURPOSE: To describe the incidence and drug susceptibility profiles of uropathogenic extended-spectrum-ß-lactamase-producing Escherichia coli (ESBL-EC) during a 10-year period and to identify differences in resistance patterns between urological and non-urological ESBL-EC isolates. METHODS: Retrospective analysis of 191,564 urine samples obtained during 2001 to 2010 at the University Hospital Basel, Switzerland. The computerized database of the Clinical Microbiology Laboratory and the Division of Infectious Diseases and Hospital Epidemiology was used to identify ESBL-EC positive urine samples. ESBL-EC isolates were stratified according their origin into two groups: Urology and non-Urology isolates. RESULTS: The rate of ESBL-EC positive urine samples increased significantly during the study period (3 in 2001 compared to 55 in 2010, p < 0.05). The most active agents were imipenem, meropenem, and fosfomycin (100%), followed by amikacin (99.1%) and nitrofurantoin (84%). The least active substances were ampicillin-clavulanate (20%), sulfamethoxazole (28%), and ciprofloxacin (29.6%). ESBL-EC isolates from urological and non-urological patients showed similar susceptibility profiles. However, ESBL-EC isolates from urological patients were significantly less susceptible to ciprofloxacin compared to non-urological isolates (14.7 vs. 32.7%, p < 0.05). CONCLUSIONS: The rate of urinary ESBL-EC isolates is increasing. Their susceptibility to nitrofurantoin, fosfomycin, and carbapenems is excellent, whereas ampicillin-clavulanate, sulfamethoxazole, and ciprofloxacin demonstrate only low susceptibility. In particular, the use of ciprofloxacin should be strictly avoided in urologic patients with suspicion for an ESBL-EC urinary tract infection as well as routine antibiotic prophylaxis prior to urological interventions if not explicit indicated by current international guidelines or local resistance patterns.

Comparison of the roll-plate and sonication techniques in the diagnosis of microbial ureteral stent colonisation: results of the first prospective randomised study.

BACKGROUND: Microbial ureteral stent colonisation (MUSC) is one leading risk factor for complications associated with ureteral stent placement. As MUSC remains frequently undetected by standard urine cultures, its definitive diagnosis depends on microbiological investigation of the stent. However, a standard reference laboratory technique for studying MUSC is still lacking. MATERIALS AND METHODS: A total of 271 ureteral stents removed from 199 consecutive patients were investigated. Urine samples were obtained prior to device removal. Stents were divided into four parts. Each part was separately processed by the microbiology laboratory within 6 h. Ureteral stents were randomly allocated to roll-plate or sonication, respectively, and analysed using standard microbiological techniques. Demographic and clinical data were prospectively collected using a standard case-report form. RESULTS: Overall, roll-plate showed a higher detection rate of MUSC compared with sonication (35 vs. 28 %, p < 0.05) and urine culture (35 vs. 8 %, p < 0.05). No inferiority of Maki's technique was observed even when stents were stratified according to indwelling time below or above 30 days. Compared with roll-plate, sonication commonly failed to detect Enterococcus spp., coagulase-negative staphylococci (CoNS) and Enterobacteriaceae. In addition, sonication required more hands-on time, more equipment and higher training than roll-plate in the laboratory. CONCLUSIONS: This prospective randomised study demonstrates the superiority of Maki's roll-plate technique over sonication in the diagnosis of MUSC and that urine culture is less sensitive than both methods. The higher detection rate, simplicity and cost-effectiveness render roll-plate the methodology of choice for routine clinical investigation as well as basic laboratory research.

Use of isothermal microcalorimetry to quantify the influence of glucose and antifungals on the growth of Candida albicans in urine.

AIMS: Urinary tract infection (UTI) caused by Candida spp. is an increasing problem in clinical practice. Risk factors include diabetes mellitus, extremes of age, urinary tract abnormalities and indwelling catheters. Here, we determined the applicability of isothermal microcalorimetry (IMC) for the detection and antifungal drug susceptibility testing of Candida albicans in artificial urine. METHODS AND RESULTS: Isothermal microcalorimetry was used to monitor the metabolic heat production rates of C. albicans at 37 °C (µW = µJ s(-1) ). The influence of increasing concentrations of glucose and antifungal drugs on the growth of C. albicans was investigated. The growth rate increased linearly from 0.024 ± 0.010 to 0.203 ± 0.006 h(-1) with increasing concentration of glucose from 20 to 1640 mg l(-1) . The minimum inhibitory concentrations (MIC) against C. albicans were determined at a fixed glucose concentration of 560 mg l(-1) . These MIC were 0.5 µg ml(-1) for amphotericin B, 5 µg ml(-1) for flucytosine, 0.8 µg ml(-1) for fluconazole and 0.5 µg ml(-1) for tioconazole, respectively. CONCLUSIONS: IMC is able to detect and quantify growth of C. albicans in artificial urine and to determine the MIC of antifungal drugs against C. albicans. This study demonstrated that IMC can be used for basic research on Candida-UTI and opens promising avenue for the use of IMC as rapid drug resistance screening tool and diagnostic tool. SIGNIFICANCE AND IMPACT OF STUDY: Little is known on the growth of C. albicans in urine. Our study provides measurements of the growth rate of this yeast in urine with various glucose concentrations. Thus, important insights are gathered for risk group such as patients with diabetes or patients with prolonged parenteral nutrition resulting in higher urinary glucose concentration.

Microbial ureteral stent colonization in renal transplant recipients: frequency and influence on the short-time functional outcome.

Ureteral stent insertion at the time of renal transplantation significantly decreases complications of urine leakage and obstruction, but bears an intrinsic risk of microbial colonization. Associated urinary tract infection (UTI) may pose a significant risk for graft infection and subsequent graft failure, in particular, during high-level immunosuppression in the early phase after transplantation. The aims of this prospective study were (i) to assess the frequency of microbial ureteral stent colonization (MUSC) in renal transplant recipients by sonication, (ii) to compare the diagnostic value of sonication with that of conventional urine culture (CUC), (iii) to determine biofilm forming organisms, and (iv) to investigate the influence of MUSC on the short-time functional outcome. A total of 80 ureteral stents from 78 renal transplant recipients (deceased donors n = 50, living donors n = 28) were prospectively included in the study. CUC was obtained prior to renal transplantation and at ureteral stent removal. In addition, a new stent sonication technique was performed to dislodge adherent microorganisms. CUCs were positive in 4% of patients. Sonicate-fluid culture significantly increased the yield of microbial growth to 27% (P < 0.001). Most commonly isolated microorganisms by sonication were Enterococcus species (31%), coagulase-negative staphylococci (19%), and Lactobacillus species (19%), microorganisms not commonly observed in UTIs after renal transplantation. The median glomerular filtraton rate (GFR) of the study population increases from 39 mL/min immediately after transplantation (time point A) to 50 mL/min 6 month post transplantation (time point B). In patients without MUSC, the GFR improves from 39 mL/min (A) to 48 mL/min (B) and in patients with MUSC from 39 mL/min (A) to 50 mL/min (B), respectively. In summary, MUSC in renal transplant recipients is common and remains frequently undetected by routine CUC, but colonization had no measurable effect on renal function.

The impact of intraluminal thrombus failure on the mechanical stress in the wall of abdominal aortic aneurysms.

OBJECTIVES: The role of the intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) rupture is controversial, and it is still not clear if an ILT increases or decreases AAA rupture risk. Specifically, signs of bleeding in the ILT are considered to increase AAA rupture risk. To further explore this hypothesis, intact AAAs (n = 4) with clear signs of fissures in the ILT, identified by computed tomography angiography (CTA) were investigated. METHODS: Two different cases of ILT fissuring were investigated, where (1) ILT fissures were extracted directly from the CTA data and (2) a hypothetical fissure was introduced in the otherwise-intact ILT tissue. Wall stress distributions were predicted based on detailed Finite Element (FE) models. RESULTS: ILT fissures extracted from CTA data locally increase the mechanical stress in the underlying wall by up to 30%. The largest impact on wall stress was observed if the ILT crack reaches the aneurysm wall, or if it involves large parts of the ILT. By contrast, a concentric failure in the medial ILT, which does not reach the aneurysm wall, has almost no impact on wall stress distribution. Hypothetical ILT fissures that connect the lumen with the wall cause a twofold increase of the stress in the underlying wall. CONCLUSIONS: ILT fissures increase the stress in the underlying wall, whereas regions other than that remain unaffected. If ILT fissures reach the wall or involve large parts of the ILT, the resulting increase in wall stress could possibly cause AAA rupture.

Biomechanical rupture risk assessment of abdominal aortic aneurysms: model complexity versus predictability of finite element simulations.

OBJECTIVE: Investigation of the predictability of finite element (FE) models regarding rupture risk assessment of abdominal aortic aneurysms (AAAs). MATERIALS AND MATERIALS: Peak wall stress (PWS) and peak wall rupture risk (PWRR) of ruptured (n = 20) and non-ruptured (n = 30) AAAs were predicted by four FE models of different complexities derived from computed tomography (CT) data. Two matching sub-groups of ruptured and non-ruptured aneurysms were used to investigate the usability of different FE models to discriminate amongst them. RESULTS: All FE models exhibited a strong positive correlation between PWS and PWRR with the maximum diameter. FE models, which excluded the intra-luminal thrombus (ILT) failed to discriminate between ruptured and non-ruptured aneurysms. The predictability of all applied FE models was strengthened by including wall strength data, that is, computing the PWRR. The most sophisticated FE model applied in this study predicted PWS and PWRR 1.17 (p = 0.021) and 1.43 (p = 0.016) times higher in ruptured than diameter-matched non-ruptured aneurysms, respectively. CONCLUSIONS: PWRR reinforces PWS as a biomechanical rupture risk index. The ILT has a major impact on AAA biomechanics and rupture risk, and hence, needs to be considered in meaningful FE simulations. The applied FE models, however, could not explain rupture in all analysed aneurysms.

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer.

Molecular mechanisms of prostate cancer progression are poorly understood. Here, we studied gene amplification of the large conductance calcium-activated potassium channel alpha subunit (KCNMA1), which is located at the chromosomal region 10q22. Fluorescence in situ hybridization (FISH) revealed KCNMA1 amplification in 16% of 119 late-stage human prostate cancers and in the hormone-insensitive prostate cancer cell line PC-3. In contrast, KCNMA1 amplification was absent in 33 benign controls, 32 precursor lesions and in 105 clinically organ-confined prostate cancers. Amplification was associated with mRNA and protein overexpression as well as increased density of BK channel protein and beta-estradiol-insensitive BK currents in PC-3 cells as compared to non-amplified control cell lines. Specific blockade of BK channels by iberiotoxin or RNA(i) significantly inhibited K(+) currents and growth of PC-3 cells. The data demonstrate that 10q22 amplification drives KCNMA1 expression and cell proliferation. Thus, KCNMA1 qualifies as a promising diagnostic and therapeutic target in patients with prostate cancer.

Impact of isotropic constitutive descriptions on the predicted peak wall stress in abdominal aortic aneurysms.

Biomechanics-based assessment of Abdominal Aortic Aneurysm (AAA) rupture risk has gained considerable scientific and clinical momentum. However, computation of peak wall stress (PWS) using state-of-the-art finite element models is time demanding. This study investigates which features of the constitutive description of AAA wall are decisive for achieving acceptable stress predictions in it. Influence of five different isotropic constitutive descriptions of AAA wall is tested; models reflect realistic non-linear, artificially stiff non-linear, or artificially stiff pseudo-linear constitutive descriptions of AAA wall. Influence of the AAA wall model is tested on idealized (n=4) and patient-specific (n=16) AAA geometries. Wall stress computations consider a (hypothetical) load-free configuration and include residual stresses homogenizing the stresses across the wall. Wall stress differences amongst the different descriptions were statistically analyzed. When the qualitatively similar non-linear response of the AAA wall with low initial stiffness and subsequent strain stiffening was taken into consideration, wall stress (and PWS) predictions did not change significantly. Keeping this non-linear feature when using an artificially stiff wall can save up to 30% of the computational time, without significant change in PWS. In contrast, a stiff pseudo-linear elastic model may underestimate the PWS and is not reliable for AAA wall stress computations.

Reluctance over right-sided retroperitoneoscopic living donor nephrectomy: justified or not?

UNLABELLED: We retrospectively compared perioperative donor outcomes and early complication rate of right- and left-sided retroperitoneoscopic living donor nephrectomy (RLDN). METHODS: From November 2001 to April 2006, we performed 118 RLDN. Including 24% (n = 28) right-sided RLDN and 76% (n = 90) left-sided RLDN. Perioperative results and the rate of adverse events were compared for both sides. RESULTS: We observed no significant difference in operation time, blood loss, warm ischemia time, or postoperative creatinine levels between right- and left-sided kidney donors. RLDN was successfully performed in 116 of 118 donors. One donor in each group had to be converted to an open approach. We observed one graft loss due to renal artery kinking in one recipient after left-sided RLDN. Two right donations needed a saphenous venous patch due to a short right renal vein (<2 cm). Overall, intraoperative and postoperative complications were comparable between the two donor groups. CONCLUSION: Right-sided RLDN provides comparable perioperative and postoperative results to those of left-sided RLDN. Our results demonstrated that groups with significant experience in RLDN can perform right living donor nephrectomy safely and efficiently with minimal invasiveness.

Stress-driven collagen fiber remodeling in arterial walls.

A stress-driven model for the relation between the collagen morphology and the loading conditions in arterial walls is proposed. We assume that the two families of collagen fibers in arterial walls are aligned along preferred directions, located between the directions of the two maximal principal stresses. For the determination of these directions an iterative finite element based procedure is developed. As an example the remodeling of a section of a human common carotid artery is simulated. We find that the predicted fiber morphology correlates well with experimental observations. Interesting outcomes of the model including local shear minimization and the possibility of axial compressions due to high blood pressure are revealed and discussed.

Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays.

BACKGROUND: The molecular mechanisms underlying the progression of prostate cancer during hormonal therapy have remained poorly understood. In this study, we developed a new strategy for the identification of differentially expressed genes in hormone-refractory human prostate cancer by use of a combination of complementary DNA (cDNA) and tissue microarray technologies. METHODS: Differences in gene expression between hormone-refractory CWR22R prostate cancer xenografts (human prostate cancer transplanted into nude mice) and a xenograft of the parental, hormone-sensitive CWR22 strain were analyzed by use of cDNA microarray technology. To validate the data from cDNA microarrays on clinical prostate cancer specimens, a tissue microarray of specimens from 26 prostates with benign prostatic hyperplasia, 208 primary prostate cancers, and 30 hormone-refractory local recurrences was constructed and used for immunohistochemical detection of protein expression. RESULTS: Among 5184 genes surveyed with cDNA microarray technology, expression of 37 (0.7%) was increased more than twofold in the hormone-refractory CWR22R xenografts compared with the CWR22 xenograft; expression of 135 (2.6%) genes was reduced by more than 50%. The genes encoding insulin-like growth factor-binding protein 2 (IGFBP2) and 27-kd heat-shock protein (HSP27) were among the most consistently overexpressed genes in the CWR22R tumors. Immunohistochemical analysis of tissue microarrays demonstrated high expression of IGFBP2 protein in 100% of the hormone-refractory clinical tumors, in 36% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). Overexpression of HSP27 protein was demonstrated in 31% of the hormone-refractory tumors, in 5% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). CONCLUSIONS: The combination of cDNA and tissue microarray technologies enables rapid identification of genes associated with progression of prostate cancer to the hormone-refractory state and may facilitate analysis of the role of the encoded gene products in the pathogenesis of human prostate cancer.

Intratumoral heterogeneity of von Hippel-Lindau gene deletions in renal cell carcinoma detected by fluorescence in situ hybridization.

Although chromosome 3p deletions are considered an initial event in clear cell renal cell carcinoma (RCC), the reported prevalence of 3p deletions is highly variable. Because molecular analyses may be influenced by intratumoral heterogeneity, this study was performed to evaluate the genetic heterogeneity of the von Hippel-Lindau (VHL) gene (on 3p25.5) in RCC. Fifty-three clear cell and papillary RCCs were examined by dual-labeling fluorescence in situ hybridization with probes for the VHL gene and chromosome 3 centromere. The results were compared with histopathological phenotype, proliferative activity (Ki-67 labeling index) and 8p/17p deletions (both suggested to be linked to RCC progression). A clear-cut VHL deletion (in more than 40% of cells) was detectable in 69% of clear cell RCCs but was not detectable in nine papillary RCCs. A considerable genetic heterogeneity of VHL deletions was seen in clear cell RCCs including VHL-deleted subpopulations with different chromosome 3 counts within individual tumors as well as populations with and without VHL deletions. 8p22 and 17p13 deletions (each of which were detected in 18% of clear cell RCCs) were both linked to VHL deletions. However, 8p and 17p deletions were not associated with tumor grade, stage, or Ki-67 labeling index. The data indicate that some clear cell RCCs may develop independently of VHL alterations.

Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization.

Little is known about the genetic changes underlying invasive tumor growth in bladder cancer. Because alterations that are linked to invasive tumor growth may be detectable in minimally invasive (stage pT1) but not in noninvasive (stage pTa) tumors, we searched for genetic differences between 28 pTa and 28 papillary pT1 bladder tumors by comparative genomic hybridization. Losses of 9q (54%), 9p (39%), and Y (28%) and gains of 1q (14%) were most prevalent in pTa tumors. These changes may play a role in the initiation of noninvasive papillary bladder cancer. The total number of aberrations was higher in pT1 tumors (6.5 +/- 5.4) than in pTa tumors (2.3 +/- 2.1; P = 0.0003), suggesting an increased genetic instability at stage pT1. Specific alterations, which were significantly more frequent in pT1 than in pTa tumors (P < or = 0.05), included deletions at 2q (36% of pT1 tumors), 8p (32%), and 11p (21%) and gains at 1q (54%), 8q (32%), 3p, 3q, 5p, 6p, and 10p (18% each). These loci are candidates for carrying genes involved in invasive tumor growth in bladder cancer. High-level amplifications at 1q22-24, 3p24-25, 6p22, 8p12, 8q21-22, 10p12.1-14, 11q13, 12q15-21, 13q31-33, Xp11-13, and Xq21-22.2 may pinpoint the location of oncogenes with relevance for bladder cancer.

Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa).

Almost 70% of urinary bladder neoplasms present as low-grade papillary noninvasive tumors (stage pTa). To determine which genomic alterations can occur in pTa tumors of different grades and to evaluate the prognostic significance of chromosomal imbalances, we analyzed 113 pTa tumors (40 grade 1, 55 grade 2, 18 grade 3) by comparative genomic hybridization. pTaG1 (1.9 +/- 2.0) and pTaG2 (3.1 +/- 2.9) tumors had only few genomic alterations with 9q- (44%), 9p- (36%), and -Y (21%) being most prevalent. Neither the total number of aberrations nor any individual alteration was linked to the risk of recurrence in 95 pTaG1/G2 tumors with clinical follow-up information. pTaG3 tumors were characterized by a high number of alterations (7.7 +/- 4.5; P < 0.0001 for G3 versus G2). Several chromosomal imbalances that have previously been reported to be typical for invasive bladder neoplasms were significantly more frequent in pTaG3 than in pTaG2 tumors, including 2q-, 5p+, 5q-, 6q-, 8p-, 10q-, 18q-, and 20q+. A malfunction of genes at these loci may contribute to the development of high-grade urothelial neoplasias. However, there is no evidence for a direct role of these alterations for development of invasive tumor growth.

Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays.

Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastat prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (> or =3X) amplifications were very rare (<2%) in primary prostate cancers However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.