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National Cancer Institute®
Ultima Vez Modificado: 21 de noviembre del 2001
UI - 21203622
AU - Williams SG; Gandour-Edwards R; Deitch AD; Toscano S; Fan JJ; Sternberg
TI - CN; Pansadoro V; Calabro F; Rossetti A; deVere White RW Differences in gene expression in muscle-invasive bladder cancer: a comparison of Italian and American patients.
SO - Eur Urol 2001 Apr;39(4):430-7
AD - Department of Urology, University of California-Davis, Sacramento, Calif, USA.
OBJECTIVE: To seek differences in gene expression in the primary muscle-invasive bladder cancers of two cohorts of patients having different survival rates. An Italian group treated by transurethral resection of the bladder tumor (TURBT) and neo-adjuvant chemotherapy using methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) followed by TURBT, partial cystectomy or radical cystectomy (75% 3-year survival) was compared to an American cohort treated by radical cystectomy (51% 3-year survival). METHODS: Immunohistochemistry was used to examine the protein expression levels of three genes that act at the G1/S cell cycle checkpoint, p53, p21/waf-1/cip1 (a downstream effector gene in the p53 pathway) and Rb, plus a major inhibitor of apoptosis, Bcl-2. RESULTS: For the bladder cancers of the Italian patient cohort, there was a significantly higher rate of p53 immunopositivity (93 vs. 63%, p = 0.002) and a significantly lower rate of Rb loss (25 vs. 54%, p = 0.009). In bivariate analysis, 72% of Italian tumors were immunopositive for both p53 and p21 (p53+/p21+) vs. 49% for the American tumors. The subset of Italian patients with p53+/p21+ tumors were more frequently disease-free (stage pT0) following chemotherapy and were less likely to fail therapy than those with p53+/p21- tumors (p = 0.0357). Loss of Rb staining was associated with a decreased 5-year survival in the Italian, but not in the American patients. CONCLUSIONS: (1) Significant differences in the expression of the p53, p21 and Rb genes were found between the 2 groups of patients. (2) Italian patients with p53+/p21+ tumors had significantly lower recurrence rates after TURBT and chemotherapy than those having p53+/p21- tumors. (3) Absence of p21 immunopositivity in the Italian tumors may identify alterations in the p53 pathway that predict poor outcome.
UI - 21203623
AU - Leissner J; Hohenfellner R; Thuroff JW; Koppen C; Wolf HK
TI - Prognostic significance of histopathological grading and immunoreactivity for p53 and p21/WAF1 in grade 2 pTa transitional cell carcinoma of the urinary bladder.
SO - Eur Urol 2001 Apr;39(4):438-45
AD - Department of Urology, Johannes Gutenberg University, Mainz, Germany.
OBJECTIVE: At present, there are no predictors of tumour behaviour for grade (G) 2 pTa transitional cell carcinomas (TCC) of the bladder. Here we analyse the prognostic relevance of histopathological grading and the immunohistochemical detection of p53 and p21/WAF1. METHODS: 70 patients were newly diagnosed with G2 pTa TCC of the bladder based on transurethral resection specimens. Two pathologists, blinded with respect to the clinical outcome, confirmed the initial grade and subclassified the G2 lesions into G2a and G2b carcinomas based on the degree of nuclear atypia and the number of mitoses. Immunoreactivity for p53 and p21/WAF1 was evaluated semiquantitatively. RESULTS: There were 52 G2a and 18 G2b tumours, mean follow-up was 49.2 months. Of all patients, 31.4% remained tumour-free, 48.6% recurred with the same tumour grade and stage, and 20.0% showed tumour progression. Patients with G2a tumours developed tumour progression in 13% in contrast to 39% with G2b lesions (p = 0.037). Of 21 p53-positive tumours, 33% (7/21) developed progressive disease, whereas 14% (7/49) of p53-negative patients showed tumour progression (p = 0.102). Neither p21/WAF1 expression alone nor the combination of p53 and p21/WAF1 correlated with clinical outcome. CONCLUSION: The more detailed grading system but not p53 or p21/WAF1 immunohistochemistry was found to be an independent prognostic factor for tumour progression.
UI - 21336421
AU - Morioka M; Jo Y; Furukawa Y; Kinugawa K; Sone A; Matsuki T; Kobayashi T;
TI - Fujii T; Tanaka H Prognostic factors for survival and bladder recurrence in transitional cell carcinoma of the upper urinary tract.
SO - Int J Urol 2001 Jul;8(7):366-73
AD - Department of Urology, Kawasaki Medical School, Kurashiki, Japan. email@example.com
BACKGROUND: Prognostic factors for survival in transitional cell carcinoma of the upper urinary tract have been extensively evaluated, but detailed analyses of patterns of bladder recurrence after surgery have been rare. METHODS: The outcome and tumor recurrence of 93 patients with transitional cell carcinoma of the upper urinary tract surgically treated between 1975 and 1999 were reviewed, retrospectively. Disease-specific survival by pathologic stage and grade were analyzed by the Kaplan-Meier METHOD: Prognostic factors for survival and bladder recurrence were examined by univariate and multivariate analysis. RESULTS: The 5-year disease-specific survival rates of the patients with pTa, T1 and T2 were 92.9%, 100% and 88.9%, respectively. However, that of the pT3 patients was 61.9% and the median survival of the pT4 cases was only 7 months. Bladder recurrence was seen in 40 cases and recurrences occurred within 1 year in 32 of these patients. The stage and grade of metachronous bladder tumors usually resembled those of primary tumors, but invasive recurrences were seen in 19% of recurrent cases with primary pTa, pT1 tumors. The significant prognostic factor for survival was pathologic stage (pT3, pT4), but no significant variables were detected for bladder recurrence by multivariate analysis. CONCLUSIONS: The prognosis of pT3, pT4 patients is poor and effective systemic adjuvant therapy is necessary. Invasive bladder recurrence occurred in 19% of patients with superficial primary tumors. As no significant prognostic variables for bladder recurrence were identified, careful follow up for bladder recurrence is important even if the primary tumors are non-invasive.
UI - 21382677
AU - Duggan BJ; Maxwell P; Kelly JD; Canning P; Anderson NH; Keane PF;
TI - Johnston SR; Williamson KE The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma.
SO - J Urol 2001 Sep;166(3):1098-105
AD - Uro-Oncology Research Group, Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland, UK.
PURPOSE: Bcl-2 is an important determinant of transitional cell carcinoma of the bladder recurrence and progression as well as a factor in patient response to chemotherapy or radiotherapy. We determined Bcl-2 down-regulation after antisense oligonucleotide therapy and synergism with mitomycin C in transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Bcl-2 protein was quantified using flow cytometry and immunohistochemistry in 4 bladder cancer cell lines, in bladder washings from 6 patients with carcinoma in situ and in 16 patient tumor samples. The synergistic effects of antisense oligonucleotides G3139 and 2009, and mitomycin C were investigated in 4 cell lines, while 2009 down-regulation was examined in 20 tumor explants in an ex vivo model. RESULTS: Bcl-2 protein expression was found in all 4 cell lines and in 5 of the 6 cell populations derived from patients with carcinoma in situ. Of the 16 tumors 7 were classified positive by frozen section immunohistochemistry and quantitative flow cytometry. G3139 and 2009 down-regulated Bcl-2 protein expression in all 4 cell lines and 2009 down-regulated Bcl-2 protein expression in half of the Bcl-2 positive tumor specimens. There was only evidence in 1 cell line, T24/83, that Bcl-2 protein expression down-regulation enhanced mitomycin C induced apoptotic cell death. CONCLUSIONS: Bcl-2 was expressed in a significant proportion of bladder tumors and in carcinoma in situ. Therefore, antisense oligonucleotides represent a viable strategy for Bcl-2 protein down-regulation. However, it may not always translate into an increased level of mitomycin C induced apoptosis in transitional cell carcinoma of the bladder.
UI - 21382595
AU - Sherif A; De La Torre M; Malmstrom PU; Thorn M
TI - Lymphatic mapping and detection of sentinel nodes in patients with bladder cancer.
SO - J Urol 2001 Sep;166(3):812-5
AD - Department of Urology, University Hospital, SE-751 85 Uppsala, Sweden.
PURPOSE: We examined the possibility for detecting sentinel nodes in patients with bladder cancer and whether the histopathological status of identified sentinel nodes reflected that of the lymphatic field. MATERIALS AND METHODS: A total of 13 patients with bladder cancer who met the criteria qualifying them for radical cystectomy had intravesical injections of radioactive tracer and blue dye marker around the tumor followed by lymphoscintigraphy to visualize lymphatic drainage and detect sentinel nodes. Sentinel nodes were identified preoperatively by the blue color and increased radioactivity and were compared histopathologically with other routinely excised lymph nodes. RESULTS: Sentinel nodes were detected in 85% (11 of 13) of patients. There were 4 patients who had sentinel nodes containing tumor cells, and each metastasis was only seen in the detected sentinel node. There were no false-negative sentinel nodes. Of the metastatic sentinel nodes 3 were located outside the normally excised lymph nodes of the obturator fossa. CONCLUSIONS: Sentinel nodes can be detected in patients with bladder cancer. The histopathological status of the identified sentinel nodes was diagnostic for all other excised lymph nodes. Sentinel nodes often seem to be located outside the obturator lymphatic field, which is normally examined during preoperative staging of bladder cancer.
UI - 21440184
AU - Kochakarn W; Chaimuangraj S; Leenanupunth C; Muangman V
TI - Risk factors of urethral involvement of bladder cancer after radical cystectomy with orthotopic neobladder in females.
SO - J Med Assoc Thai 2001 Jun;84(6):889-92
AD - Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
The cystectomy and urethrectomy specimens of 20 females with invasive bladder cancer were studied for evidence of urethral involvement. The bladder showed transitional cell carcinoma in 18 cases (90%) and squamous cell carcinoma in 2 cases (10%). Urethral involvement was found in 5 cases (25%). The trigone was the most common site of tumor (50%) which had 33 per cent chance of urethral involvement. Bladder neck was the next common site of tumor (15%) and had 66 per cent chance of urethral involvement. High stage (T3b, T4) and high grade (III) at trigone also correlated with urethral involvement. The tumor bearing node showed only 20 per cent correlation with urethral involvement. Female patients with high stage/high grade at trigone and any stage/grade at bladder neck are at high risk of urethral recurrence after radical cystectomy and orthotopic neobladder procedure.
UI - 21439132
AU - Dalbagni G; Ren ZP; Herr H; Cordon-Cardo C; Reuter V
TI - Genetic alterations in tp53 in recurrent urothelial cancer: a longitudinal study.
SO - Clin Cancer Res 2001 Sep;7(9):2797-801
AD - Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. firstname.lastname@example.org
PURPOSE: Because bladder cancer has a recurrence rate that can be as high as 90% at 2 years, we sought to clarify whether these metachronous tumors are polyclonal or monoclonal in origin. We have examined the genetic alterations of the TP53 gene in a cohort of patients with urothelial cancer who underwent multiple biopsies at different times and sites because of tumor recurrence and/or progression. We postulated that if tumor cells at different points in the natural history of the disease contain an identical mutation in the TP53 gene, this pattern could provide evidence for the monoclonality of the recurrent bladder tumors. EXPERIMENTAL DESIGN: Fifty-three biopsy specimens from 13 patients at different times and sites were selected for this study. Microdissection was used to ensure the purity of tumor cells. DNA extraction, PCR, and direct sequencing of exons 5 through 8 of the TP53 gene were conducted following protocols optimized in our laboratory. RESULTS: We found that specimens from seven patients carried tumor-specific TP53 mutations. The number of lesions in these patients ranged from two to seven, extending from 2 to 4 years. All of the seven patients displayed identical mutations in the different microdissected tumors. CONCLUSIONS: On the basis of these data, it appears that the recurrent bladder tumors originate from the same clone.
UI - 21468611
AU - Aben KK; Witjes JA; van Dijck JA; Schalken JA; Verbeek AL; Kiemeney LA
TI - Lower incidence of urothelial cell carcinoma due to the concept of a clonal origin.
SO - Eur J Cancer 2000 Dec;36(18):2385-9
AD - Department of Epidemiology, University Medical Centre Nijmegen, The Netherlands.
Synchronous and metachronous tumours are frequently observed in the urinary tract and may be explained by the concept of field cancerisation, i.e. exposure to carcinogens leads to independent transformation of many urothelial cells resulting in genetically unrelated tumours. However, increasing evidence supports the concept of clonality, i.e. the progeny of a single transformed cell spreads through the urinary system resulting in genetically related tumours. The aim of this study was to review the molecular biological evidence for both concepts and to assess the consequences of a clonality assumption on the incidence of urothelial cell carcinoma (UCC). In total 1198 non-invasive and 1113 invasive (> or = T1) UCCs of the bladder were registered as incident tumours in 1996-1997 by three Dutch cancer registries following the current registration rules of the International Association of Cancer Registries (IACR). Assuming clonality, the number of non-invasive and invasive bladder UCCs decreased by 10.9% and 11.5% respectively. A decline of 8.5% and 9.5% was found for UCCs of the ureter and renal pelvis, respectively. Current registration rules have substantial impact on the incidence estimates of UCC. New insights into the molecular biology of UCC should be translated into registration rules.
UI - 21369747
AU - Ferries E; Connan F; Pages F; Gaston J; Hagnere AM; Vieillefond A;
TI - Thiounn N; Guillet J; Choppin J Identification of p53 peptides recognized by CD8(+) T lymphocytes from patients with bladder cancer.
SO - Hum Immunol 2001 Aug;62(8):791-8
AD - INSERM U445, Laboratoire Associe No9 du Comite de Paris de la Ligue contre le Cancer, Institut Cochin de Genetique Moleculaire, Universite Rene Descartes, Paris, France. email@example.com
In many types of cancer, p53 frequently accumulates in tumor cells and anti-p53 antibodies can be detected. However, only four CD8(+) T-cell epitopes from p53 have been identified in humans so far. To further analyze the development of a T-cell response against p53, peptides having binding motifs specific for HLA-A1, -A2, -A3, -A24, -B7, -B35, -B44, and -B51 molecules have been defined. The HLA-binding capacity of those peptides was tested, and the stability of formed complexes was defined. Thirteen peptides that bound to HLA-A24 and -B44 molecules are presented. The positive peptides were then used to detect the anti-p53 response of CD8(+) T lymphocytes from patients with bladder cancer. Six peptides, presented by HLA-A2, -B51, or -A24, were able to stimulate T cells from two patients (among 16) with tumor cells that strongly accumulated p53. On the contrary, p53 peptides systematically failed to stimulate T cells from healthy donors or patients with low or undetectable levels of p53 in their tumor cells. These results have led to the identification of four new potential T CD8(+) epitopes from p53: 194-203 associating with HLA-B51 and 204-212, 211-218, and 235-243 associating with HLA-A24.
UI - 21384899
AU - van der Poel HG; Debruyne FM
TI - Can biological markers replace cystoscopy? An update.
SO - Curr Opin Urol 2001 Sep;11(5):503-9
AD - Department of Urology, Antoni van Leeuwenhoek Hospital/NKI, Amsterdam, The Netherlands. firstname.lastname@example.org
Cystoscopy is currently considered the gold standard for the detection of bladder tumors. The role of urine cytology in the initial detection and follow-up of patients is under discussion. New elaborative and rapid assays are available that may circumvent the low sensitivity and poor reproducibility of urine cytology. The methods that have been tested extensively are the nuclear matrix protein (NMP22) assay, the BTA stat assay, and the BTA TRAK enzyme-linked immunosorbent assay. Both outperform cytology in the detection of low-grade lesions. The specificity of both assays, however, lags behind that of cytology. The data from retrospective analyses are insufficient to justify clinical integration, and the need to replace cystoscopy with these novel assays remains to be proven.
UI - 21384900
AU - Oosterlinck W
TI - Recent clinical trials in superficial bladder cancer.
SO - Curr Opin Urol 2001 Sep;11(5):511-5
AD - Department of Urology, University Hospital Ghent, Ghent, Belgium. email@example.com
The present review addresses literature regarding the management of definitive winner among urinary markers of bladder cancer, because they lack specificity or are insufficiently tested. Pathologists continue in their efforts to improve prediction of evolution of superficial bladder cancer to recurrent or infiltrative disease. A few studies have confirmed the value of previously described prognostic factors for recurrence and progression, and have added some refinements. Transurethral resection is not as complete as was believed. Fluorescence detection of flat bladder carcinoma has been demonstrated to improve diagnosis and treatment. The necessity to perform a repeat transurethral resection in high-grade superficial bladder cancer became evident. Identification of the working mechanisms of bacille Calmette-Guerin on superficial bladder cancer remains an important objective, and may help to improve treatment schedules and avoid the morbidity associated with bacille Calmette-Guerin administration. Patients who are at high risk may benefit from long-term maintenance bacille Calmette-Guerin therapy. Valrubicin and keyhole limpet haemocyanin appear to be promising agents in the treatment of superficial bladder cancer.
UI - 21384901
AU - Bellmunt J; Albiol S
TI - New chemotherapy combinations for advanced bladder cancer.
SO - Curr Opin Urol 2001 Sep;11(5):517-22
AD - Medical Oncology Service, General University Vall d'Hebron Hospital, Barcelona, Spain. firstname.lastname@example.org
Transitional cell carcinoma of the urothelium is considered a chemosensitive malignancy. Until recently, the methotrexate, vinblastine, doxorubicin and cisplatin combination has been considered the standard for treating this disease. The development of new chemotherapeutic agents such as gemcitabine and the taxanes has opened up promising new perspectives in the treatment of this disease. However, the preliminary phase II data must be confirmed in adequately conducted phase III trials.
UI - 21384902
AU - Sternberg CN
TI - Second-line treatment of advanced transitional cell carcinoma of the urothelial tract.
SO - Curr Opin Urol 2001 Sep;11(5):523-9
AD - Vincenzo Pansadoro Foundation, Clinic Pio XI, Rome, Italy. email@example.com
Cisplatin-based combination chemotherapy such as methotrexate, vinblastine, adriamycin and cisplatin produces durable improvements in survival in only a minority of patients. Therefore, other therapeutic options and strategies are clearly needed. Strategies include increasing the dose of chemotherapy, modifying the sequencing of chemotherapy, and new therapeutic agents. This paper reviews recent work on high-dose chemotherapy, currently available chemotherapeutic agents and combinations, with an emphasis on gemcitabine and the taxanes. New strategies such as monoclonal antibody therapy and molecular targeted small molecule therapy are becoming a reality in the treatment of many diseases. The rationale for using epidermal growth factor receptor targeted therapies is also reviewed.
UI - 21356591
AU - Brandau S; Bohle A
TI - Bladder cancer. I. Molecular and genetic basis of carcinogenesis.
SO - Eur Urol 2001 May;39(5):491-7
AD - Division of Immunotherapy, Research Center Borstel, Medical University of Lubeck, Germany.
The transformation of a normal into a malignant cell is a multistep mechanism, which involves various alterations on the molecular and genetic level. These molecular alterations occur spontaneously or are induced by carcinogens (e.g. naphthylamine--a component of cigarette smoke and one of the most important carcinogens leading to bladder tumor carcinogenesis). This report summarizes some of the most important molecular and genetic alterations in bladder cancer. As in most other malignancies the generation of bladder cancer is caused by the accumulation of various molecular changes. The expression of oncogenes (ras, erbB-2 and EGF receptor), tumor-suppressor genes (Rb, p53), cell-cycle genes (p15, p16) and DNA-repair genes is altered mostly by mutation or chromosomal aberration. Loss of heterozygosity of chromosome 9p and 9q has been shown to be a crucial event in the transition of normal urothelium to papillary transitional cell carcinoma while p53 is primarily involved in the development of carcinoma in situ.
UI - 21356592
AU - Kausch I; Bohle A
TI - Bladder cancer. II. Molecular aspects and diagnosis.
SO - Eur Urol 2001 May;39(5):498-506
AD - Immunotherapy Research Group, Research Center Borstel, and Department of Urology, Medical University of Lubeck, Germany.
The current system used to classify bladder carcinoma by stage and histological grade is very useful, yet still has limited ability to predict the natural history, or treated natural history, of a bladder tumor. Cystoscopy and urine cytology are currently the gold standard in the diagnosis and follow-up of bladder cancer. Classical urine cytology, however, at least in the diagnosis of G1 tumors, is definitely characterized by a relative low sensitivity. The low sensitivity and subjective interpretation of cytology led to the development of several tests to detect bladder cancer in urine. We provide a current, comprehensive review of the literature on bladder tumor markers and summarize their diagnostic potential. In conclusion, under the premise that cystoscopy has never been subjected to evaluation, no diagnostic marker with a sensitivity and specificity comparable to cystoscopy currently exists. The combined analysis of several tumor markers, as in the Immunocyt test, seems to be the most promising approach. In the future, rather highly sensitive tests may be able to replace cystoscopy or prolong the intervals of cystoscopies in the follow-up of selected patients.
UI - 21356593
AU - Retz M; Lehmann J; Roder C; Weichert-Jacobsen K; Loch T; Romahn E; Luhl
TI - C; Kalthoff H; Stockle M Cytokeratin-20 reverse-transcriptase polymerase chain reaction as a new tool for the detection of circulating tumor cells in peripheral blood and bone marrow of bladder cancer patients.
SO - Eur Urol 2001 May;39(5):507-15; discussion 516-7
AD - Section of Experimental Urology, Department of Urology, Medical School, Christian Albrechts University of Kiel, Germany. firstname.lastname@example.org
OBJECTIVES: Systemic progression is the prevalent form of bladder tumor recurrence after radical cystectomy. The ability to detect circulating tumor cells in peripheral blood or bone marrow could be of prognostic value for the disease with the consequence of early adjuvant chemotherapy. We established a sensitive and specific method using a double cytokeratin-20 (CK-20) reverse-transcriptase polymerase chain reaction (RT-PCR) to detect circulating bladder cancer cells in venous blood and bone marrow MATERIAL AND METHODS: The sensitivity of the detection method was determined by a serial dilution of bladder cancer cells from the cell line HT1376 in whole blood. Bone marrow from 20 bladder cancer patients was drawn prior to radical cystectomy and CK-20 cDNA was amplified by RT-PCR. Additionally, pre- and postoperative venous blood samples from 11 of these patients with bone marrow aspirates and 9 patients undergoing only transurethral resection of the bladder as well as blood samples of 25 healthy volunteers were investigated by CK-20 RT-PCR. RESULTS: The detection limit of the method was 2 bladder cancer cells/ml whole blood containing one million peripheral blood mononuclear cells. The positive detection rate in bone marrow was 7 of 20 (35%) for bladder cancer patients of all stages. However, investigation of the preoperatively collected venous blood samples from 20 patients revealed onyl 2 positive findings, belonging to advanced tumor stages pT4pN0M0 and pT3pN2M0. In contrast, CK-20 was detected in 3 of 20 postoperatively collected venous blood samples from patients with low tumor stages (pTaNXM0 and pT1NXM0) as well as from 1 patient with pelvic lymph node metastases (pT3apN2M0). All venous blood samples of the control group (n = 25) were negative for CK-20. CONCLUSION: The detection of circulating bladder tumor cells in venous blood and bone marrow by the CK-20 RT-PCR is a promising approach that could improve risk assessment and the identification of bladder cancer patients who would benefit from adjuvant chemotherapy.
UI - 21411332
AU - Cheng L; Bostwick DG; Li G; Zhang S; Vortmeyer AO; Zhuang Z
TI - Conserved genetic findings in metastatic bladder cancer: a possible utility of allelic loss of chromosomes 9p21 and 17p13 in diagnosis.
SO - Arch Pathol Lab Med 2001 Sep;125(9):1197-9
AD - Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. email@example.com
CONTEXT: Molecular analysis of microsatellite alterations of biologically distinct tumor cell subpopulations from the same patient may aid in the determination of tumor origin and further our understanding of the genetic basis of cancer progression. DESIGN: The authors examined the pattern of allelic loss with polymorphic microsatellite markers on chromosome 9p21 (D9S161, D9S171, IFNA), regions of putative tumor suppressor gene p16, and on chromosome 17p13 (TP53), the p53 locus, in matched primary and metastatic bladder cancers from 9 patients. All patients underwent cystectomy for bladder cancer and had regional lymph node metastases at the time of surgery. Genomic DNA was prepared from primary cancers and matched synchronous lymph node metastases using a microdissection method. RESULTS: The overall frequency of allelic loss was 78% in primary cancer and 89% in paired metastatic cancer. The frequency of allelic loss in the primary cancer was 86% with D9S161, 67% with D9S171, 71% with IFNA, and 80% with TP53. The frequency of allelic loss in matched metastatic cancer was 100% with D9S161, 62% with D9S171, 71% with IFNA, and 80% with TP53. An identical pattern of allelic imbalance (allelic loss or retention) at multiple DNA loci was observed in matched primary and metastatic carcinoma in 8 (88%) cases. One case showed allelic loss in the metastasis, but not in the primary cancer. CONCLUSIONS: The pattern of allelic loss at chromosome 9p21 (p16) and 17p13 (p53) was generally maintained during cancer progression to metastasis, and identical allelic loss in primary cancer was conserved in paired metastatic carcinoma. These data suggest that these genetic changes may be useful in establishing a diagnosis and determining tumor origins in difficult cases.
UI - 21433378
AU - Bornman DM; Mathew S; Alsruhe J; Herman JG; Gabrielson E
TI - Methylation of the E-cadherin gene in bladder neoplasia and in normal urothelial epithelium from elderly individuals.
SO - Am J Pathol 2001 Sep;159(3):831-5
AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Decreased expression of the epithelial cell adhesion protein E-Cadherin occurs in several forms of human epithelial-derived cancers, including bladder cancers. We investigated the possibility that aberrant methylation of the CpG island flanking the 5' transcriptional start site of the e-cadherin gene is responsible for the decreased expression of this gene in bladder cancer, similar to the relationship previously seen between e-cadherin methylation and gene expression in other types of human cancers. Using methylation-specific polymerase chain reaction, we found methylation of this CpG island in 20 of 47 cases (43%) of bladder neoplasms ranging from low-grade papillary neoplasms to advanced, invasive cancers. When methylation status was compared to immunochemical staining for E-Cadherin, we found significantly diminished levels of E-Cadherin expression in 14 of 15 cases (93%) with methylation of the gene. We also found decreased expression of E-Cadherin, although to a somewhat lesser extent, in a high percentage (77%) of the cases without methylation of the gene. Although these data suggest a relationship between e-cadherin CpG island methylation and decreased gene expression, it evident that other mechanisms also contribute to decreased expression of this gene in bladder neoplasia. Remarkably, we also found low levels of e-cadherin methylation in urothelial cells from three of nine (33%) histologically normal bladders, with all three of the normal bladder samples with methylated e-cadherin being from individuals older than 70 years of age. Thus, methylation of the e-cadherin CpG island may occur normally in this tissue with aging as well as in low-grade papillary neoplasms, and is not specific to cancer in the bladder. This finding of methylation in normal urothelial cells from elderly individuals is provocative with respect to a possible link between aging and increased risk for bladder cancer, but it suggests limitations on the usefulness of using methylation of e-cadherin as a molecular marker for detection of bladder cancer.
UI - 21443276
AU - Lee MG; Kim HY; Byun DS; Lee SJ; Lee CH; Kim JI; Chang SG; Chi SG
TI - Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma.
SO - Cancer Res 2001 Sep 15;61(18):6688-92
AD - Department of Pathology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Allelic deletion or transcriptional silencing of RASSF1, a putative tumor suppressor at 3p21.3, has been found in a considerable proportion of lung, breast, and ovarian cancers. In this study, we analyzed the expression and mutation status of three RASSF1 isoforms (-A, -B, and -C) in 55 primary bladder carcinomas and 10 bladder and prostate cancer cell lines. The RASSF1A transcript was not found in 80% (4 of 5) and 100% (4 of 4) of bladder and prostate cell lines, respectively. Compared with normal bladder tissues, loss or significant reduction of RASSF1A was identified in 62% (34 of 55) of primary bladder carcinomas and 10 (83%) of 12 matched sets showed tumor-specific alteration of RASSF1A expression. Moreover, loss or abnormal down-regulation of RASSF1A correlated with advanced tumor stage. RASSF1B was undetectable in 60% (3 of 5) of bladder cell lines and in 31% (17 of 55) of primary tumors, but none of these tumors showed altered expression exclusively in RASSF1B. RASSF1C transcript was detected in all cell lines and primary tumors we examined. Expression of RASSF1A and RASSF1B was reactivated in all nonexpressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Bisulfite DNA sequencing analysis revealed that aberrant hypermethylation at the CpG island in the RASSF1A promoter is strongly associated with the loss of RASSF1A expression in cell lines and uncultured primary tumors. Methylation-specific PCR and BstUI digestion analyses also demonstrated that 97% (33 of 34) of RASSF1A-nonexpressing primary tumors are methylated. Although somatic mutations were not identified in RASSF1 transcripts expressed in unmethylated tumors, 24% (9 of 37) of methylated cell lines and primary tumors showed detectable reductions in genomic levels of RASSF1, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of bladder tumors. Together, our data suggest that RASSF1A inactivation may play a critical role in the malignant progression of human bladder carcinomas.
UI - 21381744
AU - Jimenez RE; Hussain M; Bianco FJ Jr; Vaishampayan U; Tabazcka P; Sakr
TI - WA; Pontes JE; Wood DP Jr; Grignon DJ Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors.
SO - Clin Cancer Res 2001 Aug;7(8):2440-7
AD - Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.
UI - 21381747
AU - Ohta JI; Miyoshi Y; Uemura H; Fujinami K; Mikata K; Hosaka M; Tokita Y;
TI - Kubota Y Fluorescence in situ hybridization evaluation of c-erbB-2 gene amplification and chromosomal anomalies in bladder cancer.
SO - Clin Cancer Res 2001 Aug;7(8):2463-7
AD - Departments of Urology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Oncogene amplification and chromosomal anomalies are found in many solid tumors and are often associated with aggressiveness of cancer. We evaluated the frequency and the role of c-erbB-2 gene amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 in bladder cancer. A total of 29 bladder cancer specimens were examined using fluorescence in situ hybridization (FISH). Dual labeling hybridization with a directly labeled centromere probe for chromosome 17 together with a probe for the c-erbB-2 locus was performed. c-erbB-2 gene amplification was found in 3.4% (1 of 29) of specimens. Relative increase in c-erbB-2 gene copy number was found in 41.4% (12 of 29) of specimens and was significantly associated with tumor grade (P = 0.044 by Fisher's exact test). Gain of chromosome 17 was identified in 65.5% (19 of 29) of specimens and was significantly associated with tumor grade (P = 0.002 by Fisher's exact test) and tumor stage (P = 0.003 by Fisher's exact test). Our results suggest that c-erbB-2 gene amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 may play important roles in the development and progression of bladder cancers. Moreover, the use of c-erbB-2 amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 using FISH, together with tumor grade and stage, may provide a more useful clinical indicator in bladder cancer.
UI - 21433337
AU - Pfau P; Chak A
TI - Detection of preinvasive cancer cells: early-warning changes in precancerous epithelial cells can now be spotted in situ and Endoscopic detection of dysplasia in patients with Barrett's esophagus using light-scattered spectroscopy.
SO - Gastrointest Endosc 2001 Sep;54(3):414-6
UI - 21438129
AU - Wolf HK; Stober C; Hohenfellner R; Leissner J
TI - Prognostic value of p53, p21/WAF1, Bcl-2, Bax, Bak and Ki-67 immunoreactivity in pT1 G3 urothelial bladder carcinomas.
SO - Tumour Biol 2001 Sep-Oct;22(5):328-36
AD - Department of Pathology, University of Mainz, Germany. firstname.lastname@example.org
pT1 G3 bladder carcinomas are heterogeneous with respect to tumor recurrence and progression. Whereas some urologists treat these carcinomas by repeated transurethral resections often followed by intravesical chemotherapy or BCG instillation, others recommend cystectomy after tumor recurrence or early cystectomy after the initial diagnosis. Our goal was to determine the prognostic value of p53, p21/WAF1, Bcl-2, Bax, Bak, and Ki-67 immunoreactivity in these tumors. There were 30 patients with a new histopathological diagnosis of pT1 G3 urothelial carcinoma based on a transurethral resection specimen. Representative sections of these specimens were examined for the above markers. All patients were followed up regularly and were classified as being tumor free or having tumor recurrence or progression. The mean follow-up period was 43 months (range: 8-102 months). Twenty-five patients underwent radical cystectomy and 7 of these (28%) suffered from tumor progression and died of bladder cancer. In 5 patients, surgery was limited to a transurethral resection and 4 of these patients developed superficial tumor recurrence. There was a significant difference in tumor-free survival between patients with p53-immunoreactive (mean: 30 months) and p53-negative tumors (mean: 82 months; p = 0.0341). Bcl-2 positivity was also associated with decreased tumor-free survival (p = 0.043). The other markers had no significant prognostic impact. We conclude that p53 and Bcl-2 immunoreactivity labels the most aggressive pT1 G3 bladder carcinomas. Copyright 2001 S. Karger AG, Basel
UI - 21450702
AU - Milord RA; Lecksell K; Epstein JI
TI - An objective morphologic parameter to aid in the diagnosis of flat urothelial carcinoma in situ.
SO - Hum Pathol 2001 Sep;32(9):997-1002
AD - Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
The diagnosis of carcinoma in situ (CIS) lacks objective criteria and is subject to misdiagnosis. We identified 20 bladder biopsy cases each of CIS, urothelial dysplasia, and normal urothelium according to the 1998 World Health Organization/International Society of Urological Pathology consensus classification of urothelial neoplasms. Lymphocytes from 10 bladder biopsy specimens were chosen as reference cells. Using an image analysis system, we measured the following nuclear features: area, diameter, roundness, ellipticity, and optical density (maximum, minimum, mean, median, standard deviation, and quartiles). We measured a mean of 75 urothelial nuclei/case and a total of 500 lymphocytes. Roundness and ellipticity were not useful in distinguishing among the 3 groups. The best discriminators were mean nuclear area and mean nuclear area of the 25% largest nuclei (upper quartile) of urothelial cells compared with lymphocytes. The mean nuclear area relative to lymphocytes was 1.8 times (1.2 to 2.5 times) in normal urothelium, 2.4 times (1.6 to 3.0 times) in urothelial dysplasia, and 3.6 times (2.8 to 5.7 times) in CIS. The mean upper quartile nuclear area relative to lymphocytes was 2.2 times (1.4 to 2.8 times) in normal urothelium (P <.0001), 2.9 times (1.8 to 3.6 times) in urothelial dysplasia (P <.0001), and 4.9 times (4.0 to 7.6 times) in CIS (P <.0001). The difference in optical density was statistically significant between CIS and the other 2 histologic categories (P <.0001). Nuclear area is an easy and objective morphologic parameter for the evaluation of bladder biopsy specimens. Pathologists can assess the size of urothelial nuclei without using an image analysis system and compare them with the size of nuclei of lymphocytes, which are almost always present in a bladder biopsy specimen. Dysplasia, which is a somewhat ambiguous lesion, overlaps in its measurements with those of benign urothelium. The most useful morphologic parameter is the mean nuclear area of the 25% largest nuclei; CIS nuclei are approximately 5 times the size of lymphocytes, whereas normal urothelial nuclei are only 2 times the size of lymphocytes. Copyright 2001 by W.B. Saunders Company
UI - 21341702
AU - Chow NH; Chan SH; Tzai TS; Ho CL; Liu HS
TI - Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder.
SO - Clin Cancer Res 2001 Jul;7(7):1957-62
AD - Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 70428, Republic of China.
In vitro experiments have demonstrated that epidermal growth factor (EGF)-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. The implications of cross-talk among ErbB family receptors in human cancer, however, remain to be clarified. This cohort study was performed to examine the expression patterns of ErbB receptors by immunohistochemistry in primary human bladder cancer (n = 245) and compared with conventional biological indicators for their prognostic significance. Expression of individual EGF receptor (EGFR) and ErbB2, ErbB3, or ErbB4 receptors was detected in 72.2, 44.5, 56.3, and 29.8% of bladder cancer cases, respectively. Expression of two of the receptors varied from 14.7 to 42.4%, of three of the receptors between 11.0 and 22.0%, and of all four of the ErbB receptors by 8.6%. Important indicators in association with patient survival were tumor staging (P = 0.017), ErbB2 (P = 0.018), EGFR-ErbB2 (P = 0.023), and ErbB2-ErbB3 (P = 0.042). In the subset of grade-2 tumors, EGFR-ErbB2-ErbB3 and EGFR-ErbB2 predicted the development of second recurrence (P = 0.026 and 0.039, respectively), and ErbB2-ErbB3 tended to correlate with patient survival (P = 0.09). The results indicate that a combination of EGFR, ErbB2, and ErbB3 expression profile may be a better prognostic indicator than any family member alone. Given that ErbB2 is the preferred coexpression partner of ErbB family members, expression of other ErbB receptors may significantly affect the prognostic implication of ErbB2 for bladder cancer patients.
UI - 21426574
AU - Gontijo AM; Elias FN; Salvadori DM; de Oliveira ML; Correa LA; Goldberg
TI - J; Trindade JC; de Camargo JL Single-cell gel (comet) assay detects primary DNA damage in nonneoplastic urothelial cells of smokers and ex-smokers.
SO - Cancer Epidemiol Biomarkers Prev 2001 Sep;10(9):987-93
AD - Departamentos de Patologia, Faculdade de Medicina, Universidade Estadual Paulista, 18618-000, Botucatu, Sao Paulo, Brazil.
A protocol for DNA damage assessment by the single-cell gel (SCG)/comet assay in human urinary bladder washing cells was established. Modifications of the standard alkaline protocol included an increase to 2% of sodium sarcosinate in the lysis solution, a reduction in the glass-slide area for comet analysis, and a cutoff value for comet head diameter of at least 30 microm, to exclude contaminating leukocytes. Distinguishing cell populations is crucial, because significant differential migration was demonstrated for transitional and nontransitional cells, phenomena that may confound the results. When applying the modified protocol to urinary bladder cells from smokers without urinary bladder neoplasia, it was possible to detect a significant (P = 0.03) increase in DNA damage as depicted by the tail moment (6.39 +/- 3.23; mean +/- 95% confidence interval; n = 18) when compared with nonsmokers (1.94 +/- 1.41; n = 12). No significant differences were observed between ex-smokers and current smokers regarding comet parameters. Inflammation was not a confounding factor, but DNA migration increased significantly with age in nonsmokers (r = 0.68; P = 0.014). Thus, age matching should be a concern when transitional cells are analyzed in the SCG assay. As it is well known, DNA damage may trigger genomic instability, a crucial step in carcinogenesis. Therefore, the present data directly support the classification of individuals with smoking history as patients at high risk for urinary bladder cancer.
UI - 21227050
AU - Sakamoto N; Naito S; Kumazawa J; Ariyoshi A; Osada Y; Omoto T; Fujisawa
TI - Y; Morita I; Yamashita H; The Kyushu University Urological Oncology Group Prophylactic intravesical instillation of mitomycin C and cytosine arabinoside for prevention of recurrent bladder tumors following surgery for upper urinary tract tumors: a prospective randomized study.
SO - Int J Urol 2001 May;8(5):212-6
AD - Department of Urology, Graduate School of Medical Sciences, Kyushu University, Japan.
BACKGROUND: A recurrence of bladder tumors following surgery for transitional cell carcinoma of the upper urinary tract is not rarely observed. A prospective randomized study was conducted to examine the significance of prophylactic intravesical instillation of mitomycin C (MMC) and cytosine arabinoside (Ara-C) to prevent recurrent bladder tumors after surgery for superficial transitional cell carcinoma of the upper urinary tract. METHODS: The patients were randomized into an instillation group, who received postoperative intravesical instillation of MMC (20 mg) and Ara-C (200 mg) 28 times over a period of 2 years, and a non-instillation group. The non-recurrence
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