UMLS:C0005684 - FACTA Search

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Query: UMLS:C0005684 (bladder cancer)
16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topical application of 5-aminolevulinic acid (5-ALA), with subsequent synthesis of protoporphyrin IX (PPIX), is a novel outstanding procedure for photodynamic treatment. So far, clinical experience has been reported with creams containing 5-ALA for the therapy of skin cancer, oral application for the treatment of gastrointestinal disease and intravesical instillation of 5-ALA solutions for fluorescence detection of superficial bladder cancer. Inhalation of 5-ALA for the staining of bronchial malignancies is a preferred method in clinical pulmonology. Since no adverse reaction was observed in lung function in a canine following inhalation of 5-ALA in increasing concentrations, clinical applications were performed. Seven patients with positive or suspicious sputum cytology, but negative white light bronchoscopy, received 5-10 wt.% 5-ALA in NaCl solution by means of a medical nebulizer. No side effects were observed during and after 5-ALA inhalation. After a period of 3 h, patients underwent fluorescence bronchoscopy using violet light for fluorescence excitation and an optical multichannel analyzer for fluorescence detection in situ. The results showed fluorescence spectra which could be related to PPIX induced by 5-ALA in the bronchial mucosa. The fluorescence intensity was sufficiently high for video imaging using a target integrating color CCD camera adapted to the flexible bronchoscope. Carcinoma in situ, as well as dysplasias, showed a clear positive fluorescence. A correlation of fluorescence contrast with histology on 30 biopsies revealed a high sensitivity, but a specificity below 50%. Improvements in light and drug dosimetry will form the basis for further clinical trials.
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PMID:Inhalation of 5-aminolevulinic acid: a new technique for fluorescence detection of early stage lung cancer. 900 54

The use of a photodynamic fluorescence marker for diagnosis of tumors is an intriguing concept to improve thoroughness of surgical tumor resection. Complete surgical resection of multifocal bladder tumors and flat lesions as carcinoma in situ is known to be difficult, and thus a source of recurrencies. We report on the recent experience with the intravesical application of the photosensitizer prodrug 5-aminolevulinic acid (5-ALA), which is a nontoxic physiological heme substrate. Initial results from fluorescence diagnosis using krypton laser light and recent results with a modified incoherent light source constantly showed a 25% increase in urothelial tumor detection compared with white light endoscopy. Because of the high sensitivity, the number of biopsies could be decreased constantly compared with routine random biopsies taken under white light endoscopy. The results show about 25% to 30% of cases with fluorescent lesions, which are histologically benign. 5-ALA is a promising tool for diagnosis of bladder cancer. The outcome of the initial study of 5-ALA in urology in Germany is positive and is continued by prospective multicenter clinical studies to prove the hypothesis of reduction of tumor recurrence with this method. 5-ALA-based fluorescence endoscopy is strongly recommended for further clinical testing.
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PMID:Photodynamic cystoscopy for detection of bladder tumors. 1045 62

The use of a photodynamic fluorescence marker for diagnosis of tumors is an intriguing concept to improve the thoroughness of surgical tumor resection. Complete surgical resection of multifocal bladder tumors and flat lesions such as carcinoma in situ is known to be difficult, and thus a source of recurrences. We report on the recent experience with the intravesical application of the photosensitizer prodrug 5-aminolevulinic acid (5-ALA), which is a nontoxic physiological heme substrate. Initial results from fluorescence diagnosis using krypton laser light, and recent results with a modified incoherent light source constantly showed a 25% increase in urothelial tumor detection in comparison to white light endoscopy. Due to the high sensitivity, the number of biopsies could be decreased constantly in comparison to routine random biopsies taken under white light endoscopy. The results show about 25-30% of cases with fluorescent lesions which are histologically benign. 5-ALA is a promising tool for the diagnosis of bladder cancer. The outcome of the admission study for 5-ALA in urology in Germany is positive, and is being continued by prospective multicenter clinical studies to prove the hypothesis of reduction of tumor recurrence with this method. 5-ALA-based fluorescence endoscopy is strongly recommended for further clinical testing.
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PMID:5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower urinary tract tumors. 1059 87

Flat urothelial hyperplasia, defined as markedly thickened urothelium without cytological atypia, is regarded in the new WHO classification as a urothelial lesion without malignant potential. Frequent deletions of chromosome 9 detected by fluorescence in situ hybridization (FISH) have been previously reported in flat urothelial hyperplasias found in patients with papillary bladder cancer. Using comparative genomic hybridization (CGH) and microsatellite analysis, these hyperplasias and concomitant papillary tumours of the same patients were screened for other genetic alterations to validate and extend the previous findings. Eleven flat hyperplasias detected by 5-ALA-induced fluorescence endoscopy and ten papillary urothelial carcinomas (pTaG1-G2) from ten patients were investigated. After microdissection, the DNA of the lesions was pre-amplified using whole genome amplification (I-PEP-PCR). Loss of heterozygosity (LOH) analyses were performed with five microsatellite markers at chromosomes 9p, 9q, and 17p. CGH was performed using standard protocols. In 6 of 11 hyperplasias and 7 of 10 papillary tumours, deletions at chromosome 9 were simultaneously shown by FISH, LOH, and CGH analyses. There was a good correlation between FISH, LOH, and CGH analyses, with identical results in 6 of 10 patients. In addition to deletions at chromosome 9, further genetic alterations were detected by CGH in 9 of 10 investigated hyperplasias, including changes frequently found in invasive papillary bladder cancer (loss of chromosomes 2q, 4, 8p, and 11p; gain of chromosome 17; and amplification at 11q12q13). There was considerable genetic heterogeneity between hyperplasias and papillary tumours, but a clonal relationship was suggested by LOH and/or CGH analyses in 5 of 10 cases. These data support the hypothesis that flat urothelial hyperplasias can display many genetic alterations commonly found in bladder cancer and could therefore be an early neoplastic lesion in the multistep development of invasive urothelial carcinoma.
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PMID:Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. 1247 26

5-aminolevulinic acid mediated changes in tissue specific fluorescence were studied in bladder cancer. Bladders of normal patients and also patients diagnosed with cancer were instilled with 5-aminolevulinic acid and the resultant protoporphyrin IX mediated fluorescence intensity was imaged and quantified with confocal laser microscopy and fluorescence image analysis. Urothelial tumour cells were observed to fluoresce more intensely than normal urothelial cells. Submucosa and muscle tissues exhibited minimal fluorescence compared to urothelial cells of malignant origin and also normal urothelial cells. Degree of fluorescence intensity was in the order of malignant urothelium > normal urothelium > normal submucosa > normal muscles. Fluorescence intensity was also found to increase with duration of ALA instillation. Grade 3 malignant cells produced more fluorescence compared to grade 2 and grade 1. Similarly, T1 transitional cell carcinoma (TCC) showed increased fluorescence intensity than that of Ta TCC. Also, tumour blood vessels fluoresced more intensely compared to blood vessels found in normal bladder tissue. Tissue specific ALA mediated PpIX micro fluorescence can be used as a diagnostic technique for early detection of neoplasms and confocal laser microscopy and fluorescence image analysis are advantageous diagnostic tools for the photodynamic diagnosis of bladder neoplasms in vivo.
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PMID:Fluorescence confocal microscopy and image analysis of bladder cancer using 5-aminolevulinic acid. 1257 4

A photosensitizer is defined as a chemical entity, which upon absorption of light induces a chemical or physical alteration of another chemical entity. Some photosensitizers are utilized therapeutically such as in photodynamic therapy (PDT) and for diagnosis of cancer (fluorescence diagnosis, FD). PDT is approved for several cancer indications and FD has recently been approved for diagnosis of bladder cancer. The photosensitizers used are in most cases based on the porphyrin structure. These photosensitizers generally accumulate in cancer tissues to a higher extent than in the surrounding tissues and their fluorescing properties may be utilized for cancer detection. The photosensitizers may be chemically synthesized or induced endogenously by an intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) or 5-ALA esters. The therapeutic effect is based on the formation of reactive oxygen species (ROS) upon activation of the photosensitizer by light. Singlet oxygen is assumed to be the most important ROS for the therapeutic outcome. The fluorescing properties of the photosensitizers can be used to evaluate their intracellular localization and treatment effects. Some photosensitizers localize intracellularly in endocytic vesicles and upon light exposure induce a release of the contents of these vesicles, including externally added macromolecules, into the cytosol. This is the basis for a novel method for macromolecule activation, named photochemical internalization (PCI). PCI has been shown to potentiate the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins, immunotoxins, gene-encoding plasmids, adenovirus, peptide-nucleic acids and the chemotherapeutic drug bleomycin. The background and present status of PDT, FD and PCI are reviewed.
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PMID:Porphyrin-related photosensitizers for cancer imaging and therapeutic applications. 1585 75

Hexyl aminolevulinate [aminolevulinic acid hexyl ester, hexyl 5-aminolevulinate, 5-ALA hexylester, hexaminolevulinate, Hexvix, Hexvix PD, Hexvix PDT, P 1206] is being developed by PhotoCure, a Norwegian company, for the diagnosis and treatment of bladder cancer. The current standard diagnosis of bladder cancer involves cystoscopic examination of urine and bladder washings and is combined with biopsy for better detection of low-grade malignancies. However, the method largely relies on the experience of the surgeon and often results in false negatives especially for low-grade malignancies and pre-cancerous tissues. Photocure believes that imaging with hexyl aminolevulinate (Hexvix) offers significant advantages over standard diagnostic methods for detection of bladder cancer and also can be used in combination with those to ensure the optimal diagnostic accuracy. PhotoCure's procedure for diagnosis of bladder cancer involves filling of the patient's bladder with hexyl aminolevulinate solution and allowing the active agent to accumulate in the cancerous tissue. Following bladder emptying, blue light illumination is applied to the bladder causing red fluorescence that is clearly visible, thus identifying the cancerous tissue. Imaging with hexyl aminolevulinate improves detection of bladder tumours and also can be used together with transurethral resection to check the completeness of tumour removal. PhotoCure is looking for the opportunity to out-license hexaminolevulinate for all regions except the Nordic regions. PhotoCure has proprietary rights for hexyl aminolevulinate from the Norwegian Radium Hospital. Under the terms of the agreement with the Norwegian Radium Hospital, PhotoCure gains an access to, and an option to acquire, all of the new photodynamic therapy technologies developed by the Norwegian Radium Hospital. For its part, PhotoCure provides research and development funding to the Norwegian Radium Hospital. This 3-year agreement was extended in February 2003 until December 2006. PhotoCure and Karl Storz GmbH of Germany have signed a formal collaboration for the development and marketing of hexyl aminolevulinate (Hexvix) and Karl Storz's D-light system. The two systems will be used in the diagnosis of bladder cancer. PhotoCure and Karl Storz GmbH will jointly apply for a marketing approval of hexyl aminolevulinate (Hexvix) and Karl Storz' D-light system in the US for detection of bladder cancer. The D-light system is already approved in Europe. PhotoCure has also formed a collaborative agreement with the Swiss Federal Institute of Lausanne and the Municipal University Hospital in Lausanne. These institutions have conducted preclinical studies and some exploratory clinical research on the active ingredient of Hexvix in approximately 100 patients. The first MAA for hexyl aminolevulinate fluorescence was filed in Sweden, the reference member state, in December 2002, and was approved in September 2004. PhotoCure plans to launch hexyl aminolevulinate in Sweden in June 2005. Phase II clinical trials were conducted in 52 patients with known or suspected bladder cancer at the university clinics in Switzerland, Germany, Sweden and Norway. Clinical data suggests that hexyl aminolevulinate (Hexvix) is useful in the early diagnosis of bladder cancers allowing treatment to be performed at an earlier stage and, thus, improve the chance of a successful clinical outcome. The company believes that the data from the US phase III programme at 19 leading urology clinics and two multicentre European trials at 28 leading hospitals across nine countries, will sufficiently support an NDA with the US FDA. The US phase III programme with hexyl aminolevulinate was initiated in December 2001. The results from the first European multicentre study conducted in 19 centres in 286 patients confirmed the advantages of hexaminolevulinate fluorescence cystoscopy over standard white light cystoscopy in the detection of bladder cancer. The second multicentre phase III study at ten centres in Germany and the Netherlands in 146 patients with known or suspected bladder cancer was sucessfully completed in March 2003. The independent blind reviewer acknowledged that imaging with hexyl aminolevulinate would result in better treatment options in every fifth patient compared with standard cystoscopy. Hexaminolevulinate is also undergoing early feasibility studies for the diagnosis and treatment of gynaecological and gastrointestinal conditions. PhotoCure was granted a European patent No. 0820432 covering hexyl aminolevulinate, an active ingredient used in Hexvix for the diagnosis and treatment of bladder cancer. The company was also granted patents in Australia, China, the Czech Republic, New Zealand, Russia, Singapore, South Korea and the US.
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PMID:Hexyl aminolevulinate: 5-ALA hexylester, 5-ALA hexylesther, aminolevulinic acid hexyl ester, hexaminolevulinate, hexyl 5-aminolevulinate, P 1206. 1599 84

The introduction of lipophilic derivatives of the naturally occurring heme precursor 5-aminolevulinic acid (5-ALA) into photomedicine has led to a true revival of this research area. 5-ALA-mediated photodynamic therapy (PDT) and fluorescence photodetection (FD) of neoplastic disease is probably one of the most selective cancer treatments currently known in oncology. To date, this method has been assessed experimentally for the treatment of various medical indications. However, the limited local bioavailability of 5-ALA has widely prevented its use in daily clinical practice. Although researchers were already aware of this drawback early during the development of 5-ALA-mediated PDT, only recently have well-established concepts in pharmaceutical science been adapted to investigate ways to overcome this drawback. Recently, two derivatives of 5-ALA, methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), gained marketing authorization from the regulatory offices in Europe and Australia. MAL is marketed under the trade name Metvix for the treatment of actinic keratosis and difficult-to-treat basal cell carcinoma. HAL has recently been launched under the trade name Hexvix to improve the detection of superficial bladder cancer in Europe. This review will first present the fundamental concepts underlying the use of 5-ALA derivatives in PDT and FD from a chemical, biochemical and pharmaceutical point of view. Experimental evidences from preclinical data on the improvements and limits observed with 5-ALA derivatives will then be introduced. The state-of-the-art from clinical studies with 5-ALA esters will be discussed, with special emphasis placed on the process that led to the development of MAL in dermatology and to HAL in urology. Finally, we will discuss promising medical fields in which use of 5-ALA derivatives might potentially lead to further use of this methodology in photomedicine.
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PMID:5-Aminolevulinic acid derivatives in photomedicine: Characteristics, application and perspectives. 1654 12

As a disease characterized by a polymorphic and fluctuant nature in its evolution, superficial transitional cell carcinoma of the bladder remains a perpetual therapeutic challenge. This raises a great interest in the development of new diagnostic and therapeutic photodynamic applications. This article describes recent facts in the field of bladder cancer photodiagnosis and gives a survey on ongoing research in photodynamic therapy. Fluorescence cystoscopy induced by different aminolevulinic acid compounds (e.g., ALA-HAL) is well accepted in the urological community as a user-friendly new diagnostic tool in the endoscopic management of bladder tumors and CIS. Photodynamic therapy based on the same photosensitizing agents remains experimental, but recent results raise hopes of new therapeutic directions.
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PMID:Photodynamic applications in superficial bladder cancer: facts and hopes! 1656 34

Flat urothelial hyperplasias (FUHs) in patients with papillary bladder tumours frequently show deletions of chromosome 9, suggesting that FUH could be the first neoplastic step in the development of papillary bladder cancer. FGFR3 mutations are frequent in non-invasive papillary tumours with low risk of progression. Our aim was to investigate the frequency of FGFR3 mutations and deletions of chromosomes 9p/q and 8p/q in FUH. Thirty FUH and 9 simultaneous or consecutive tumours were detected by 5-ALA-based photodynamic cystoscopy. DNA was isolated from frozen sections and whole genome amplification was done by I-PEP-PCR, followed by LOH analysis on chromosomes 8p/q and 9p/q. FGFR3 mutations were detected by SNaPshot analysis. LOH analysis on FUH revealed deletions at 9p/q (11/30, 37%) and 8p/q (3/30, 10%). FGFR3 mutations were found in 7/30 FUH (23%). Only 2 FUH showed an FGFR3 mutation without deletions of chromosome 9. In contrast, 6 FUH revealed chromosome 9 deletions but wild type FGFR3 (p = 0.03). These results suggest that chromosome 9 deletions are the earliest genetic alterations in bladder cancer. The detection of FGFR3 mutations in FUH further supports the role of this lesion as precursor of papillary bladder cancer.
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PMID:Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder. 1657 Feb 85

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