Oligoclonality in Bladder Cancer:: The Implication for Molecular Therapies

Duggan, Brian; Gray, Sam B.; McKnight, J.J.; Watson, Chris; Johnston, S. R.; Williamson, Kate E.

doi:10.1097/01.ju.0000100105.27708.6c

Cited by 62 publications

(27 citation statements)

References 58 publications

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“…However, multiple independent tumor clones secondary to field-cancerization might not be detected using the same molecular diagnostic techniques. In addition, determining the clonal origins of multifocal urothelial carcinomas may affect the development of new therapeutic options, such as gene therapy, which might be more effective against a monoclonal population of tumors than against multifocal tumors that arise independently and that are genetically unrelated (10). A variety of specific molecular genetic alterations have been reported in urothelial carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis

Jones¹,

Wang²,

Eble³

et al. 2005

Clinical Cancer Research

170

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Purpose: Human urothelial carcinoma is thought to arise from a field change that affects the entire urothelium. Multifocality of urothelial carcinoma is a common finding at endoscopy and surgery. Whether these coexisting tumors arise independently or are derived from the same tumor clone is uncertain. Molecular analysis of microsatellite alterations and X-chromosome inactivation status in the cells from each coexisting tumor may further our understanding of urothelial carcinogenesis. Experimental Design: We examined 58 tumors from 21patients who underwent surgical excision for urothelial carcinoma. All patients had multiple separate foci of urothelial carcinoma (two to four) within the urinary tract. Genomic DNA samples were prepared from formalin-fixed, paraffinembedded tissue sections using laser-capture microdissection. Loss of heterozygosity (LOH) assays for three microsatellite polymorphic markers on chromosome 9p21 (IFNA and D9S171), regions of putative tumor suppressor gene p16, and on chromosome17p13 (TP53), the p53 tumor suppressor gene locus, were done. X-chromosome inactivation analysis was done on the urothelial tumors from 11female patients. Results: Seventeen of 21 (81%) cases showed allelic loss in one or more of the urothelial tumors in at least one of the three polymorphic markers analyzed. Concordant allelic loss patterns between each coexisting urothelial tumor were seen in only 3 of 21 (14%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the multiple coexisting urothelial tumors was seen in only 3 of 11 female patients; of these 3 cases, only one displayed an identical allelic loss pattern in all of the tumors on LOH analysis. Conclusion: LOH and X-chromosome inactivation assays show that the coexisting tumors in many cases of multifocal urothelial carcinoma have a unique clonal origin and arise from independently transformed progenitor urothelial cells, supporting the ''field effect'' theory for urothelial carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis

Jones¹,

Wang²,

Eble³

et al. 2005

Clinical Cancer Research

170

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“…To date, 2 hypotheses have been proposed to describe why bladder recurrence occurs after nephroureterectomy [6,26,27] : (1) the intraluminal seeding and implantation 318 of cancer cells and (2) field cancerization. Notably, the 'seeding' hypothesis has been supported by an increasing number of molecular studies [6,27,28] and growing clinical evidence [20] .…”

Section: Discussionmentioning

confidence: 99%

Prevention of Recurrent Bladder Tumors after Nephroureterectomy for Primary Upper Urinary Tract Urothelial Carcinoma: An Individualized Selection Strategy Based on Patient Risk Stratification Is Needed

Long

et al. 2016

Urol Int

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Objective: To evaluate the efficacies of different chemotherapy regimens in different risk sub-groups for the prevention of bladder recurrence after radical nephroureterectomy (RNU). Materials and Methods: Between 2004 and 2012, we recruited 685 patients who underwent RNU for upper tract urothelial carcinoma at 4 Chinese institutions. We assessed whether the type of intravesical chemotherapy regimen affected the bladder recurrence rate in patients with different risk levels after RNU. Results: For all patients, the bladder recurrence rate was lower with intravesical chemotherapy than without, but no significant differences were found between the 2 intravesical chemotherapy regimens (single dose or relatively long-term therapy). We used multivariate analysis to define the risk factors for bladder recurrence and stratified patients into low-, intermediate-, and high-risk sub-groups accordingly. The bladder recurrence rate in the low-risk patients was not significantly different between patients with or without intravesical chemotherapy. However, in the intermediate-risk and high-risk patients, the rate was greater in patients without intravesical chemotherapy than in patients with. Furthermore, the rate was not significantly different between the 2 intravesical chemotherapy regimens in the intermediate-risk patients, while the efficacy of the relatively long-term regimen in high-risk patients remains unclear. Conclusions: Our study showed that an individualized strategy based on patient risk stratification is needed.

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“…This cancer behaviour can be related to the incomplete resection of primary tumor, the polychronotopic urothelial dysplasia preluding tumor development, the presence of undetected flat tumor and the potential cell seeding early after transurethral resection [28]. To date the main goal of reducing recurrence in patients with Ta-T1 NMIBC is obtained by intravesical chemotherapy, even if it does not prevent progression [29]. The European Association of Urology (EAU) guidelines recommend an early single instillation at TURBT in patients with NMIBC [30].…”

Section: Pharmacokinetics Of Chemotherapeutic Agents Administered As mentioning

confidence: 99%

Intravesical Chemotherapy and Chemohyperthermia in Non-Muscle-Invasive Bladder Cancer; An Overview on Drug Administration Technologies and Pharmacokinetics

Campodonico

Stasi

Lev³

et al. 2017

CDM

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Background: Tumor recurrence is the most expected clinical event after the resection of non-muscle invasive bladder cancer, depending on histological findings of the initial lesion. In patients with low and intermediate risk of disease, the intravesical instillation of chemotherapy agents is recommended as a standard treatment to reduce recurrences. Methods:A comprehensive review covering various aspects of different treatments with intravesical drugs is presented.Results: Drugs may be instilled into the bladder starting with a single, 'early' postoperative administration or, after tumor resection with adjuvant intent or, before tumor resection under a neo-adjuvant regimen. Both latter protocols would consist of weekly treatments followed by monthly maintenance treatments. Different methods of administering drugs intravesically have been proposed to enhance the depth of drug penetration and its absorption into the bladder wall thus increasing the rate of drug-DNA reaction. These device-assisted therapies therefore have set a goal to potentiate the drug's effect and efficaciousness. The Radiofrequency-Induced Thermochemotherapeutic Effect (RITE) and the Electromotive-Drug Administration (EMDA) are the two most relevant modalities used to increase the activity of intravesical chemotherapy. Despite the widely adopted international guidelines' recommendations, and recent clinical trials of device-assisted chemotherapy instillations showing markedly enhanced recurrence-free survival compared even to the standard of care, clinicians and pharmacologists are not familiar with the in-depth physical aspects, pharmacokinetics and systemic absorption of chemotherapeutic drugs following their intravesical administration. Conclusion:Knowledge of drug diffusion mechanisms into the tissue and cellular cytoplasm following bladder instillation is a key to understand the safety profile and clinical activity of chemotherapy.

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Oligoclonality in Bladder Cancer:: The Implication for Molecular Therapies

Abstract: The presence of oligoclonality has implications for the potential efficacy of novel molecular therapeutic agents for bladder cancer. The molecular targets for such therapies must be widely sampled in a tumor population to assess expression in separate clones.

Cited by 62 publications

References 58 publications

Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis

Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis

Prevention of Recurrent Bladder Tumors after Nephroureterectomy for Primary Upper Urinary Tract Urothelial Carcinoma: An Individualized Selection Strategy Based on Patient Risk Stratification Is Needed

Intravesical Chemotherapy and Chemohyperthermia in Non-Muscle-Invasive Bladder Cancer; An Overview on Drug Administration Technologies and Pharmacokinetics

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