In-depth investigation of the molecular pathogenesis of bladder cancer in a unique 26-year old patient with extensive multifocal disease: A case report

Background. The molecular characteristics and the clinical disease course of bladder cancer (BC) in young patients remain largely unresolved. All patients are monitored according to an intensive surveillance protocol and we aim to gain more insight into the molecular pathways of bladder tumors in young patients that could ultimately contribute to patient stratification, improve patient quality of life and reduce associated costs. We also determined whether a biomarker-based surveillance could be feasible. Case Presentation. We report a unique case of a 26-year-old Caucasian male with recurrent non-muscle invasive bladder tumors occurring at a high frequency and analyzed multiple tumors (maximal pTaG2) and urine samples of this patient. Analysis included FGFR3 mutation detection, FGFR3 and TP53 immunohistochemistry, mircosatellite analysis of markers on chromosomes 8, 9, 10, 11 and 17 and a genome wide single nucleotide polymorphism-array (SNP). All analyzed tumors contained a mutation in FGFR3 and were associated with FGFR3 overexpression. None of the tumors showed overexpression of TP53. We found a deletion on chromosome 9 in the primary tumor and this was confirmed by the SNP-array that showed regions of loss on chromosome 9. Detection of all recurrences was possible by urinary FGFR3 mutation analysis. Conclusions. Our findings would suggest that the BC disease course is determined by not only a patient's age, but also by the molecular characteristics of a tumor. This young patient contained typical genetic changes found in tumors of older patients and implies a clinical disease course comparable to older patients. We demonstrate that FGFR3 mutation analysis on voided urine is a simple non-invasive method and could serve as a feasible follow-up approach for this young patient presenting with an FGFR3 mutant tumor

The importance urinary glycosaminoglycan as a marker for superficial bladder tumors

Urinary glycosaminoglycan/creatinine ratio (GAG/Cr) was determined in 42 patients with superficial bladder tumors (before and after the treatment) and in 34 healthy subjects. Before the treatment, the mean GAG/Cr ratio in patients group was not significantly different from the control group's figure (11.65 +/- 3.25 and 10.11 +/- 2.67). However, comparison of urinary GAG levels of T-1, and Grade III tumors with the control group revealed statistically significant results (p < 0.01 and p < 0.001, respectively), All patients were previously operated by transurethral resection (TUR) and then intravesical chemotherapy applied [(BCG (n:20), 4-epidoxorubicin (n:12), interferon ar-l (n:10)]. Three months after the treatment, urinary GAG levels were determined in 19 of the 24 patients whose pretreatment urinary GAG levels were higher than the control group, tumor completely remitted and their urinary GAG excretion decreased. The tumor of the three, gradually progressed and their GAG excretions were normal. The two hadn't any tumor mass and their urinary GAG excretion was higher than the pretreatment levels. The remaining 18 patients didn't show any clinical modification and their urinary GAG excretion did not differ from the control's and pretreatment levels

URINARY-EXCRETION OF SIALIC-ACID IN PATIENTS WITH BLADDER-TUMORS

The pre- and post-treatment urinary total sialic acid/creatinine (TSA/Cr) ratios of patients with bladder tumor (n = 60) were determined. We found a significant increase in the mean urinary TSA/Cr ratio in patients with bladder tumors than in healthy people (99.80 +/- 15.60 mu g/g Cr, 52.57 +/- 15.60 mu g/g Cr, P < 0.001). We determined that the mean post-treatment TSA/Cr ratio of 44 patients was significantly lower than their pretreatment ratio and this value also decreased to the level in healthy people. (TSA/Cr ratios of 44 patients: in the pre-treatment period, 105.30 +/- 25.20 mu g/g Cr; in the post-treatment period, 54.50 +/- 15.80 mu g/Cr; healthy people, 52.57 +/- 15.60 mu g/g Cr, P < 0.001). The patients with decreased TSA/Cr ratio in the post-treatment period showed complete or partial regression of their disease. In 8 patients, urinary TSA/Cr ratio in the post-treatment period increased to 105 +/- 14.5 mu g/g Cr value. In clinical and pathologic evaluation, it was shown that disease progressed in all of these 8 patients. The mean post-treatment TAS/Cr ratio of 8 patients did not differ from the pretreatment ratio (87.44 +/- 20.20 mu g/g Cr) and it was shown that their clinical status did not change. These findings show that urinary excretion of TSA correlates with the clinical status of bladder tumor and it could be used to follow the course of the disease, and follow-up treatment

Intermediate-Risk Group in Patients with Transitional Cell Carcinoma of the Bladder: Prediction of High-Risk Patients in This Heterogeneous Group

Objective: To determine whether recurrence at first follow-up cystoscopy predicts future recurrence in patients with an intermediate risk of superficial bladder cancer. Methods: In total, 304 patients were classified as low (n = 60), intermediate (n = 177) or high risk (n = 67) based on the primary pathological/clinical findings, as previously described in literature. The intermediate-risk group was further divided into 2 subgroups based on recurrence at the first follow-up cystoscopy: A (recurrence negative) and B (recurrence positive). Results: The mean recurrence rates of low-, intermediate- and high-risk patients were 1.76, 6.41 and 9.49, respectively (p < 0.05). Similarly, the difference in the recurrence rates between subgroups A (4.37) and B (9.12) was found to be statistically significant (p = 0.00). Additionally, while the difference between the low-risk group and subgroup A was statistically significant (p = 0.008), there was no significance between subgroup B and the high-risk group (p = 0.892). In the multivariate analysis, the most significant prognostic parameter for recurrence was the outcome of the first follow-up cystoscopy, followed by tumor multiplicity and grade. Conclusions: Patients showing recurrence at first follow-up cystoscopy in the intermediate-risk group should be classified as high-risk patients and treated accordingly. Copyright (C) 2009 S. Karger AG, Base

Molecular mechanisms underlying the role of microRNAs (miRNAs) in anticancer drug resistance and implications for clinical practice

Drug resistance remains a major problem in the treatment of cancer patients for both conventional chemotherapeutic and novel biological agents. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) changes, drug resistance mechanisms might also be regulated by microRNAs (miRNAs). In this review we provide an overview on the role of miRNAs in anticancer drug resistance, reporting the main studies on alterations in cell survival and/or apoptosis pathways, as well as in drug targets and determinants of drug metabolism, mediated by deregulation of miRNA expression. The current status of pharmacogenetic studies on miRNA and their possible role in cancer stem cell drug resistance are also discussed. Finally, we integrated the preclinical data with clinical evidences, in lung and pancreatic cancers, showing how the study of miRNAs could help to predict resistance of individual tumours to different anticancer drugs, and guide the oncologists in the selection of rationally based tailor-made treatments