Characteristics of Upper Urothelial Carcinoma in an Area of Balkan Endemic Nephropathy in South Serbia. A fifty-year Retrospective Study

Čukuranović, Rade; Ignjatović, Ivan; Visnjic, Milan; Veličković, Ljubinka Janković; Petrović, Branislav; Potic, Milan; Stefanović, Vladisav

doi:10.1177/030089161009600505

Cited by 19 publications

(24 citation statements)

References 12 publications

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“…A similar gender distribution also was noted in BEN patients with UUC . In contrast, UUC patients residing in non‐endemic villages in the Balkans were predominantly male . In our study, two‐thirds of AA‐UUC patients were female, while two‐thirds of non‐AA‐UUC patients were male.…”

Section: Discussionsupporting

confidence: 84%

“…However, the gender distribution of Taiwanese UUC patients was approximately equal . A similar gender distribution also was noted in BEN patients with UUC . In contrast, UUC patients residing in non‐endemic villages in the Balkans were predominantly male .…”

Section: Discussionsupporting

confidence: 66%

“…Specifically, approximately two‐thirds of patients aged less than 50 years were AA‐UUC cases. In contrast, the mean ages of UUC patients residing in Balkan endemic and non‐endemic villages are comparable . The level and duration of AA exposure may contribute to the variation in age of AA‐UUC patients between the Balkans and Taiwan) .…”

Section: Discussionmentioning

confidence: 92%

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Aristolochic acid‐induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes

Chen

Dickman

Huang

et al. 2013

Intl Journal of Cancer

110

109

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Aristolochic acid (AA), a component of all Aristolochia‐based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA‐induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam‐DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T‐to‐T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam‐DNA adducts and A:T‐to‐T:A transversions in TP53 were defined as AA‐UUC, whereas patients lacking both of these biomarkers were classified as non‐AA‐UUC. Cases with either biomarker were classified as possible‐AA‐UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA‐UUC, possible‐AA‐UUC and non‐AA‐UUC, respectively. AA‐UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end‐stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible‐AA‐UUC and non‐AA‐UUC patients. All 14 patients who developed contralateral UUC had aristolactam‐DNA adducts; ten of these also had signature mutations. The contralateral UUC‐free survival period was shorter in AA‐UUC compared to possible‐ or non‐AA‐UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA‐UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 66%

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Aristolochic acid‐induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes

Chen

Dickman

Huang

et al. 2013

Intl Journal of Cancer

110

109

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“…The incidence of UTUC in Western countries is relatively low (5% of all urothelial carcinoma); however, the prognosis of UTUC is considerably worse than that at the same pathological stage of urothelial carcinoma of the bladder (UCB) [1][2][3]. The incidence of UTUC in Taiwan is considerably higher than the worldwide incidence (30%-40% of all urothelial carcinoma cells (UCs)), which indicates that some unknown carcinogenic or environmental factors contribute to tumor development and growth [4][5][6][7]. Histologically, UCs arising from the upper urinary tract and urinary bladder are grossly identical.…”

Section: Introductionmentioning

confidence: 99%

Galectin-1 Overexpression Activates the FAK/PI3K/AKT/mTOR Pathway and Is Correlated with Upper Urinary Urothelial Carcinoma Progression and Survival

Luo

Huang

et al. 2020

Cells

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Galectin-1 (GAL1) is a β-galactoside-binding protein involved in multiple aspects of tumorigenesis. However, the biological role of GAL1 in upper tract urothelial carcinoma (UTUC) has not been entirely understood. Herein, we investigated the oncological effects of GAL1 expression in tumor specimens and identified related gene alterations through molecular analysis of GAL1. Clinical parameter data and tumor specimens were collected from 86 patients with pT3N0M0 UTUC who had undergone radical nephroureterectomy. We analyzed the difference in survival by using Kaplan–Meier analyses and Cox proportional regression models and in GAL1 expression by using immunohistochemical (IHC) methods. Public genomic data from the Cancer Genome Atlas (TCGA) and GSE32894 data sets were analyzed for comparison. Using four urothelial carcinoma (UC) cell lines (BFTC-909, T24, RT4, and J82) as in vitro models, we evaluated the functions of GAL1 in UC cell growth, invasiveness, and migration and its role in downstream signaling pathways. The study population was classified into two groups, GAL1-high (n = 35) and GAL1-low (GAL1 n = 51), according to IHC interpretation. Univariate analysis revealed that high GAL1 expression was significantly associated with poor recurrence-free survival (RFS; p = 0.028) and low cancer-specific survival (CSS; p = 0.025). Multivariate analysis revealed that GAL1-high was an independent predictive factor for RFS (hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.17–5.05, p = 0.018) and CSS (HR 4.04; 95% CI 1.25–13.03, p = 0.019). In vitro studies revealed that GAL1 knockdown significantly reduced migration and invasiveness in UTUC (BFTC-909) and bladder cancer cells (T24). GAL1 knockdown significantly reduced protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, which increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and promoted epithelial–mesenchymal transition (EMT). Through gene expression microarray analysis of GAL1 vector and GAL1-KD cells, we identified multiple significant signaling pathways including p53, Forkhead box O (FOXO), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). We validated microarray results through immunoblotting, thus proving that downregulation of GAL1 reduced focal adhesion kinase (FAK), p-PI3K, p-AKT, and p-mTOR expression. We concluded that GAL1 expression was highly related to oncological survival in patients with locally advanced UTUC. GAL1 promoted UC invasion and metastasis by activating the FAK/PI3K/AKT/mTOR pathway.

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“…In Chinese populations, the use of traditional Chinese medicine containing aristolochic acid (AA) might affect tumor multifocality, and a previous study of UTUC in Balkan endemic nephropathy patients indicated that malignancy was lower in UTUCs caused by AA [20]. Our previous research also suggests specific treatments that may be most effective for multiple or bilateral UTUC [21, 22], but choosing the best surgical approach remains difficult.…”

Section: Discussionmentioning

confidence: 99%

Fluorescencein situhybridization status of voided urine predicts invasive and high-grade upper tract urothelial carcinoma

Hao

et al. 2017

Oncotarget

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Here, we assessed the diagnostic accuracy of fluorescence in situ hybridization (FISH) for detecting aggressive upper tract urothelial carcinoma (UTUC). A total of 210 UTUC patients from a single hospital in China were enrolled in this retrospective study between 2012 and 2016. Patients were classified as FISH-positive or -negative based on FISH analysis of voided urine, and the clinicpathological characteristics of these two patient groups were compared. Patients with positive FISH results had more advanced tumor stages and higher tumor grades than those with negative results. The overall sensitivity of FISH for detecting advanced UTUC was 62.4% (131/210). The sensitivity and positive predictive values of positive FISH results were 76.5% and 59.5% for high-grade UTUC and 71.7% and 58.0% for muscle-invasive UTUC. These data suggest that voided urine FISH results accurately predict advanced UTUC and might help distinguish patients with aggressive disease from those who might benefit from conservative management.

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Characteristics of Upper Urothelial Carcinoma in an Area of Balkan Endemic Nephropathy in South Serbia. A fifty-year Retrospective Study

Cited by 19 publications

References 12 publications

Aristolochic acid‐induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes

Aristolochic acid‐induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes

Galectin-1 Overexpression Activates the FAK/PI3K/AKT/mTOR Pathway and Is Correlated with Upper Urinary Urothelial Carcinoma Progression and Survival

Fluorescencein situhybridization status of voided urine predicts invasive and high-grade upper tract urothelial carcinoma

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