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Background
Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive...
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Context 1
... performed PCR for methylated and also unmethylated sequences. The PCR conditions and pri- mers used for each gene is shown in Table 1. We used commercially available methylated human genomic DNA (Qiagen, Hilden, Germany) as positive control, and we used water blanks and PCR mixtures as negative control. ...
Citations
... After an initial search of selected electronic databases, we identified a total of 6380 articles regarding the sequencing platform results of UTUC and methylation molecular markers of UTUC. Finally, 11 studies 7,[13][14][15][16][17][18][19][20][21][22] were included in the final analysis. A flow diagram of the detailed selection process was presented in Figure 1. ...
Purpose
Numerous studies suggested methylation modifications play an important role in upper tract urothelial carcinoma (UTUC), but few have depicted DNA methylation architecture on the pathological process of UTUC. We aimed to better understand the pathogenesis of UTUC and provide precision medicine references when managing UTUC patients.
Methods
PubMed, Cochrane Library, EMBASE, and Scopus were searched for UTUC until Dec.31st, 2020. Methodological quality assessment was conducted according to NIH recommendations. Meta-analysis was conducted to assess the prognostic effect of methylated genes. Kaplan-Meier survival analyses were performed to validate methylated genes and cytosine-phosphate-guanine (CpG) sites.
Results
11 studies (3619 patients) were eligible to investigate 12 methylated genes and 10 CpGs. The quality of all the studies was fair to good. Meta-analysis found the pooled effect of eligible methylated genes had a low risk of tumor recurrence (HR = 0·67; 95%CI: 0·51 to 0·87; P = 0·003), but a high risk of tumor progression (HR = 1·60; 95%CI: 1·17 to 2·18; P = 0·003) and cancer-specific mortality (HR =1·35; 95%CI: 1·06 to 1·72; P = 0·01). For individual methylation status of GDF15, HSPA2, RASSF1A, TMEFF2, and VIM, the pooled effect of each gene was found pleiotropic on both diagnosis and prognosis. Survival analysis suggested higher methylation of SPARCL1 had a better disease-specific survival (P = 0·048).
Conclusion
We combined meta-analysis and Kaplan-Meier survival analysis using the most updated evidence on the methylation of UTUC. Candidate biomarkers with essential diagnosis and prognosis function might provide precision medicine references for personalized therapies.
... The development of contralateral UTUC after removal of the primary lesion is uncommon, with an estimated incidence of 0.6-6.9% [2,[4][5][6][7][8][9]. Identifying patients at risk of contralateral recurrence can help early detection to prevent another RNU for recurring contralateral tumors and permanent dialysis. ...
... The 3-and 5-year contralateral recurrence rates were 4.6% and 7.7%, respectively. We confirmed the finding of previous studies [4,8,9] that advanced CKD is an independent risk factor for contralateral recurrence. Our results also indicated that an elevated WBC count was associated with a higher contralateral recurrence rate. ...
... In contrast, patients with CKD have no increased risk of prostate, colorectal, lung, or breast cancer [22]. Similar to previous studies [4,8,9], our results indicate that advanced CKD is an independent factor predicting the recurrence of contralateral UTUC after RNU. Of note, because of the lack of CKD data, the significance of CKD in contralateral recurrence has not been studied in non-Asian populations [5][6][7], and our subgroup analysis demonstrated its predictive value in American patients ( Figure 2F, p = 0.032). ...
This study aimed to examine the prognostic significance of preoperative inflammation-associated blood cell markers in the metachronous contralateral recurrence of upper tract urothelial carcinoma (UTUC). Patients with nonmetastatic UTUC treated in Taiwan and the U.S. between 1990 and 2017 were included. The Kaplan–Meier method was used to calculate the contralateral recurrence rate, and multivariate logistic regression was performed to study the association of blood cell markers and clinicopathological characteristics with contralateral recurrence. Overall, a total of 1039 patients were included in this study, 52 of whom (5.0%) developed metachronous recurrence of the contralateral side. Kaplan–Meier analysis indicated that a history of bladder cancer (p = 0.006), multiple tumors (p = 0.016), advanced chronic kidney disease (CKD; p < 0.001), elevated serum white blood cell (WBC) count (p < 0.001), and decreased hemoglobin levels (p = 0.001) significantly reduced the contralateral recurrence-free survival. Multivariate analysis showed that multiple tumors (hazard ratio (HR), 1.87; p = 0.030), advanced CKD (HR, 2.63; p = 0.002) and increased WBC count (HR, 2.60; p = 0.001) were independent risk factors for higher contralateral recurrence rate. Notably, advanced CKD was a significant factor regardless of the patient’s region. In summary, multiple tumors, advanced CKD and elevated serum WBC count are independent predictors of contralateral recurrence in patients with UTUC. It is recommended that patients with these adverse characteristics be closely followed up to monitor the opposite upper urinary tract.
... Methylation of at least one gene promoter was found in 89 % of UTUC, more frequently and extensively as compared to UBC. Furthermore, the presence and degree of methylation was associated with worse prognosis, with higher progression and mortality rates (Zhang et al., 2015;Catto et al., 2005). ...
Background
Advanced upper tract urothelial carcinoma (UTUC) has different molecular and genetic features from the commonest carcinoma of the bladder, suggesting a possible different sensitivity to immune-checkpoint inhibitors (ICI).
Methods
A systematic review and meta-analysis of all relevant clinical studies including advanced UTUC patients treated with ICI was conducted according to PRISMA guidelines.
Results
Six prospective trials for a total 2537 patients, including 396 (15.6%) with advanced UTUC, were eligible for the analysis. In UTUC patients, the pooled ORR was 21.2% (95% CI, 12.5%-33.7%); the risk of death was reduced by 24% over the standard platinum-based chemotherapy, but this was not statistically significant (hazard ratio = 0.76; 95% confidence interval, 0.41–1.40; p = 0.37, χ2 = 3.28, p = 0.07; I2 = 70%).
Conclusions
The current evidence does not support a statistically significant effect from ICI over the standard treatment for advanced UTUC patients. Properly performed pre-planned subgroup analyses from randomized clinical trials are eagerly awaited.
... Locoregional and contralateral recurrences after RNU are infrequently reported in the literature. The 5-year contralateral RFS in the present series was 93.5%, similar to other series (95.0%) [27]. Rates of local recurrence were relatively low in the present study, with a 5-year local RFS rate of 89.0% comparable to that reported in the literature (80.5-94.2%) ...
Objectives
To describe the Agarwal loop‐ligation technique for the management of the distal ureter during laparoscopic radical nephroureterectomy (LRNU) for upper tract urothelial carcinoma (UTUC) and report on long‐term oncological outcomes.
Patients and Methods
In the Agarwal loop‐ligation technique, the distal ureteric stump is controlled using endoscopic Endoloop® or PolyLoop® ligation to ensure en bloc excision of the bladder cuff and prevent spillage of upper tract urine into the perivesical space. A retrospective review of the medical records of 76 patients who underwent the Agarwal loop‐ligation technique for UTUC at participating centres from July 2004 to December 2017 was performed. Data collected included demographics, perioperative, and long‐term oncological outcomes. Survival was calculated using Kaplan–Meier survival analyses.
Results and Limitations
A total of 76 patients were included. The median age was 71.5 years and median operative time was 4.3 h. The intramural ureter and bladder cuff were completely excised in all patients. Distal surgical margins were clear in all, with only two patients found to have tumour extending to the circumferential surgical margin. There were no cases of perivesical recurrence or port‐site metastasis. The 5‐year bladder, local, and contralateral recurrence‐free survival was 59.6%, 89.0% and 93.5%, respectively. Metastasis‐free survival at 5‐years was 73.5%. The 5‐year overall survival and cancer‐specific survival rates were 70.3% and 84.7%, respectively.
Conclusions
We have described the Agarwal loop‐ligation technique for the management of the distal ureter in LRNU. This technique complies with oncological principles outlined in the European Association of Urology guidelines, which minimises tumour spillage. Long‐term oncological outcomes are satisfactory, with no cases of perivesical recurrence detected in this series.
... 18 Contralateral UTUC after RNU is very rare and is associated with preoperative renal insufficiency and a history of renal transplantation. 19 Because of its rarity and the retrospective study design, the present study did not include or analyze patients with previous or metachronous contralateral UTUC. Although UTUC is histologically similar to bladder UC, to date only a very few reports focusing on UTUC with VH have been published. ...
Purpose:
To determine the prognostic effect of upper tract urothelial carcinoma (UTUC) with variant histology (VH) after radical nephroureterectomy (RNU).
Patients and methods:
The data of 1173 patients who received RNU for UTUC without neoadjuvant chemotherapy in 11 institutions between 2002 and 2016 were retrospectively reviewed. A matched propensity score analysis was performed. Clinicopathologic variables, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were compared between patients with pure UTUC and patients with UTUC and VH. Univariate and multivariate Cox proportional regression models were used to determine the independent variables associated with oncologic outcomes.
Results:
UTUC with VH was observed in 93 patients (7.9%). After propensity score matching, UTUC with VH showed no difference in clinicopathologic features compared to pure UTUC; however, it was associated with shorter RFS, CSS, and OS (log rank, P = .011, P = .002, P = .006, respectively). Additionally, the multivariate analysis revealed that VH was independently associated with a poor RFS [hazard ratio (HR) = 1.92; 95% confidence interval (CI), 1.27-2.89; P = .002], CSS (HR = 4.47; 95% CI, 1.99-10.1; P = .001), and OS (HR = 3.00; 95% CI, 1.55-5.78; P = .001). However, the Kaplan-Meier method revealed that differences in RFS, CSS, and OS were not significant in patients who received adjuvant chemotherapy (log rank, P = .562, P = .060, P = .153, respectively).
Conclusion:
UTUC with VH was independently associated with poor oncologic outcomes in patients with UTUC after RNU. Although patients with UTUC and VH had a poor prognosis compared to patients with pure UTUC, adjuvant chemotherapy would be helpful in improving the survival rates of these patients.
... [3][4][5] However, in our previous studies, the incidence, oncological characteristics, chronic kidney disease (CKD) prevalence, epigenetic biomarkers, and outcomes of tumor were different in Chinese populations. [6][7][8][9][10] Gender was a factor that indicated a significant difference. Unlike Western populations where the male-to-female ratio of UTUC patients is approximately 3:1, Chinese female UTUCs have a higher prevalence than males -though they are less likely to develop worse histology outcomes (at higher stages and LNM). 5 Furthermore, being male is considered a significant prognostic factor for poorer survival. ...
Background:
In China, upper tract urothelial carcinoma (UTUC) is less prevalent but more malignant in males. This study investigates the prognostic factors and causes of gender-based differences in Chinese populations.
Methods:
Between 1999 and 2011, 687 UTUC patients who underwent surgery were utilized for this study. We evaluated the differences in oncological characteristics, epigenetic biomarkers, cancer-specific survival (CSS), bladder recurrence (BR) rate, and contralateral upper tract recurrence (CUTR) rate. Smoking history, benzene exposure history, and the history of using aristolochic acid (AA) containing herbs were analyzed in detail.
Results:
Compared with male patients, female patients showed poorer renal function, lower proportions of tumor stage III/IV, and smaller tumor diameters. The CSS in male patients was lower than that in female patients. Significant gender-related differences were observed concerning various prognostic factors. In female patients, poorer survival rates were attributed to the primary tumor location in the ureter, large diameter primary tumors, severe chronic kidney disease, papillary tumor architecture, high tumor stages, positive N status, and methylated ABCC6 promoters. In male patients, older age, ipsilateral hydronephrosis, large tumor diameters, sessile tumor architecture, high tumor stages, and methylated TMEFF2 promoters were associated with higher cancer-specific mortality. AA might be the main cause of these gender-based differences. The AA-induced UTUC patients presented smaller tumor diameters, lower tumor stages, fewer positive N statuses, more multifocal tumors, lower methylation indices, and poorer renal function. Although AA-induced UTUC patients exhibited better survival rates, BR and CUTR rates were significantly worse.
Conclusion:
In China, there exist significant AA-induced differences between male and female UTUC patients. The bladders and contralateral upper urinary tracts of AA-induced UTUC patients should be carefully monitored after surgery.
... Follow-up was performed according to institutional protocols. 16 The follow-up interval was every 3 months during the first 2 years and once a year thereafter. Routine follow-up consisted of history, physical examination, urinalysis, serum creatinine measurement, ultrasonography, chest radiography, computed tomography (and/or magnetic resonance imaging), urine cytology (or urine fluorescence in situ hybridization) and cystoscopy. ...
Objective
To investigate the effect of aristolochic acids (AA) exposure, including exposure duration and years since last exposure, on oncologic outcomes of patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU).
Methods
We retrospectively collected clinicopathologic and AA exposure variables for 942 UTUC patients treated with RNU between 1999 and 2014 in a high-volume center of China. AA exposure duration was categorized as (>3 vs ≤3 years) and time since last AA exposure to surgery as (>5 vs ≤5 years).
Results
A total of 856 patients (90.9%) had none or possible AA exposure and 86 patients (9.1%) had credible AA exposure history. Among the 86 patients, 57 (66.3%) had AA exposure for ≤3 years and 29 (33.7%) had exposure for >3 years. The median follow-up duration was 60 months. By multivariate analysis, AA exposure history was significantly associated with cancer specific survival (hazard ratio [HR]: 0.43, p=0.02), intravesical recurrence (IVR) (HR: 2.25, p<0.001) and contralateral UTUC recurrence (HR: 2.71, p=0.001). After adjusted for the effects of standard clinicopathologic characteristics, exposure duration was independent risk factor for subsequent IVR (exposure duration ≤3 years vs none/possible AA, HR: 1.87, p=0.009; exposure duration >3 years vs none/possible AA, HR: 3.07, p<0.001), but not for cancer-specific survival (p=0.06). Also, of those patients who had AA exposure, those having exposure within 5 years prior to RNU did not differ from patients having last exposure >5 years ago regarding cancer specific mortality (p=0.67) and IVR (p=0.54).
Conclusion
AA exposure was associated with worse cancer-specific survival, higher rate of IVR and contralateral UTUC recurrence of UTUC treated with RNU. The association between AA exposure and IVR seems to be time-dependent. Exposure cessation >5 years prior to RNU cannot mitigate the impact of AA on the UTUC prognosis.
... DNA methylation is an important epigenetic modification that affects chromatin structure and gene expression [10]. Tumor suppressor gene silence is involved in carcinogenesis, drug resistance and recurrence [11][12][13]. High levels of methylation were associated with disease recurrence. Particularly, MLH1, ATM and FHIT gene promoters are found to be significantly hypermethylated in recurring adenomas [14]. ...
Background
Claudin-6 (CLDN6), a member of claudin transmembrane protein family, has recently been reported to be undetectable or at low levels in human breast cancer cell lines and tissues and plays a role in suppression of migration and invasion in breast cancer cells. In addition, it is reported that CLDN6 expression is regulated by DNA methylation in various human cancers and cell lines. However, it is unclear how DNA methylation regulates CLDN6 expression. Here we show the mechanism by which DNA methylation regulates CLDN6 expression in human breast cancer cell line MCF-7.
Methods
RT-PCR, Western blot and immunofluorescent staining were utilized to investigate CLDN6 expression in breast cancer tissues and MCF-7 cells. Methylation-Specific PCR (MSP) was applied to determine DNA methylation status in CLDN6 gene promoter region. Wound-healing assay and invasion assay were utilized to test mobility of MCF-7 cells treated with 5-aza-dC (DNA methyltransferase inhibitor). MeCP2 binding, H3Ac and H4Ac in CLDN6 promoter region were analyzed by ChIP assay. Nuclease accessibility assay was performed for analysis of the chromatin conformation of CLDN6 gene. To study the role of CLDN6 in malignant progression, we used RNAi to knockdown CLDN6 expression in MCF-7 cells treated with 5-aza-dC, and examined the mobility of MCF-7 cells by wound-healing assay and invasion assay.
Results
5-aza-dC and TSA (histone deacetylase inhibitor) application induced CLDN6 expression in MCF-7 cells respectively and synergistically. 5-aza-dC treatment induced CLDN6 demethylation, inhibited MeCP2 binding to CLDN6 promoter and increased H3Ac and H4Ac in the promoter. In addition, TSA increased H4Ac, not H3Ac in the promoter. The chromatin structure of CLDN6 gene became looser than the control group after treating with 5-aza-dC in MCF-7 cells. 5-aza-dC up-regulated CLDN6 expression and suppressed migration and invasion in MCF-7 cells, whereas CLDN6 silence restored tumor malignance in MCF-7 cells.
Conclusions
DNA methylation down-regulates CLDN6 expression through MeCP2 binding to the CLDN6 promoter, deacetylating H3 and H4, and altering chromatin structure, consequently promoting migratory and invasive phenotype in MCF-7 cells.
Objectives:
To investigate the significant predictors of contralateral upper tract recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.
Methods:
Between January 2001 and December 2015, 548 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy in a single institution were included in this retrospective cohort study. Several clinicopathological characteristics and outcomes were explored. The crucial end-point was the diagnosis of contralateral upper tract recurrence after radical nephroureterectomy.
Results:
Of the 548 patients, the median age was 68 years (range 24-93 years), and the median follow-up time after radical nephroureterectomy was 41 months (range 8-191 months). Contralateral upper tract recurrence occurred in 28 patients (5.1%). The median time period between radical nephroureterectomy and contralateral upper tract recurrence was 15.4 months (range 3.4-52.4 months). In the multivariate analysis, preoperative estimated glomerular filtration rate <30 mL/min/1.73 m2 (hazard ratio 3.08, P = 0.003) and tumor multifocality (hazard ratio 2.16, P = 0.043) were independent risk factors.
Conclusion:
Preoperative estimated glomerular filtration rate <30 and tumor multifocality are significant predictors of contralateral upper tract recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.
Tumor recurrence after radical nephroureterectomy (RNU) for upper tract urothelial cell carcinoma (UTUCC) can occur in the bladder, the contralateral upper urinary tract, or systemically. Therefore, oncologic monitoring after RNU requires a multimodal approach that accounts for the various sites and patterns of recurrence. In this chapter, we describe the different rates of recurrence, associated factors, and recommendations for oncologic monitoring for post-RNU recurrence by site of tumor relapse (intravesical, contralateral upper urinary tract, and systemic) and by risk category as defined by NCCN stages (low-risk: stage 0 or 1; high-risk: stage ≥2 or positive lymph nodes) (Fig. 38.1).
