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Radical cystectomy with pelvic lymphadenectomy represents the gold standard for treatment of muscle-invasive bladder cancer. Extent of the lymph node dissection and lymph node involvement during radical cystectomy are the most powerful prognostic factors associated with poor oncological outcome. However, the optimal boundaries of the lymph node dis...
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Context 1
... lesions have been reported, but their rarity suggests that the pelvic LNs are the primary landing site and that metastasis occurs in an orderly progression [2,[4][5][6][7][8]. Figure 1 shows the template of extended PLND during RC. Extended PLND include LNs between the aortic bifurcation International Journal of Surgical Oncology and common iliac vessels (proximally), the genitofemoral nerve (laterally), the circumflex iliac vein and LN of Clo- quet (distally), and the internal iliac vessels (posteriorly), including the obturator fossa and the presacral LNs anterior to the sacral promontory. ...
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PurposeTo systematically review the relevant literature that evaluates the LN topographical distribution and propose a uniform template.MethodsA bibliographic search of PubMed/Medline, Embase and SCOPUS was performed for studies reporting data of LN imaging and/or nodal resection.Results101 and 26 articles met the inclusion criteria for PCa and BCa...
Citations
... Muscle invasive bladder cancer (MIBC) accounts for virtually all the mortality from BC and represents a major therapeutic challenge of this disease [41]. Therefore, an endeavor to identify new anticancer compounds with strong inhibition of cancer invasion and understand the mechanisms underlying their inhibitory effect on BC invasion are the key step to discover the unmet future medicines against the invasive malignant BCs. ...
Although our previous studies have identified that isorhapontigenin (ISO) is able to initiate autophagy in human bladder cancer (BC) cells by activating JNK/C-Jun/SESN2 axis and possesses an inhibitory effect on BC cell growth, association of autophagy directly with inhibition of BC invasion has never been explored. Also, upstream cascade responsible for ISO activating JNK remains unknown. Thus, we explored both important questions in the current study and discovered that ISO treatment initiated RAC1 protein translation, and its downstream kinase MKK7/JNK phosphorylation/activation, and in turn promoted autophagic responses in human BC cells. Inhibition of autophagy abolished ISO inhibition of BC invasion, revealing that autophagy inhibition was crucial for ISO inhibition of BC invasion. Consistently, knockout of RAC1 also attenuated induction of autophagy and inhibition of BC invasion by ISO treatment. Mechanistic studies showed that upregulation of RAC1 translation was due to ISO inhibition of miR-365a transcription, which reduced miR-365a binding to the 3’-UTR of RAC1 mRNA. Further study indicated that inhibition of miR-365a transcription was caused by downregulation of its transcription factor SOX2, while ISO-promoted Dicer protein translation increased miR-145 maturation, and consequently downregulating SOX2 expression. These findings not only provide a novel insight into the understanding association of autophagy induction with BC invasion inhibition by ISO, but also identify an upstream regulatory cascade, Dicer/miR145/SOX2/miR365a/RAC1, leading to MKK7/JNKs activation and autophagy induction.
... Keywords: WDR5 inhibitor, OICR-9429, Bladder cancer, PD-L1, Target therapy, Chemosensitivity, Metastasis Background Worldwide, bladder cancer (BCa) is the most common malignancy of the urinary system with more than 573, 278 new cases and 212,536 deaths worldwide in 2020 [1,2]. Muscle-invasive BCa (MIBC) represents 25-40% of all BCa and is a life-threatening disease that can spread from the bladder to other organs, leading to almost 100% of deaths from this disease [3,4]. Cisplatin-based chemotherapy is the standard treatment for MIBC, but it provides a median survival of only approximately 14 months for metastatic BCa. ...
Background
Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer.
Methods
We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition.
Results
First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner.
Conclusions
Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.
... Radical cystectomy with lymph node dissection is the standard treatment for these patients, of whom 18.0-30.4% harbored nodal metastasis (Youssef and Raj, 2011;Hautmann et al., 2012). Lymph node dissection provides accurate node staging and predictive information for oncologic outcomes except for the tumor stage and grade. ...
Background: Lymph node metastasis (LNM) is an important pathological characteristic of bladder cancer (BCa). However, the molecular mechanism underlying LNM was not thoroughly elaborated. Identification for LNM-related biomarkers may contribute to making suitable therapies. So, the current study was aimed to identify key genes and construct a prognostic signature.
Methods: Based on the Cancer Genome Atlas (TCGA) database, gene expression and clinical information were obtained. Then, the weighted gene co-expression network analysis (WGCNA) was performed to identify the key modules and hub genes. A function analysis and a gene set enrichment analysis were applied to explore biological functions and pathways of interested genes. Furthermore, a prognostic model based on LNM-related genes was constructed by using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis.
Results: Finally, nine co-expression modules were constructed, and two modules (turquoise and green) were significantly associated with LNM. Three hub genes were identified as DACT3, TNS1, and MSRB3, which were annotated in actin binding, actin cytoskeleton, adaptive immune response, and cell adhesion molecular binding by the GSEA method. Further analysis demonstrated that three hub genes were associated with the overall survival of BCa patients. In addition, we built a prognostic signature based on the genes from LNM-related modules and evaluated the prognostic value of this signature.
Conclusion: In general, this study revealed the key genes related to LNM and prognostic signature, which might provide new insights into therapeutic target of BCa.
... In our medical center, standard pelvic lymph node resection (sPLNR) is still the most common choice for patients without enlarged lymph nodes above the bifurcation of the iliac artery in preoperative imaging and intraoperative exploration. The upper-lower boundary of sPLNR was from the bifurcation of the common iliac artery to the circumflex iliac vein, the internal-lateral boundary was from the internal iliac artery to the reproductive femoral nerve (14). ...
Background:
Postoperative ileus (POI) is one of the most common complications after laparoscopic radical cystectomy (LRC). Albeit its high incidence, its risk factors are obscure, and few studies have attempted to explore them. Meanwhile, risk-assessing tools for predicting its happening are lacking.
Methods:
Clinical data of 197 patients who underwent LRC between March 2014 and October 2019 were retrospectively collected. All cases of POI were identified and double-checked. Data pertaining to the following categories were extracted as well: patients' general characteristics, preoperative laboratory tests results and preparations, intraoperative and postoperative general items, pathological results. The correlation between candidate risk factors and ileus was analyzed by multivariable binary logistic regression. Clinical and pathophysiological explanations for those results were explored. Finally, a points-based prediction model was developed and validated for predicting the happening of POI.
Results:
A total of 63 out of 197 patients (31.98%) suffered from POI. Multivariate logistic regression analysis showed chronic constipation, increased dosage of laxative, elevated preoperative serum creatinine level, delayed postoperative ambulation, intestine-related urine derivations were statistically significant for developing POI (P<0.05). No significant differences were found between POI and age, gender, body mass index (BMI), antibiotics, hypertension, diabetes, smoking, hard-drinking, preoperative hemoglobin level, preoperative albumin level, history of previous abdominal surgery, surgery time, intraoperative blood loss, blood transfusion, tumor size, lymph nodes yields, TNM staging and intensive care unit hospitalization. An external cohort had been used for testing the validation of the assessment scale, and the results were promising.
Conclusions:
Early recognition is of great importance in protecting vulnerable patients from developing POI, knowing the above-mentioned risk factors and using the assessment scale should help to screen them better. Cases from diverse backgrounds might contribute to a more accurate and complete scale.
... 3 However, NMIBC patients are at a high risk of progressing to invasive bladder tumor. 4 Patients with poor prognosis often suffer from the invasive form, and in cases of distant metastasis, the 5-year survival rate is only 6%. 5 MIBC is responsible for almost all deaths from BC. 6 However, current treatments for metastatic BC are ineffective, and the current grades and stages do not accurately predict early metastasis. Therefore, new molecular markers that can predict the recurrence and metastasis of BC are especially important, and novel treatments to combat invasive BC based on identified targets are urgently needed. ...
Background
Metastasis is the leading cause of death in patients with bladder cancer (BC). However, current available treatments exert little effects on metastatic BC. Moreover, traditional grading and staging have only a limited ability to identify metastatic BC. Accumulating evidence indicates that the aberrant expression of microRNA is intimately associated with tumor progression. So far, many miRNAs have been identified as molecular targets for cancer diagnosis and therapy. This study focused on the role of miR‐516a‐5p (miR‐516a) in BC.
Methods
MiR‐516a expression and its downstream signaling pathway were detected using molecular cell biology and biochemistry approaches and techniques. Fresh clinical BC tissue was used to study the clinicopathological characteristics of patients with different miR‐516a expression. The biological functions of miR‐516a in BC were tested both in vivo and in vitro.
Results
A more invasive BC phenotype was significantly and positively correlated with miR‐516a overexpression in BC patients. MiR‐516a inhibition significantly decreased BC cell invasion and migration in vitro and in vivo. Furthermore, miR‐516a attenuated the expression of PH domain leucine‐rich repeat‐containing protein phosphatase 2 protein and inhibited SMAD‐specific E3 ubiquitin protein ligase 1 transcription by activating the AKT/Forkhead box O3 signaling pathway, which stabilized MMP9 and slowed down its proteasomal degradation, ultimately promoting BC motility and invasiveness.
Conclusions
Our findings reveal the crucial function of miR‐516a in promoting BC metastasis, and elucidate the molecular mechanism involved, suggesting that miR‐516a may be a promising novel diagnostic and therapeutic target for BC.
... Bladder cancer is a common malignant tumor which occurs in the urinary system [1] and ranks the fourth most common malignant cancer among males [2]. Muscle-invasive bladder cancer (MIBC) accounts for 25-40% of bladder cancer cases and can spread to the pelvic lymph nodes and even the visceral organs [3]. Metastasis is a complex multistep process which contains cancer cell dissemination, transport, and colonization expansion [4,5]. ...
Purpose:
The long noncoding RNA LUCAT1 (lung cancer-associated transcript 1) has been reported to be highly expressed in bladder cancer samples, but its role and molecular mechanisms need to be elucidated.
Methods:
Bioinformatics methods show that miR-181c-5p is a target of LUCAT1. Here, we aimed to reveal whether LUCAT1 participates in the development of bladder cancer via targeting miR-181c-5p. The expression levels of LUCAT1 and miR-181c-5p were detected by RT-PCR technology in bladder cells and tissues. The effects of the LUCAT1/miR-181c-5p axis on cell proliferation, migration, invasion, and apoptosis were tested by CCK-8, wound healing, Transwell chambers, and flow cytometry assays. The expressions of apoptosis/migration-related proteins were detected by western blotting assays.
Results:
The results demonstrated that LUCAT1 was overexpressed in bladder cancer tissue and cells, while miR-181c-5p showed a low expression pattern as compared to normal bladder cells and tissues. Cell proliferation, migration, and invasion capacities were significantly impaired, and cell apoptosis was enhanced when LUCAT1 was silenced in UM-UC-3 and T24 cell lines, but this effect was abolished by miR-181c-5p downregulation. In addition, miR-181c-5p downregulation impaired LUCAT1 downregulation which mediated the decreased expressions of Bcl2 and N-cadherin and the increased expressions of Bax and E-cadherin. Moreover, we found that KRAS was a direct target of miR-181c-5p and was under the positive regulation of LUCAT1.
Conclusion:
Collectively, this study reveals that knockdown of LUCAT1 inhibits the migration and invasion of bladder cancer cells in a miR-181c-5p-dependent manner, which may be related to KRAS downregulation.
... Radical cystectomy (RC), following neoadjuvant chemotherapy (NAC), is the standard of care for non-metastatic muscleinvasive bladder cancer (MIBC) and also for high-risk recurrent non-muscle-invasive disease [1]. Incidence of pelvic lymph node (LN) metastasis correlates with the T stage of the disease and ranges from 25% in T2 to 40-45% in T3/4 disease [2]. This makes pelvic LN dissection (PLND) an essential component of RC. ...
Objectives
To compare the lymph node (LN) yield and adequacy of laparoscopic pelvic lymph node dissection (L-PLND) and robot-assisted PLND (R-PLND), as PLND is a fundamental component of radical cystectomy (RC) for bladder cancer (BCa), where a positive status is the most powerful predictor of disease recurrence and survival.
Patents and methods
We retrospectively reviewed patients undergoing RC with PLND for BCa from January 2007 to July 2019 and grouped them in to L- and R-PLND. Until 2011, patients underwent a standard PLND (S-PLND) with the cranial limit as bifurcation of common iliac artery. Since 2012, an extended PLND (E-PLND) up to aortic bifurcation has been performed. An adequate S- and E-PLND were defined as those that yielded at least 10 and 16 LNs, respectively. The groups were compared for LN yield and adequacy of PLND.
Results
During the study period, 305 patients underwent minimally invasive RC in our centre, of which 274 (89.8%) underwent a concomitant PLND (98 L-PLND, 176 R-PLND). R-PLND resulted in a significantly greater median LN yield compared to L-PLND, both in the S-PLND (16 vs 11, P < 0.001) and the E-PLND (19 vs 14, P < 0.001) eras. Also, a significantly higher proportion of patients in the R-PLND group had an adequate PLND compared to the L-PLND group. Surgical approach to PLND (R- vs L-PLND) was the only variable that was significantly associated with an adequate PLND on both univariable (odds ratio [OR] 1.860, 95% confidence interval [CI] 1.114–3.105; P = 0.01) and multivariable (OR 2.109, 95% CI 1.222–3.641; P = 0.007) analyses.
Conclusion
R-PLND leads to a higher LN yield and a greater probability of an adequate PLND compared to L-PLND for both standard and extended templates. Therefore, the robot-assisted approach would lead to more accurate staging following RC with PLND.
... Bladder cancer (BCa) is the most common malignancy of the urinary system in China (1) and worldwide (2), and is the primary cause of mortality in patients with urinary tract disease (3). Muscle-invasive BCa (MIBC) represents 25-40% of all BCa, and may spread from the bladder to the pelvic lymph nodes and then to visceral organs (4). The 5-year mortality rate of MIBC patients with lymph node (LN) metastasis (77.6%) is higher compared with that of MIBC patients without LN metastasis (18.6%) even when treatment with radical cystectomy was available (5,6). ...
The prognosis for patients with metastatic bladder cancer (BCa) is poor, and has not been improved by current treatment methods. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including bladder cancer. However, the role of zinc finger E‑box‑binding homeobox 1‑antisense 1 (ZEB1‑AS1) in BCa progression and metastasis remains unclear. The present study determined the expression level of ZEB1‑AS1 in BCa and additionally investigated the functional role of ZEB1‑AS1 in BCa metastasis. Reverse transcription quantitative polymerase chain reaction analysis showed that ZEB1‑AS1 was upregulated in BCa cells compared with normal epithelial cells. Functionally, knockdown of ZEB1‑AS1 suppressed BCa cell migration and invasion in vitro, and metastasis in vivo. Mechanistic investigations revealed that ZEB1‑AS1 bound to heterogenous nuclear ribonucleoprotein D0 (AUF1), thereby activating the translation of ZEB1 mRNA without affecting its mRNA level. In addition, ZEB1‑AS1 was significantly upregulated in BCa tissues and muscle‑invasive BCa cases. ROC curve analysis demonstrated that ZEB1‑AS1 expression was associated with metastasis in patients with BCa. In conclusion, the data from the present study demonstrated that ZEB1‑AS1 induced BCa metastasis via an AUF1‑mediated translation activation of ZEB1 mRNA mechanism. ZEB1‑AS1 may serve as a promising target for clinical intervention in advanced BCa.
... Extended PLND with RC is a treatment option performed routinely for patients with MIBC. However, there are controversies regarding the extent of lymph nodes dissection [25]. It has been shown that LNs involvement and unrecognized metastasis might be present in almost onethird of MIBC patients, which is detected by the resection of LNs; so, bilateral PLND is suggested to be associated routinely with cystectomy even for CN0 MIBC patients [2]. ...
Objectives:
To determine the application of sentinel node biopsy in urothelial carcinoma of the bladder, we performed a systematic review and meta-analysis.
Methods:
Pooled false negative rate and detection rate were presented using Meta-Disc (version 1.4), and comprehensive meta-analysis (version 2). Publication bias and heterogeneity were assessed using funnel plot, Cochrane Q test, and I2 index.
Results:
The pooled detection rate was 91% (95% CI 87-93%) and pooled sensitivity was 79% (95% CI 0.69-0.86%). When the neoadjuvant chemotherapy group of patients was omitted, the pooled sensitivity changed to 82% (95% CI 74-88%), and the Cochrane Q and I2 statistics were 15.44 and 48.2%, respectively. The pooled sensitivity of studies that included > 50% of pT 3 or 4 patients was 70% (59-80), by omitting studies that enrolled > 50% of patients at pT stage of 3 or 4, the pooled sensitivity increased to 93% (81-98).
Conclusions:
Although the studies on SN biopsy of muscle invasive bladder cancer patients resulted in a high detection rate and sensitivity, further validated multicenter trials with larger sample size are essential to confirm the reliability and accuracy of this approach and obtain a standardized method. We showed that pT1 or pT2 bladder cancer patients with clinically negative lymph nodes are the most appropriated group for sentinel lymph node mapping.
... 3 Muscle-invasive BCa (MIBC) represents 25%-40% of all BCa, and it can spread from the bladder to the pelvic lymph nodes (LNs) and then to visceral organs. 4 The probability of death from MIBC with LN metastasis is significantly higher than that from MIBC without LN metastasis. The death rate increases from 18.6% to 77.6% within 5 years, even when the MIBC is treated with radical cystectomy. ...
The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. In this study, we discover that DANCR was significantly upregulated in BCa tissues and cases with LN metastasis. DANCR expression was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that DANCR promoted BCa cell migration, invasion, and proliferation in vitro and enhanced tumor LN metastasis and growth in vivo. Mechanistic investigations revealed that DANCR activated IL-11-STAT3 signaling and increased cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA. Moreover, oncogenesis facilitated by DANCR was attenuated by anti-IL-11 antibody or a STAT3 inhibitor (BP-1-102). In conclusion, our findings indicate that DANCR induces BCa LN metastasis and proliferation via an LRPPRC-mediated mRNA stabilization mechanism. DANCR may serve as a multi-potency target for clinical intervention in LN-metastatic BCa.
