Upper tract urothelial carcinoma is more rare than bladder cancer, although they are both categorized as urothelial carcinoma. Because of the low incidence, little clinical evidence is available ...regarding the treatment of the former. However, recently such evidence has slowly begun to accumulate. The guideline presented herein was compiled for the purpose of ensuring proper diagnosis and treatment by physicians involved in the treatment of upper tract urothelial carcinoma. We carefully selected 16 clinical questions essential for daily clinical practice and grouped them into four major categories: epidemiology, diagnosis, surgery and systemic chemotherapy/other matters. Related literature was searched using PubMed and Japan Medical s Society databases for articles published between 1987 and 2013. If the judgment was made on the basis of insufficient or inadequate evidence, the grade of recommendation was determined on the basis of committee discussions and resultant consensus statements. Here, we present a short English version of the original guideline, and overview its key clinical issues.
Objectives
To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between ...radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions.
Methods
This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance.
Results
Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73–0.91). The urologists’ sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively.
Conclusions
The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively.
Key Points
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VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists.
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The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score.
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The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions).
The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is ...available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9‐xCT system in order to enhance cisplatin (CDDP)‐induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer‐specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho‐p38MAPK protein expression by SSZ with or without CDDP were assessed in MBT‐2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT‐2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT‐2V cells by inhibiting CD44v9 expression and upregulating phospho‐p38MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT‐2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.
This is the first report to show the therapeutic effects of not only sulfasalazine (SSZ), but also the combination of SSZ and cisplatin (CDDP) in a metastatic bladder cancer model, suggesting the potential of SSZ and CDDP combination therapy for metastatic bladder cancer.
Objectives
Despite just a 4‐year interval from the last version (2015) of the Clinical Practice Guidelines for Bladder Cancer, several dramatic paradigm shifts have occurred in the latest clinical ...practice regarding both the diagnosis and treatment of bladder cancer. Herein, we updated the 2019 version of the Clinical Practice Guidelines for Bladder Cancer under the instruction of the Japanese Urological Association.
Methods
We previously reported in a revision working position paper for Clinical Practice Guidelines for Bladder Cancer 2019 edition and described the methods of revision detail.
Results
The major points of change in the 2019 version are presented and explanations are given as follows: (i) introduction of the new reference assessment system; (ii) modification of the risk classification for non‐muscle‐invasive bladder cancer; (iii) addition of clinical questions for the new tumor‐visible techniques in non‐muscle‐invasive bladder cancer; (iv) inclusion of minimally invasive surgeries for muscle‐invasive bladder cancer and immune checkpoint inhibitors for locally advanced/metastatic muscle‐invasive bladder cancer; (v) overview chapter of the histological variant of urothelial cancer and rare cancers of the bladder; and (vi) recommendation of follow up in non‐muscle‐invasive bladder cancer and muscle‐invasive bladder cancer.
Conclusions
Guidelines should be updated based on the current evidence and updates carried out without delay. The hope is that this guidelines will be assessed by many urologists and will be the cornerstone for the next revision.
Mucin 1 C‐terminal subunit (MUC1‐C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1‐C in urothelial carcinoma (UC) cells ...remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1‐C oncoprotein in UC cells. MUC1‐C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP‐based perioperative chemotherapy. As a result, moderate to high MUC1‐C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP‐resistant (CR) cell lines, we compared the expression levels of MUC1‐C, multiple drug resistance 1 (MDR1), the PI3K‐AKT‐mTOR pathway, and x‐cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1‐C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K‐AKT‐mTOR pathway. MUC1‐C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down‐regulation showed MDR1 inhibition along with PI3K‐AKT‐mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1‐C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1‐C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1‐C inhibitor may become a novel therapeutic option in CR UC patients.
Our present study demonstrated that mucin 1 C‐terminal peptide (MUC1‐C) plays a pivotal role in the acquisition of cisplatin (CDDP) resistance via multiple drug resistance 1 regulation and x‐cystine/glutamate transporter stabilization in urothelial cancer cells. The combined treatment of CDDP with a MUC1‐C inhibitor, GO‐203, may become a novel therapeutic option in CDDP‐resistant UC patients.
A comprehensive survey has not yet been conducted to investigate care patterns by urologists for the management of upper tract urothelial carcinoma.
We conducted a nationwide survey for urologists ...treating upper tract urothelial carcinoma patients. The questionnaire was approved by the Japanese Urological Association and sent by mail in February 2014 to 1119 institutes in Japan. We identified 627 responders for this study.
Our survey demonstrated that (i) the mean number of radical nephroureterectomy cases per institution in 2013 was 7.6, (ii) the main detecting tool for upper tract urothelial carcinoma is contrast-enhanced computed tomography, (iii) the need for ureteroscopic evaluations is highly dependent on voiding urine cytology results, (iv) 67% of urologists always or often perform radical nephroureterectomy by laparoscopic surgery, (v) more than half of the urologists do not aggressively perform lymph node dissection, (vi) 75% of the urologists perform bladder cuff incision through an extravesical approach, (vii) urologists perform kidney-sparing surgery following various indications, (viii) 59% of the urologists always perform adjuvant systemic chemotherapy for high-risk upper tract urothelial carcinoma patients, (ix) the combination of gemcitabine and cisplatin is the most frequent chemo-regimen for metastatic upper tract urothelial carcinoma, and gemcitabine and cisplatin with dose reductions is also the first choice even in patients with impaired renal function and (x) 10.5% of urologists always or sometimes perform single intravesical chemotherapy immediately after radical nephroureterectomy.
The management strategy for upper tract urothelial carcinoma has changed with the introduction of new devices and development of instruments. The lack of clear evidence for relatively uncommon upper tract urothelial carcinoma affects the consistency of its treatment strategies.
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