High Stage Bladder Cancer Research Articles

2004P The combination of high levels of serum cytokeratin fragment 21-1 and VI-RADS≧4 has diagnostic and prognostic value in high-stage bladder cancer

2004P The combination of high levels of serum cytokeratin fragment 21-1 and VI-RADS≧4 has diagnostic and prognostic value in high-stage bladder cancer

P195 - Efficacy of the vesical imaging reporting and data system and serum CYFRA 21-1 in diagnosing high-stage bladder cancer

P195 - Efficacy of the vesical imaging reporting and data system and serum CYFRA 21-1 in diagnosing high-stage bladder cancer

RalGPS2 Interacts with Akt and PDK1 Promoting Tunneling Nanotubes Formation in Bladder Cancer and Kidney Cells Microenvironment.

Simple SummaryCell-to-cell communication in the tumor microenvironment is a crucial process to orchestrate the different components of the tumoral infrastructure. Among the mechanisms of cellular interplay in cancer cells, tunneling nanotubes (TNTs) are dynamic connections that play an important role. The mechanism of the formation of TNTs among cells and the molecules involved in the process remain to be elucidated. In this study, we analyze several bladder cancer cell lines, representative of tumors at different stages and grades. We demonstrate that TNTs are formed only by mid or high-stage cell lines that show muscle-invasive properties and that they actively transport mitochondria and proteins. The formation of TNTs is triggered by stressful conditions and starts with the assembly of a specific multimolecular complex. In this study, we characterize some of the protein components of the TNTs complex, as they are potential novel molecular targets for future therapies aimed at counteracting tumor progression.RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In particular, TNTs are a novel mechanism of cell–cell communication in the tumor microenvironment, playing a central role in cancer progression and metastasis formation. However, the molecular mechanisms involved in TNTs formation still need to be fully elucidated. Here we demonstrate that mid and high-stage bladder cancer cell lines have functional TNTs, which can transfer mitochondria. Moreover, using confocal fluorescence time-lapse microscopy, we show in 5637 cells that TNTs mediate the trafficking of RalA protein and transmembrane MHC class III protein leukocyte-specific transcript 1 (LST1). Furthermore, we show that RalGPS2 is essential for nanotubes generation, and stress conditions boost its expression both in 5637 and HEK293 cell lines. Finally, we prove that RalGPS2 interacts with Akt and PDK1, in addition to LST1 and RalA, leading to the formation of a complex that promotes nanotubes formation. In conclusion, our findings suggest that in the tumor microenvironment, RalGPS2 orchestrates the assembly of multimolecular complexes that drive the formation of TNTs.

Prognostic Significance of Lymphocyte Infiltration and a Stromal Immunostaining of a Bladder Cancer Associated Diagnostic Panel in Urothelial Carcinoma.

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder cancer-associated diagnostic signature were chemokines, cytokines, or secreted proteins, we set out to report the stromal staining pattern of the diagnostic signature as well as CD3+ (T-cell) cell and CD68+ (macrophage) cell staining in human bladder tumors as a snapshot of the tumor immune landscape. Immunohistochemical staining was performed on 213 tumor specimens and 74 benign controls. Images were digitally captured and quantitated using Aperio (Vista, CA). The expression patterns were correlated with tumor grade, tumor stage, and outcome measures. We noted a positive correlation of seven of the 10 proteins (excluding A1AT and IL8 which had a negative association and VEGFA had no association) in bladder cancer. The overexpression of MMP10 was associated with higher grade disease, while overexpression of MMP10, PAI1, SDC1 and ANG were associated with high stage bladder cancer and CA9 was associated with low stage bladder cancer. Increased tumor infiltration of CD68+ cells were associated with higher stage disease. Overall survival was significantly reduced in bladder cancer patients’ whose tumors expressed eight or more of the 10 proteins that comprise the bladder cancer diagnostic panel. These findings confirm that the chemokines, cytokines, and secreted proteins in a urine-based diagnostic panel are atypically expressed, not only in the epithelial component of bladder tumors, but also in the stromal component of bladder tumors and portends a worse overall survival. Thus, when assessing immunohistochemical staining, it is important to report staining patterns within the stroma as well as the entire stroma itself.

71 - Men have an increased incidence of high stage bladder cancer

71 - Men have an increased incidence of high stage bladder cancer

Correlation of metabolic syndrome with tumor grade and stage of primary bladder carcinoma

Objective To evaluate the relationship between metabolic syndrome, its components and the histopathological findings in bladder cancer patients. Methods The data of 326 patients in our department between October 2010 and October 2013 were retrospectively analyzed. Age, gender, stature, weight, histologic stage, grade, and the presence of hypertension, diabetes mellitus, body mass index (BMI) were evaluated. There were 64 females, 262 males, aged 23-89 years, including 241 low stage, 85 high stage, 155 low grade, and 171 high grade, respectively. There were 117 cases with hypertension, 95 cases with diabetes mellitus, 139 cases with BMI ≥25 kg/m2 and 49 cases with metabolic syndrome. The TNM classification was used, with Ta and T1 tumor accepted as low stage, T2, T3 and T4 tumor as high stage bladder cancer. In addition, the pathological grading system adopted by the 2004 World Health Organization was applied. Non-invasive papillary urothelial neoplasms of low malignant potential were regarded as low grade. Analyses were completed using Chi-square tests to evaluate the correlation of diabetes mellitus, hypertension and obesity with the pathologic stage and grade. Moreover, the pathologic stage, grade and recurrence were compared between metabolic syndrome and non-metabolic syndrome groups. Results Metabolic syndrome was significantly associated with histological grade and stage (P=0.001, P=0.011). Diabetes mellitus and obesity were also associated with histological grade and stage (P=0.006, P<0.01). Conclusions Patients with metabolic syndrome were found to have significant higher T stage and grade of bladder cancer. Diabetes mellitus and obesity may promote the grading and staging of bladder cancer. Key words: Urinary bladder neoplasms; Metabolic syndrome; Diabetes mellitus; Obesity; Histological grade and stage

Overexpression of PTP4A3 is associated with metastasis and unfavorable prognosis in bladder cancer.

Bladder cancer (BC) is the most common malignancy in urinary system. The prognosis of metastatic BC is poor, but there remains no reliable marker to early detect metastasis. Dysregulated prenylated protein tyrosine phosphatases (PTPs) are commonly associated with cancer metastasis. From a published BC transcriptome, we identified that PTP IVA3 (PTP4A3) was the most significantly upregulated gene implicated in tumor progression among genes related to prenylated PTPs. We therefore analyzed PTP4A3 expression in our well-characterized cohort of BC. By immunohistochemistry, PTP4A3 expression was determined using H-score. PTP4A3 expression of 295 BCs was compared with clinicopathological parameters, and the effect of PTP4A3 on cancer-specific survival (CSS) and metastasis-free survival (MFS) was also examined. Two independent sets of BCs were used to assess PTP4A3 protein and transcript expression in normal urothelium and different stage tumors. PTP4A3 overexpression was significantly associated with higher pT stage (P<0.001), nodal metastasis (P<0.001), vascular invasion (P<0.001), and perineural invasion (P=0.021). In multivariate analysis, PTP4A3 overexpression was an independent predictor for CSS (P<0.001) and MFS (P=0.007). Notably, the difference in CSS and MFS between high and low PTP4A3-expressing tumors was also significant in muscle-invasive BCs. PTP4A3 protein expression showed significant and stepwise increments from normal urothelium to noninvasive BC, invasive BC, and metastatic foci (P<0.001). PTP4A3 transcript was also obviously upregulated in high-stage BC (P<0.001). PTP4A3 may play a role in BC oncogenesis and is a predictive marker of metastasis. PTP4A3 overexpression represents an independent prognosticator for BC, suggesting its potential theranostic value.

Validation and clinicopathologic associations of a urine-based bladder cancer biomarker signature.

BackgroundTo validate the expression of a urine-based bladder cancer associated diagnostic signature comprised of 10 targets; ANG, CA9, MMP9, MMP10, SERPINA1, APOE, SDC1, VEGFA, SERPINE1 and IL8 in bladder tumor tissues.MethodsImmunohistochemical analyses were performed on tumor specimens from 213 bladder cancer patients (transitional cell carcinoma only) and 74 controls. Staining patterns were digitally captured and quantitated (Aperio, Vista, CA), and expression was correlated with tumor stage, tumor grade and outcome measures.ResultsWe revealed a positive association of 9 of the 10 proteins (excluding VEGF) in bladder cancer. Relative to control cases, a reduction in SDC1 and overexpression of MMP9, MMP10, SERPINE1, IL8, APOE, SERPINA1, ANG were associated with high stage bladder cancer. Reduced VEGF and increased SERPINA1 were associated with high-grade bladder cancer. Disease-specific survival was significantly reduced in tumors with high expression of SERPINE1 and/or IL8.ConclusionsThese findings confirm that the proteins in a urine-based diagnostic signature are aberrantly expressed in bladder tumor tissues, and support the potential additional utility of selected biomarkers for the clinicopathological evaluation of excised tissue or biopsy material.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_200

Histogram Analysis of Apparent Diffusion Coefficient at 3.0 T in Urinary Bladder Lesions: Correlation with Pathologic Findings

To investigate the potential value of histogram analysis of apparent diffusion coefficient (ADC) obtained at standard (700s/mm(2)) and high (1500s/mm(2)) b values on a 3.0-T scanner in the differentiation of bladder cancer from benign lesions and in assessing bladder tumors of different pathologic T stages and to evaluate the diagnostic performance of ADC-based histogram parameters. In all, 52 patients with bladder lesions, including benign lesions (n=7) and malignant tumors (n=45; T1 stage or less, 23; T2 stage, 7; T3 stage, 8; and T4 stage, 7), were retrospectively evaluated. Magnetic resonance examination at 3.0 T and diffusion-weighted imaging were performed. ADC maps were obtained at two b values (b=700 and 1500s/mm(2); ie, ADC-700 and ADC-1500). Parameters of histogram analysis included mean, kurtosis, skewness, and entropy. The correlations between these parameters and pathologic results were revealed. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic value of histogram parameters. Significant differences were found in mean ADC-700, mean ADC-1500, skewness ADC-1500, and kurtosis ADC-1500 between bladder cancer and benign lesions (P=.002-.032). There were also significant differences in mean ADC-700, mean ADC-1500, and kurtosis ADC-1500 among bladder tumors of different pathologic T stages (P=.000-.046). No significant differences were observed in other parameters. Mean ADC-1500 and kurtosis ADC-1500 were significantly correlated with T stage, respectively (ρ=-0.614, P< .001; ρ=0.374, P=.011). ROC analysis showed that the combination of mean ADC-1500 and kurtosis ADC-1500 has the maximal area under the ROC curve (AUC, 0.894; P< .001) in the differentiation of benign lesions and malignant tumors, with a sensitivity of 77.78% and specificity of 100%. AUCs for differentiating low- and high-stage tumors were 0.840 for mean ADC-1500 (P< .001) and 0.696 for kurtosis ADC-1500 (P=.015). Histogram analysis of ADC-1500 at 3.0 T can be useful in evaluation of bladder lesions. A combination of mean ADC-1500 and kurtosis ADC-1500 may be more beneficial in the differentiation of benign and malignant lesions. Mean ADC-1500 was the most promising parameter for differentiating low- from high-stage bladder cancer.

Uretero‐ureterocutaneostomy (wrapped by omentum)

The tubularized-incised plate urethroplasty has traditionally been used in children for repairing hypospadias. As shown here, it can also be used successfully in adults, with very good results. The rate of wound healing, infection and complications is the same as in children, as are the cosmetic and functional outcomes. To evaluate the outcome of uretero-ureterocutaneostomy (UUC) wrapped by omentum for palliative cystectomy in symptomatic elderly high-risk patients with high-stage bladder cancer. The study included 15 patients (14 men and one woman, aged 72-87 years, American Society of Anesthesiology score 3) with symptomatic recurrent bleeding bladder cancer (T2/T3) who were treated with palliative cystectomy. UUC was performed by mobilizing the right pre-vesical divided ureter up to the pelvi-ureteric junction and a high retroperitoneal crossover to the divided left ureter. A stoma was created with a circular 2-cm skin excision and resecting the fatty subcutaneous tissue. Wrapped by the omentum, both well-vascularized ureteric stumps were pulled through a cross-like fascia incision up to skin level. Spatulated and everted, the 'butterfly' flaps were fixed to the skin and underlying omentum. Soft splints were inserted for 21 days and a Karaya ring placed. The postoperative course and stoma healing was normal in 14 of the 15 patients; the sigmoid was resected because of sigmoid diverticulitis in one. The median (range) follow-up was 15 (6-24) months. There was pyelonephritis in one patient, and the dilatation of the upper tract (grade 3) in two returned to grade 2, with new asymptomatic grade 1 dilatation in one other. All patients were without stents and stoma care was provided at home. This modified UUC by omental wrapping in 15 high-risk patients after palliative cystectomy was simple and safe, and their recovery was uneventful. To date the few patients with stomal obstruction were managed by J catheters, changed every 4-6 months.

Clinical Evaluation of Adjuvant Chemotherapy for High Stage Bladder Cancer

Thirty-seven patients who had undergone radical cystectomy and pelvic node dissection for pathologic stage pT2-4 and/or N+ disease received adjuvant chemotherapy involving the injection of cis-platinum alone or in its combination from June 1982 to April 1989. Adjuvant chemotherapy was performed using the following three protocols. Protocol 1 entails the administration of cis-platinum alone. Protocol 2, involving the administration of a combination of cis-platinum, adriamycin and 5-fluorouracil (CAF), was used for deeply invasive bladder cancer. Protocol 3, consisting of cis-platinum, vp-16 and adriamycin (CVA), was employed in patients with deeply invasive bladder cancer instead of protocol 2 from July 1987. Of the 37 patients, 27 were alive with no evidence of disease for an average of 42 months. One patient died as a result of factors unrelated to cancer. Local recurrence and/or distant metastases occurred in 9 patients and all died of cancer progression. The survival rate for all 37 patients at 87 months was 64.4%. The rates were 75% in pT2, 80% in pT3a, 50.8% in pT3b, and 44.4% in pT4. Although adjuvant chemotherapy combined with radical cystectomy seemed to be effective in cases with pathological stage pT3a or less, more intensive chemotherapy is needed in an attempt to improve poor prognosis in cases with pathological stages pT3b-4 or node involvement.

異型度3膀胱癌患者の予後

The pathological features and clinical outcome of grade 3 transitional cell carcinoma of the bladder, excluding CIS, encountered between 1972 and 1988 were studied to clarify the clinical characteristics of the disease. The subjects of this study were 108 patients consisting of 76 males and 32 females aged 33-87 years, with a mean age of 66 years. The survival rate according to each factor was calculated by Kaplan-Meier method, and the survival curves were compared by generalized Wilcoxon test. Grade 3 bladder cancer was often papillary, sessile and about 3 cm in diameter and showed a tendency of multiple occurrence. Histopathologically, it was often in high stages of pT2 or above and frequently with vascular invasion. Total cystectomy is not considered to be an absolute necessity for pT1, G3 bladder cancer patient, because, in our experience, it did not improve the prognosis. However, bladder-preserving operation requires strict postoperative follow-ups. After this operation, the 5-year survival rate was higher in the no-recurrence group than in the recurrence group, and the out come tended to be better in the group that had undergone intravesical instillation chemotherapy for prevention of recurrence than in the group without this therapy. Ample intravesical instillation chemotherapy after bladder-preserving operation seems to improve the postoperative course of bladder cancer patients. Total cystectomy may be unavoidable in patients with pT2 or above, and no effect of postoperative adjuvant chemotherapy was noted in our series. The establishment of multidisciplinary approaches is considered to be needed for improvement of the prognosis of high stage bladder cancer.

Analysis of natural killer activity and natural killer cell subsets in patients with bladder cancer.

In order to analyze the state of the natural resistance system of bladder cancer patients in vivo, we measured natural killer (NK) activity and NK cell subsets of peripheral blood lymphocytes (PBL) from 46 patients with bladder cancer and 25 age- and sex-matched healthy volunteers. The mean NK activity in patients with low-stage bladder cancer was similar to that in the controls, while NK activity in patients with high-stage bladder cancer was significantly depressed. The mean proportions of Leu7+ cells in patients with both low-stage and high-stage bladder cancer were significantly higher than that in the controls. The mean proportion of Leu11 a+ cells in patients with low-stage bladder cancer was similar to that in the controls, while in patients with high-stage bladder cancer it was significantly higher. This study demonstrates the abnormal immunological state of bladder cancer patients: namely, abnormalities exist not only in NK activity but also in the proportions of circulating NK cell subsets.

High-stage bladder cancer: bladder preservation or reconstruction?

The availability of potentially effective systemic chemotherapy for transitional cell carcinoma of the bladder and the functional improvements afforded by new methods of urinary diversion have both contributed to significant changes in the treatment of high-stage bladder cancer. The clinician must decide at the beginning of therapy whether to use a bladder-preservation or bladder-reconstruction approach. The decision may be based on survival or on quality of life--two different goals that require different studies. When multiple types of treatments are combined, cumulative toxicity must be examined carefully.

Clinical Studies on Cell‐mediated Immunity in Patients with Urinary Bladder Carcinoma: Blastogenic Response, Interleukin‐2 Production and Interferon‐y Production of Lymphocytes

Patients with advanced malignant neoplasms have a variety of abnormal lymphocyte functions. We examined the PHA blastogenic response, interleukin-2 (IL-2) production and interferon-gamma (IFN-gamma) production of lymphocytes in 39 bladder cancer patients and 20 control subjects. Correlation between these parameters was also studied. IL-2 production was measured by 3H-thymidine-labelled CTLL-2 assay, and IFN-gamma production was measured by immunoradiometric assay using 2 mouse monoclonal antibodies. As a result, in high stage bladder cancer patients, the PHA blastogenic response, IL-2 production and IFN-gamma production were impaired. However, these parameters were not significantly different between low stage bladder cancer patients and control subjects. There was a significant correlation between the PHA blastogenic response and IL-2 production but no significant correlation between the PHA blastogenic response and IFN-gamma production.

Defective Interleukin‐1 Production of Monocytes in Patients with Bladder Cancer

Patients with advanced malignant neoplasms have a variety of abnormal lymphocyte and monocyte functions. We examined the PHA (phytohaemagglutinin) blastogenic response of lymphocytes and interleukin-1 (IL-1) production of monocytes in 40 bladder cancer patients and 16 control subjects. The correlation between the 2 parameters was also studied. The PHA blastogenic response was measured by the incorporation of 3H-thymidine into lymphocytes. IL-1 production was assayed by the murine thymocyte 3H-thymidine incorporation assay. As a result, the PHA blastogenic response and IL-1 production were significantly lower in the high stage bladder cancer patients compared to the control subjects and low stage patients. However, there was no significant correlation between the 2 parameters. Furthermore, with the addition of indomethacin, IL-1 production in the control subjects and low stage patients improved to the same degree, but it did not reach the control level in the high stage patients.

Correlation of tumor necrosis factor and prostaglandin E2 production of monocytes in bladder cancer patients.

Patients with advanced malignant neoplasms have a variety of abnormal monocyte and lymphocyte functions. The authors examined tumor necrosis factor (TNF) and prostaglandin E2 (PGE2) production of monocytes in 48 patients with bladder cancer and 16 control subjects. Monocytes were isolated from peripheral blood mononuclear cells by adherence to plastic tissue. They were cultured with lipopolysaccharide for 24 hours, and the culture supernatant was obtained. The TNF was measured by enzyme immunoassay using anti-recombinant human TNF antibody, and PGE2 was measured by radioimmunoassay. As a result, in high-stage bladder cancer patients, there was a significant inverse correlation between TNF and PGE2 production of monocytes. However, there was no significant correlation in control subjects and low stage patients. Accordingly, some patients with high-stage bladder cancer had higher TNF production but lower PGE2 production of monocytes, and vice versa.