Background:We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer.Methods:Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months.Results:Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model.Conclusion:Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.
What ' s known on the subject? and What does the study add? Adjuvant intravesical BCG therapy is the most effective regimen for non-muscleinvasive bladder cancer. Previously, patients who experienced recurrences after BCG therapy tended to be lumped together as patients with ' BCG failure ' , but BCG failure was defi ned inconsistently in each study and several studies indicated that patients with a particular pattern of BCG failure had a worse prognosis.We divided patients with BCG failure into four groups, which were based mainly on the responsiveness to BCG therapy and duration until tumour recurrence. Patients in the BCG-refractory group, in particular, had a higher risk for subsequent stage progression and disease-specifi c death over a long duration compared with patients in the other BCG-failure groups. As the defi nitions of BCG failure used to date have been decidedly heterogeneous, we recommend that standardized treatment decisions, protocols and recommendations be established according to individual BCG failure patterns. OBJECTIVE• To investigate the differences in the clinical features and subsequent stage progression and disease-specifi c survival among patients with Bacillus CalmetteGu é rin (BCG) failure, after dividing these patients into BCG-refractory, -resistant, -relapsing, and -intolerant groups. PATIENTS AND METHODS• We identifi ed 173 patients with initial BCG failure from 521 patients who had undergone induction BCG therapy for non-muscle-invasive bladder cancer, excluding CIS, between 1987 and 2009.• Patients were stratifi ed into four BCG-failure groups, and each prognostic outcome was evaluated. RESULTS• Median follow-up period from initial BCG failure was 4.7 years.• A total of 42 patients (24.3%) were stratifi ed into the BCG-refractory, three (1.7%) into the BCG-resistant, 106 (61.3%) into the BCG-relapsing, and 22 (12.7%) into the BCG-intolerant group.• Twenty-four patients (13.9%) experienced stage progression during follow-up.• Multivariate analysis showed that pathological G3 at BCG failure ( P = 0.014; risk ratio 2.84) and BCG-refractory ( P < 0.001; risk ratio 4.68) were independent predictors for stage progression. The 10-year progression-free survival rates were 53.2%, 91.1% and 93.8% in the BCG-refractory, BCG-relapsing and BCG-intolerant groups, respectively. The stage progression rate was higher in the BCG-refractory than in the BCG-relapsing ( P < 0.001) and BCG-intolerant ( P = 0.007) groups.• Similarly, the 10-year disease-specifi c survival rate in the BCG-refractory group was signifi cantly worse than those in the other BCG failure groups ( P < 0.001). CONCLUSIONS• Stratifi cation of BCG failure into the above-mentioned four groups can identify patients with BCG-failure in terms of their prognosis.• The potential risk for critical adverse events was higher in the BCG-refractory group than in the other BCG-failure groups, despite the fact that patients in each group all underwent induction BCG therapy, therefore, treatment decisions, protocols and recommendations shou...
What ' s known on the subject? and What does the study add? So far, few previous reports have analysed the risk factors for tumour recurrence and stage progression with a special focus on BCG-relapsing disease, defi ned as the recurrence after achieving a disease-free status by initial BCG instillations for 6 months. There are no guidelines outlining a specifi c treatment strategy for BCGrelapsing disease, although many BCG failure cases are attributable to BCG-relapsing disease.In this study, additional BCG instillation was shown to decrease the subsequent tumour recurrence rate against BCG-relapsing tumours with intermediate pathological risk features; however, a BCG-relapsing tumour with a pathologically high risk was a signifi cant risk factor for both subsequent tumour recurrence and stage progression. This information might identify a therapeutic strategy for BCG-relapsing tumours. OBJECTIVE• To investigate the risk of subsequent tumour recurrence and stage progression in bacillus Calmette-Gu é rin (BCG)-relapsing non-muscle-invasive bladder cancer, defi ned as recurrence after achieving a disease-free status for 6 months. PATIENTS AND METHODS• A total of 183 patients with BCGrelapsing tumours were treated with conservative therapy between 1985 and 2008 at our three institutions.• We analysed the association between their clinicopathological parameters and subsequent tumour recurrence or stage progression. RESULTS• Additional induction courses of BCG or anticancer drug (mitomycin C or epirubicin) instillations were performed in 119 patients and 24 patients, respectively. The remaining 40 patients did not undergo any adjuvant therapy.• Multivariate analysis showed that a relapsing tumour with a pathologically high risk (defi ned as tumours with G3 and/or pT1 and/or concomitant carcinoma in situ ) was a signifi cant risk factor for subsequent tumour recurrence ( P = 0.002; hazard ratio [ HR ] 2.15). Additional BCG instillation signifi cantly decreased the subsequent tumour recurrence rate ( P < 0.001; HR 0.41).• Multivariate analysis also showed that a relapsing tumour with a pathologically high risk was also signifi cantly associated with stage progression ( P < 0.001; HR 8.05). CONCLUSIONS• An additional course of BCG instillation might be effective in patients with BCG-relapsing tumours with pathologically intermediate risk.• Nevertheless, some patients with high-risk pathological features developed subsequent stage progression. Such patients should be followed up closely and counselled on the need for aggressive therapeutic options, such as radical cystectomy. KEYWORDSBCG relapsing , tumour recurrence , stage progression , bacille Calmette-Gu é rin , BCG failure , non-muscle-invasive bladder cancer Study Type -Therapy (case series) Level of Evidence 4
A total of 96 cases of renal carcinoma with distant metastasis at the time of diagnosis was studied. The patients were classified into 4 groups: Group O (16) in whom nephrectomy was not performed, Group A (51) who died due to carcinoma within 1 year of nephrectomy, Group B (25) who died due to carcinoma 1 to 3 years after nephrectomy, and Group C (4) who survived for 3 years or more after nephrectomy. Six clinical measurements were evaluated: haemoglobin, ESR, alpha 2 globulin, temperature, weight and C reactive protein. In addition, performance status, the number of organs with metastases, number of metastatic lesions and tumour growth rate were measured. The results showed that in patients surviving for 1 year or more after nephrectomy, there was an abnormality in the results of 3 or less of the 6 clinical measurements, performance was 0 or 1, and the carcinoma had metastasised to only one organ. In addition, it was found that the growth of metastatic lesions in patients who survived for 3 years or more was much slower than in the other patients. Nephrectomy was found to be effective in only 27% of our cases and we consider that careful deliberation should be made pre-operatively as to whether nephrectomy is really necessary in patients with metastasis. The decision should be made on the basis of the results obtained in the 6 clinical measurements given above.
In conclusion, renal cell carcinoma accompanied by later development of pancreatic metastasis tend to occur in younger patients and have higher incidence in females than in males when compared with otherwise similar renal cell carcinomas. Furthermore, they tend to be of low stage and grade, have longer intervals to the occurrence of metastasis and carry a poor prognosis.
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