Intravesical BCG Instillation Research Articles

1133 - Intravesical BCG instillation is strongly associated with a decreased risk of upper tract urothelial carcinoma recurrence as well as intravesical recurrence in elderly male patients with non-muscle invasive bladder cancer

1133 - Intravesical BCG instillation is strongly associated with a decreased risk of upper tract urothelial carcinoma recurrence as well as intravesical recurrence in elderly male patients with non-muscle invasive bladder cancer

Tuberculous spondylitis following intravesical bcg-instillation in the treatment of transitional cell carcinoma: Case report and systematic review

ObjectivesTuberculous spondylitis (TS), also known as Pott’s disease (PD), is a form of tuberculosis in which the vertebral column is affected. Since the first description by Katz et al. in 1992, it became clear that Bacillus Calmette-Guérin (BCG) instillations in the treatment of superficial transitional cell carcinoma (TCC) form a plausible way in which PD is introduced. Nowadays, BCG forms the most effective treatment modality for superficial TCC. The incidence of other than minor complications have been estimated under five per cent. Here we report a case of TS after BCG-instillation in the treatment of TCC. Furthermore, all available literature concerning this topic was gathered into a systematic review. The primary objective was to create an overview of all available literature concerning TS after intravesical BCG-instillations, with an emphasis on the neurosurgical approach of these patients, forming a scaffold at which future case reports can be compared. As a secondary objective, we tried to raise the awareness concerning this very rare complication of intravesical BCG-instillation as a possible cause of low back pain (LBP). Patients and MethodsWe performed a systematic review, in which patients who developed TS after intravesical BCG-therapy in the treatment of TCC, were examined. A total of twenty-three articles (twenty-four cases) obtained from MEDLINE were included. Search terms included: “tuberculous spondylitis”, “Pott’s disease”, “vertebral osteomyelitis”, “intravesical”, “Bacillus Calmette-Guérin” and “transitional cell carcinoma”. Additional studies were identified by checking reference lists. Furthermore, we present a case concerning one of our own patients who consulted our Neurosurgical department with a similar clinical presentation. This systematic review is in conformity with the PRISMA-guidelines. The case report is in accordance with the CARE statement guidelines. ResultsResults are based on twenty-five cases (twenty-four cases extracted from previous literature and our case report). All included articles are case reports written in English. Publication year and recruitment time varies from 1992 to 2018. Mean age at clinical presentation varies from 35 to 94 years old (mean 74). All patients were male. Surgery was performed in 17 out of 25 cases (68%). A posterior approach was performed in seven cases (41%), zero anterior approaches (0%), a combined approach in five cases (29%) and not specified in five cases (29%). All patients received intravesical BCG-instillation in the treatment of TCC, ranging from one month to twelve years before clinical presentation (mean 26). Radiographic abnormalities were seen in thoracic vertebral segments in thirteen cases (52%), eleven cases in lumbar segments (44%), one at the thoracolumbar transition level (4%) and not in cervical vertebral segments. ConclusionAlthough very rare, TS should be part of the differential diagnosis in patients with LBP, even years after BCG-instillation for TCC. It mostly affects elderly men and involves the thoracolumbar spine through hematogenous spread via Batson’s plexus. Antitubercular therapy remains the mainstay in the treatment of TS. A posterior surgical approach, with debridement and stabilization, should be preferred when surgical intervention seems necessary. To our knowledge, this systematic review forms one of the first comprehensive reviews evaluating neurosurgical intervention for PD following intravesical BCG-therapy in the treatment of TCC.

MP82-18 INTRAVESICAL BCG INSTILLATION IS STRONGLY ASSOCIATED WITH A DECREASED RISK OF UPPER TRACT UROTHELIAL CARCINOMA RECURRENCE AS WELL AS INTRAVESICAL RECURRENCE IN ELDERLY MALE PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP82)1 Apr 2020MP82-18 INTRAVESICAL BCG INSTILLATION IS STRONGLY ASSOCIATED WITH A DECREASED RISK OF UPPER TRACT UROTHELIAL CARCINOMA RECURRENCE AS WELL AS INTRAVESICAL RECURRENCE IN ELDERLY MALE PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER Hiroki Ide*, Naoya Niwa, Yuto Baba, and Mototsugu Oya Hiroki Ide*Hiroki Ide* More articles by this author , Naoya NiwaNaoya Niwa More articles by this author , Yuto BabaYuto Baba More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000974.018AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The incidence of elderly males with VUR increases with age, likely to be due to the higher number of men with bladder outlet obstruction. Therefore, intravesical BCG instillation after transurethral resection of bladder tumor (TURBT) may effectively prevent upper tract urothelial carcinoma (UTUC) recurrence as well as bladder recurrence, particularly in elderly males. In the present study, we investigated these relationships in non-muscle invasive bladder cancer (NMIBC) patients. METHODS: Our study population comprised 1128 NMIBC patients without a history of UTUC. Tumor grade and stage were 62.0% low and 38.0% high grade; 68.4% Ta and 31.6% T1 and/or CIS. The mean follow-up period and age were 64 months and 68.2 years old, respectively. We investigated the relationships between clinicopathological factors, including BCG instillation, and UTUC development in NMIBC patients. RESULTS: During the follow-up period, recurrent bladder cancer and UTUC developed in 437 (38.7%) and 38 (3.4%) out of all NMIBC patients, among whom 548 (48.6%) received BCG instillation after surgery. Five-year bladder and UTUC recurrence rates were 33.3 (30.1% in Ta and 37.6% in T1 and/or CIS) and 1.9%, respectively, in patients treated with BCG, which were significantly lower than in those without BCG {47.7 (44.7% in Ta and 47.0% in T1 and/or CIS) and 4.7%, p=0.001 and 0.005, respectively}. A multivariate Cox regression analysis identified BCG instillation as an independent factor for bladder and UTUC recurrence in all NMIBC patients (p=0.001 and 0.001, hazard ratio=0.517 and 0.260, respectively). Furthermore, in male patients, the 5-year UTUC recurrence rate was significantly lower in patients treated with BCG (2.0%) than in those without BCG (4.3%, p=0.022), whereas no significant differences were observed in female patients. In subgroups of older male patients (≥70 years), the 5-year UTUC recurrence rate was significantly lower in patients treated with BCG (1.6%) than in those without BCG (5.9%, p=0.031). In subgroups of younger male patients (<70 years), no significant differences were noted between these two groups. CONCLUSIONS: Intravesical BCG instillation after TURBT may prevent UTUC as well as bladder recurrence, particularly in older male NMIBC patients. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1253-e1254 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroki Ide* More articles by this author Naoya Niwa More articles by this author Yuto Baba More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement PDF downloadLoading ...

PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV (PD47)1 Apr 2020PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY Alok Singh*, Monali Praharaj, Kara Lombardo, Andres Matoso, Gregory Joice, Takahiro Yoshida, Max Kates, David McConkey, William Bishai, and Trinity J. Bivalacqua Alok Singh*Alok Singh* More articles by this author , Monali PraharajMonali Praharaj More articles by this author , Kara LombardoKara Lombardo More articles by this author , Andres MatosoAndres Matoso More articles by this author , Gregory JoiceGregory Joice More articles by this author , Takahiro YoshidaTakahiro Yoshida More articles by this author , Max KatesMax Kates More articles by this author , David McConkeyDavid McConkey More articles by this author , William BishaiWilliam Bishai More articles by this author , and Trinity J. BivalacquaTrinity J. Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000934.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Trained immunity (TI) involving metabolic and epigenetic reprogramming of monocytes/macrophages confers a heightened immune status, and BCG has been shown to be a potent inducer of TI. We hypothesized that a genetically engineered BCG overexpressing a STING agonist may be a stronger inducer of antitumor TI. Using a recombinant BCG strain (BCG-disA-OE) which releases high levels of the STING agonist c-di-AMP, we tested induction of TI phenotypes in NMIBC models in vitro and in vivo. METHODS: WT-BCG (Tice strain) and BCG-disA-OE were compared for their induction of cytokines and phagocytic capacity in primary human and murine macrophages using ELISA, flow-cytometry, and immunofluorescence. We also measured epigenetic changes in the promoter regions of key cytokines using ChIP-PCR in human PBMC-derived monocytes. Antitumor efficacy was tested in the rat MNU-carcinogen model of NMIBC following intravesical BCG instillation weekly x 6 using histochemical tumor grading and qRT-PCR of bladder tissue. RESULTS: Compared with BCG-WT, BCG-disA-OE strains showed increased IFN I, IL-6, TNF-α, MCP-1 and IL-12 levels in primary macrophages and bladder cancer cell lines We observed increased M1 polarization shift and higher phagocytic capacity in primary macrophages after infection with rBCG-disA-OE. The modified BCG also elicited more pronounced epigenetic changes (H3K4Me3) on the TNF-α and IL-6 gene promoters following monocyte training. Intravesical instillations of BCG-disA-OE in MNU-rats resulted into significantly lower tumor involvement index and a more a potent induction of Th1 cytokines compared to BCG-WT. CONCLUSIONS: BCG-disA-OE demonstrated superior antitumor efficacy in the rat NMIBC model. It also elicited greater levels of pro-inflammatory cytokine secretion, M1 macrophage polarization, and epigenetic reprogramming. These observations suggest that BCG-disA-OE elicits more potent trained immunity changes monocytic cell populations in the bladder, and that elevated trained immunity may correlate with treatment outcome. BCG-disA-OE shows promise as a novel intravesical immunotherapy for NMIBC. Source of Funding: Maryland Tedco, Willowcroft Foundation, and Cigarette Restitution Fund © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e928-e928 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alok Singh* More articles by this author Monali Praharaj More articles by this author Kara Lombardo More articles by this author Andres Matoso More articles by this author Gregory Joice More articles by this author Takahiro Yoshida More articles by this author Max Kates More articles by this author David McConkey More articles by this author William Bishai More articles by this author Trinity J. Bivalacqua More articles by this author Expand All Advertisement PDF downloadLoading ...

PD03-09 QUALITY CONTROL INDICATORS (QCIS) FOR TRANSURETHRAL RESECTIONS OF BLADDER TUMORS: CORRELATION OF QCIS WITH CLINICAL OUTCOME IN A BELGIAN MULTI-CENTER PROSPECTIVE REGISTRY

You have accessJournal of UrologyBladder Cancer: Non-invasive I (PD03)1 Apr 2020PD03-09 QUALITY CONTROL INDICATORS (QCIS) FOR TRANSURETHRAL RESECTIONS OF BLADDER TUMORS: CORRELATION OF QCIS WITH CLINICAL OUTCOME IN A BELGIAN MULTI-CENTER PROSPECTIVE REGISTRY Tim Muilwijk*, Murat Akand, Yannic Raskin, Cedric Jorissen, Lorenz Vanhoucke, Kathy Vander Eeckt, Siska Van Bruwaene, Ben Van Cleynenbreugel, Steven Joniau, and Frank Van Der Aa Tim Muilwijk*Tim Muilwijk* More articles by this author , Murat AkandMurat Akand More articles by this author , Yannic RaskinYannic Raskin More articles by this author , Cedric JorissenCedric Jorissen More articles by this author , Lorenz VanhouckeLorenz Vanhoucke More articles by this author , Kathy Vander EecktKathy Vander Eeckt More articles by this author , Siska Van BruwaeneSiska Van Bruwaene More articles by this author , Ben Van CleynenbreugelBen Van Cleynenbreugel More articles by this author , Steven JoniauSteven Joniau More articles by this author , and Frank Van Der AaFrank Van Der Aa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000823.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Quality control indicators (QCIs) can objectively evaluate guideline adherence. We assessed 6 QCIs, based on guideline recommendations, in the treatment of NMIBC using a prospective transurethral resection of bladder tumor (TURBT) registry in 3 Belgian centers and assessed whether these QCIs correlated with clinical outcome of patients. METHODS: TURBT procedures were collected using electronic case report forms (eCRFs) in a prospective TURBT registry in 3 centers between 06-2013 and 03-2017. Outcomes of interest were recurrence-free survival (RFS), overall survival (OS), and cystectomy-free survival (CFS). Six QCIs were assessed for their indication: complete resection status (CRS), repeat resection (re-TUR), presence of detrusor muscle (DM) in the resection specimen, single post-operative instillation of Mitomycin C (MMC), adjuvant intravesical instillation of BCG, and initial therapy ≤6 weeks after diagnosis. Kaplan-Meier plots were used for visualization of outcome data and log-rank to compare clinical outcome for each QCI. RESULTS: A total of 1350 TURBTs were collected, 1165 TURBTs met inclusion criteria for a total of 907 patients. Median follow up was 21.8 mo (IQR: 12.1-34.3). RFS, OS, and CFS at 4-year were 63.5% (95%CI: 59.7-67.5), 78.9% (95%CI: 75.2-82.8), and 93.1% (95%CI: 91.4-94.9) respectively. Scores on QCI were: CRS: 97.1%, re-TUR: 33.6%, DM: 45.8%, MMC: 69.6%, BCG: 39.6%, and timing ≤6 weeks 87.7%. The following QCIs had a significant impact on outcome: CRS on OS, and CFS; re-TUR on OS (Figure 1A), and CFS; MMC on RFS (Figure 1B); BCG on RFS (Figure 1C), and OS (Figure 1D). CONCLUSIONS: We demonstrate that we can assess QCIs (based onguideline recommendations) using a Belgian prospective multicenter TURBT registry. Furthermore, we demonstrate that the following QCIs were correlated with clinical outcome of patients: CRS, re-TUR, MMC, and BCG. Therefore, QCIs could be used to check guideline adherence, and allow for comparison between centers, with the ultimate goal of increasing guideline adherence. Source of Funding: NA © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e75-e75 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tim Muilwijk* More articles by this author Murat Akand More articles by this author Yannic Raskin More articles by this author Cedric Jorissen More articles by this author Lorenz Vanhoucke More articles by this author Kathy Vander Eeckt More articles by this author Siska Van Bruwaene More articles by this author Ben Van Cleynenbreugel More articles by this author Steven Joniau More articles by this author Frank Van Der Aa More articles by this author Expand All Advertisement PDF downloadLoading ...

Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS).

436 Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.

PD-L1/PD-1 expression as a predictor of response to BCG in patients with high-risk non–muscle invasive bladder cancer.

4550 Background: Intravesical BCG instillation (IBI) is the gold standard adjuvant treatment after transurethral resection of the bladder in high risk non muscle invasive bladder cancer (HR-NMIBC). IBI induce a type of Th1 immune response requiring a recruitment of cytotoxic cells. This response is downregulated by the PD-1/PD-L1 checkpoint inhibitors through an inhibition of the action of CD8+ T cells against their target. Our purpose was to assess whether PD-1/PD-L1 expression was associated with IBI response in HR-NMIBC. Methods: Histologically confirmed HR-NMBC from 5 academic French institutions which underwent maintenance IBI were retrospectively included. The following data were collected: pathological stage, grade, concomitant carcinoma in situ, number of lesions and size. From a paraffin embedded samples of initial resection, a unique dedicated uropathologist quantified immunochemistry expression of CD3, CD8, PD-L1 (antibody SP263/ SP142, E1L3N, 28 8) in both tumour cells and tumoral microenvironment. Univariate and multivariate analyses were performed using Cox proportional hazards model. Results: Overall 140 patients (median age 66.5 years, range:35-87; sex ratio male vs female:6:1) were included. The distribution of NMIBC tumour for stage and grade was: Ta 37.2% (n = 52), T1 62.8% (n = 88) and high grade 100% (n = 140) respectively. The median number of IBI which were delivered was 12 (range 7-36). The median length of follow-up was 54.24 mo (95% CI = 49.91-58.68). Overall, 25 patients (17.9%) had a recurrence/or progression. The 72mo Disease free survival (DFS) rate was 81.11% (95% CI = 72.20-87.41). Using univariate analysis, we found that Age (HR = 1.07; [1.02-1.12] p = 0.005), CD3/CD8 ratio (HR per 10 units = 3.43 [1.62-7.23] p = 0.014) and PD-L1(HR per 10 units = 1.65 [1.15-2.38] p = 0.046) were associated with DFS. In multivariate analysis, Age (HR = 1.07 [1.02-1.13] p = 0.009), CD3/CD8 ratio (HR per 10 units = 1.96 [1.28-3.00] p = 0.02) and PD-L1 expression in tumour cells (HR per 10 units = 3.38 [1.61-7.11] p = 0.01) remained significantly associated with DFS. Conclusions: PD-L1 expression in tumour cells and the T cells population in tumour microenvironment were both predictive factors of BCG response in HR-NMIBC. These results build a scientific rationale for pharmacological intervention on a molecular target using immuno-oncology.

MP63-19 IMMUNOGENICITY INVESTIGATION ON RECOMBINANT BCG CONTAINING NY-ESO-1 UPON VACCINATION

INTRODUCTION AND OBJECTIVES:Bladder cancer is one of the most common malignant tumors in the urinary system. Intravesical instillation of BCG has been proved to reduce the recurrence of bladder can...

İntravezikal BCG Uygulaması Sonrası Gelişen BCG Sepsisi: Bir Olgu Sunumu

İntravezikal BCG Uygulaması Sonrası Gelişen BCG Sepsisi: Bir Olgu Sunumu

710 - Treatment of high grade non-muscle invasive bladder carcinoma by standard number and dose of intravesical BCG instillations versus reduced number and dose of intravesical BCG instillations. An initial report of the phase III clinical trial ‘NIMBUS’

710 - Treatment of high grade non-muscle invasive bladder carcinoma by standard number and dose of intravesical BCG instillations versus reduced number and dose of intravesical BCG instillations. An initial report of the phase III clinical trial ‘NIMBUS’

Efficacy and complications of intravesical instillation of BCG for prevention of recurrence of moderate and high-risk non muscle invasive bladder cancer

Objective To assess the efficacy and side effects of intravesical instillation of BCG after transurethral resection of the bladder tumor (TURBT) in non-muscle invasive bladder cancer (NMIBC) patients. Methods The clinical data of patients treated with BCG 120 mg per course induced perfusion or more after TURBT from December 2013 to October 2016 in 18 hospitals of northeast China region, were analyzed retrospectively. The first part, data of 106 patients with moderate, high-risk NMIBC were collected. A total of 83 patients were male, while the other 23 patients were female. The average age was 66.7 years old.The clinical staging were T1 in 86(81.1%) cases, Ta in 20(18.9%) cases and carcinoma in situ in 6(5.7%)patients. Intravesical instillation of BCG was executed after transurethral resection of the bladder tumor. The incidence rate of recurrence and progression during more than 6 months’ follow-up time were observed. Multivariate analyses were done by using logistic analysis and Cox proportional hazards regression model with Kaplan-Meier method. The second part, treatment compliance of 276 patients with bladder cancer, including moderate/high-risk NMIBC in 263 cases, moderate/high-risk NMIBC followed with renal pelvis/ureteral carcinoma in 8 cases were and moderate/high-risk NMIBC with renal pelvis/ureteral carcinoma in 5 cases who treated with BCG after the surgeries, were observed. Patients consisted of 211 males and 65 females with average age of 68.3 years. Results With a median follow-up of 12 months, 9(8.5%) patients experienced tumor recurrence and 2(1.9%)patients were found progression in the first part. The one-year cancer free recurrence rate of the patients was 91.5%. Statistically significant prognostic factors for recurrence identified by multivariable analyses were prior recurrence of the tumors (OR=3.214, 95%CI 0.804-12.845, P=0.099). In the second port, an incidence rate of adverse effects was 64.1% (177/276). The Ⅲ/Ⅳ degree complications were occurred in 11 patients and satisfactory outcomes achieved with active treatment. A total of 36 patients withdrawal with the major causes were recurrence and progression of bladder tumor in 12 cases (4.4 %), 9 cases (3.3 %) with economic reasons and 11 cases(4.0%)with serious complications. Conclusions NMIBC patients treated with intravesical BCG therapy have approving cancer free recurrence rates and acceptable adverse effects. Prior recurrence may be prognostic factor of recurrence after intravesical BCG therapy. Key words: Non-muscle invasive bladder cancer; Bacillus Calmette Guerin; Recurrence; Adverse effects

A Case of PT1 Plasmacytoid Variant Bladder Cancer Treated by Bladder Conserving Therapy

Plasmacytoid variant bladder cancer is a highly malignant subtype associated with a high propensity for invasion, metastasis and poor prognosis. Among approximately 100 reported cases, most were diagnosed at an advanced stage and only 10 were diagnosed at a non-muscle-invasive stage. Due to the limited data on clinical features of non-muscle-invasive plasmacytoid variant bladder cancer, its treatment has not been established. We report a long-surviving patient with pT1 plasmacytoid variant bladder cancer in whom the bladder was conserved after detailed pathological examinations of the transurethral resection (TUR) specimen and intensive follow-up. A 65-year-old man presented with macroscopic hematuria. Cystoscopy revealed a nodular tumor 11 millimeters in diameter and no metastasis was observed on computed tomography. The histopathological diagnosis of the TUR specimen was pT1 plasmacytoid variant urothelial carcinoma of the bladder. Microvascular invasion was not found by immunohistochemical staining and histopathological examination of the specimen from the second TUR indicated no residual cancer. The patient strongly desired bladder conservation and additionally underwent intravesical instillation therapy with 40 mg of mitomycin C weekly for 6 consecutive weeks. Follow-up cystoscopy demonstrated 3 small papillary tumors 12 months after intravesical instillation therapy, but histopathologically, the recurrent tumors were pTa with pTis urothelial carcinomas without plasmacytoid components. To treat pTis disease, he subsequently underwent intravesical BCG instillation therapy. The plasmacytoid variant bladder cancer has not recurred for 26 months since the initial diagnosis. Non-muscle-invasive and localized plasmacytoid variant bladder cancer may be treated with bladder conserving therapy.

Results of Postoperative Instillation of Mitomycin C in Non Muscle Invasive Bladder Cancer after Complete Resection Versus BCG (Recurrence and Progression)

AbstractBackground: Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well-established treatment for preventing or delaying tumour recurrence after tumour resection. However, up to 70% of patients may fail. New protocols and new intravesical agents with improved effectiveness are neededAim of Study: Is to evaluate the oncological outcome as regard progression, local recurrence and side effects of non-muscle invasive transitional cell carcinoma of the urinary bladder managed by complete resection followed by postop-erative intravesical instillation of Mitomycin C compared with BCG.Patients and Methods: This is a prospective study that included 51 patients with non-muscle invasive TCC bladder (Ta and T1) at Urology Department, Al-Azhar University hospitals between 2011 and 2015. Patients divided into two groups, the Mitomycin group received immediate MMC and periodic 6 doses of MMC and the other group, BCG received 6 doses of BCG one dose per week. Follow-up by cystoscope for two years at 3th, 6th, 9th, 12th, 18th, 24th month to detect the recurrence, progression and side effects.Results: The mean age of the patients was 60.58 (37 yrs. - 79 yrs.) in the MMC group and 61.76 (48 yrs-83 yrs) in the BCG group. The main comparison in this study is recurrence rate and progression rate of the tumor. Three patients (11.5%) had recurrence in the 1st year while four patients (15.4%) in the 2nd year with total recurrence seven patients (26.9%) in MMC group.In the BCG group, patients who had a recurrence in the 1st year were, two patients (8%) and three patients (12%) in the 2nd year with total recurrence, five patients (20%).The total progression in two years were 4 pts (15.38%) (One patient (3.8%) in the 1st year) (3 patients (11.5%) in the 2nd year) in the MMC group while were 4 pts (16%) (One patient (4%) in the 1st year) (year 3 patients (12%) in the 2nd year) in the BCG group.Conclusion: Our study confirmed the positive effect of immediate Mitomycin C intravesical instillation in patients who received periodic Mitomycin C instillation and either the positive effect of intravesical instillation of BCG in patients with non-muscle-invasive bladder tumors. Our present study showed that MMC and BCG equally reduced recurrence and progression in NMIBC patients while showed the superiority of MMC regarding to the adverse effects.

Analytical study of bladder tumor

Background: Treatment of bladder tumor still provides the romance in Urology. The purpose of this study is to study the prevalence of various types of bladder tumors, to compare various treatment modalities for bladder tumors, to study different presentations of patients with bladder tumor.Methods: The present study was a prospective analytical study of 30 patients of bladder tumor conducted at Dhiraj General Hospital attached to S.B.K.S Medical College from October 2011 to July 2013. All the details of patients in term of demography, risk factors, symptoms and sign, radiological, endoscopic, histopathological features, various treatment modalities offered, and follow-up of patients were studied and analysed using descriptive statistics.Results: Maximum number of patients was presented in sixth decade of life. Youngest patient was 30 years old and oldest patient was 77 years old. 80% patients were male, and 20% patients were female. History of smoking was present in 22 patients, history of exposure to occupational hazards was present in 4 patients and only 2 patients had positive family history. Majority 93.3% patients were presented with haematuria and 16 patients had anaemia. 15 patients had high grade muscle invasive TCC, followed by 10 patients with low grade non-muscle invasive TCC. 3 patients were having low grade non-muscle invasive SCC, 1 patient was having high grade muscle invasive SCC and 1 patient was having high grade non-muscle invasive TCC.Conclusions: The findings of the study conclude that TURBT followed by intravesical instillation of BCG gave good results in patients with low grade and high grade non-muscle invasive tumor. For muscle invasive tumor radical cystectomy with urinary diversion is the ideal treatment but TURBT followed by radiotherapy has also given good results with fewer side effects.

High-grade superficial bladder tumors (PT1G3): Prognostic factors of recidive and progression

PT1G3 High-grade bladder tumors are superficial, poorly differentiated, they are characterized by there architectural disorganization and marked cytologic abnormalities. These tumors pose a diagnostic problem for the pathologist and a therapeutic problem for the urologist. The aim of this work is to study the predictive factors for recurrence and progression of pT1G3 bladder tumors. Material and method We undertook in this work a retrospective descriptive study, including 100 patients who were treated in the urology department between January 2010 and December 2012 at the University Hospital of Rabat (Morocco) for urothelial carcinoma classified T1G3. Rates of recurrence, progression were studied, and specific survival was done by the Kaplan–Meier method. The prognostic factors associated with this type of tumor were then investigated by Cox regression. The overall mean decline in the study was 53.7 months about 4.5 years. The patients were 91 (91%) men and 9 (9%) women. The average age of our patients was 58 years old with extremes ranging from 25 to 71 years old. Of the 100 patients in the study, 66 (66%) were classified T1G3 from the outset, while 34 were classified T1G3 during a recurrence (T1G3 secondary). Initial treatment consisted of deep and complete transurethral resection (RTU) in all patients. Follow-up of a BCG protocol therapy in 56 patients, among 56 (56%) patients who received BCG therapy 15 (26%) recidivated including 5 in progression, for another 44 (44%) patient group 30 (68%) recidivated, 12 of which were under progression. In univariate analysis, the significantly identified risk factors for recurrence were: tumor size > 5 cm (P = 0.01), multifocality of lesions and the lack of the adjuvant treatment to the transurethral resection of the bladder (P = 0.001) including BCG therapy. In multi-varied analysis, the significantly identified risk factors for progression and recurrence were: the presence of carcinoma in situ and the failure of BCG therapy (P = 0.001). The primary or secondary character of the tumor was not significant (P = 0.4). Thus, the difference in overall survival as a function of the initial or secondary status of T1G3 tumors was not significant when the other prognostic factors were taken into consideration. The results of this retrospective study suggest that T1G3 tumors can be safely controlled by the RTU + BCG combination. These results justify a good deep resection followed by a second resection at 6-week intervals and intravesical BCG instillations. This study also identifies PT1G3 patients at high-risk of recurrence and progression and requires close monitoring.

Predictive factors of failure of BCG therapy in high-level superficial bladder tumors

Introduction High-grade bladder tumors are superficial, poorly differentiated, they are characterized by there architectural disorganization and marked cytologic abnormalities. The treatment of superficial tumors of the bladder has a twofold objective: the first one is to reduce the frequency of local recurrences and, on the second one is to prevent progression towards muscular infiltration. Hence, the indication of the adjuvant treatment to the transurethral resection of the bladder. The purpose of our work is to study the predictive factors for the failure of intravesical BCG instillations in the management of these tumors. Failure was defined by the progression or recurrence of superficial high-grade bladder tumors. Material and method We undertook in this work a retrospective descriptive study, including 80 patients who were treated in the urology department “A” at the RABAT CHU for high-grade urothelial carcinoma PTa and PT1 between January 2010 and June 2013. Rates of recurrence, progression after BCG therapy were studied. The prognostic factors associated with this type of tumor were then sought after by Cox regression. The overall average decline in the study was 50 months or about 4.5 years. Results The patients were 71 men and 9 women. The average age of our patients was 60 years old with extremes ranging from 38 to 71 years old. At 50 months, 60% of patients treated with BCG therapy are free from recurrence. This rate is 69% for PTa tumors and 53% for pT1 tumors ( P = 0.03); 22 (27%) patients had a recurrence under the same histological grade in the first 24 months, 11 (13%) patients had tumor progression, 4 of which were infiltrating cystectomy treated. In univariate analysis, the significantly identified risk factors for recurrence were: multifocal lesions ( P = 0.001), presence of associated in situ carcinoma, vascular invasion ( P P = 0.001), and the lack of maintenance therapy with BCG therapy. The risk factors for progression were: the presence of CIS, the crossing of the lamina propria especially in PT1G3 tumors, and the size greater than 5 cm. In multi-varied analysis, the presence of CIS, crossing the lamina propria and the tumor size in case of tumor PT1G3 are the significant factors of the failure of BCG therapy ( P = 0.001). The primary or secondary character of the high histological grade of tumor, patient age and multifocality ( P = 0.4) were not significant. This multi-varied study also showed a strong correlation between tumor size and invasion of the lamina propria. Conclusion The results of this retrospective study suggest that high-grade tumors must be compulsorily controlled by BCG therapy with a maintenance protocol. This study also made it possible to select patients with very high-risk of recurrence and progression after BCG therapy who should receive close monitoring and cystectomy if BCG therapy fails.

Availability and Patterns of Intravesical BCG Instillations.

Intravesical BCG instillations improve recurrence free survival in patients with non-muscle-invasive bladder cancer (NMIBC). This is a national survey study, covering 223 urological centres, aimed at reliable identification of BCG availability and implemented treatment patterns. Response rate was 93.7%. BCG was used in 56.5% of urological departments. Another 22.7% referred patients to other hospitals for instillations, while 20.8% did not recommend BCG at all. The most common indications for BCG instillations were as follows: T1 tumours (88.5%), carcinoma in situ (83.6%) and high grade tumours (73.8%). Maintenance therapy was routinely abandoned in 16.4% of centres or was scheduled for <1 year, 1 year, 3 years and 1-3 years in 6.6%, 19.7%, 21.3% and 31.2% of centres, respectively. Continuation of BCGdespite treatment failure in carcinoma in situ cases was considered in 21.3% of departments. Our findings indicate that BCG is underused, while patterns of maintenance and follow-up are suboptimal.

Prognostic value of P53 nuclear overexpression in bladder cancer

Introduction: Urinary bladder cancer is one of the common genitourinary malignancy presenting to the urology department. Prognosis of these patients will depend upon the number of clinicopathological factors. Overexpression of p53 is associated with aggressive behaviour of bladder cancer. The purpose of the present study is to assess the role of p53 tumour suppressor gene as an independent prognostic marker. Materials & Methods: Thirty-three (33) consecutive cases of urinary bladder cancer attending Department of Urology between August 2006 to December 2008 were studied. In this study P53 protein, nuclear over expression was assessed in Formalin-fixed, paraffin-embedded tissue sections by the immunohistochemical method using monoclonal antibody. This p53 nuclear over expression was correlated with tumour grade and stage. Over all survival rate was assessed in p53 positive and negative patients. Results: Two patients with T1G1 tumours developed recurrence with initial TURBT and intravesical BCG instillation after 6 months and responded to Re TURBT and intravesical BCG instillation therapy. One patient of T1G3 developed recurrence after 1 year with initial TURBT and intravesical BCG instillation and responded to Re TURBT and intravesical BCG instillation therapy. One patient of T1G3 progressed to muscle invasive disease after 1 year and underwent Radical cystoprostatectomy with ileal conduit received adjuvant chemotherapy and radiotherapy. Two patients developed post-operative urinary leak and underwent bilateral cutaneous ureterostomy. Nine patients died in followup period. Conclusion: There was a strong positive correlation between the expression of mutant p53 and tumour grade, with none of the low-grade tumours were positive for mutant p53, in contrast to 60% of high-grade tumours. In this study, there was no significant difference in the mortality between p53 positive and negative patients.

Characterization of a human anti-tumoral NK cell population expanded after BCG treatment of leukocytes

ABSTRACTImmunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dim NK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56bright NK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56bright cells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with these in vitro data, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56bright cells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer.

Recommandations en onco-urologie 2016-2018 du CCAFU : Tumeurs de la vessie

ObjectiveThe purpose of the guidelines national committee CCAFU on bladder cancer was to propose updated french guidelines for non-muscle invasive (NMIBC) and invasive (MIBC) bladder cancers. MethodsA Medline search was achieved between 2013 and 2016, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence. ResultsDiagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumour. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment : instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on pelvic-abdominal and thoracic CT-scan; MRI and FDG-PET remain optional. Cystectomy associated with extensive pelvic lymph nodes resection is considered the gold standard for non metastatic MIBC. An orthotopic bladder substitution should be proposed to both male and female patients lacking any contraindications and in cases of negative frozen urethral samples. The interest of neoadjuvant chemotherapy is well known for all MIBC, wathever the stage. Thus, neoadjuvant chemotherapy is recommended for all eligible patients according PS (PS <2) and renal function (clearance > 60ml/mn). As regards metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC). In second line treatment, only chemotherapy using vinflunine has been validated to date, even if results of immunotherapy clinical trials are encouraging. ConclusionThese updated french guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC.© 2016 Elsevier Masson SAS. All rights reserved.