BCG Instillation Research Articles

BCG Medac® for the treatment of non-muscle-invasive bladder tumors: adverse events and predictive factors for tolerance.

Adjuvant treatment with endovesical BCG instillations after resection of a bladder urothelial tumor remains the gold standard for intermediate- or high-risk non-muscle-invasive tumors. However, it is associated with frequent and sometimes serious adverse events (AEs). To comprehensively assess the frequency, intensity, and potential risk factors of BCG instillation AEs following the field experience of a single French center using only the Medac® BCG. A database obtained through a query to the Medical Information Department identified 127 patients who received 1498 Medac® BCG instillations from July 2016 to July 2021. The study focused on the instillations performed in the 1st year (induction treatment and the first two maintenance cycles). Data included demographics, tumor characteristics, treatment conduct and adverse events and their characteristics. Logistic regression completed the descriptive statistics to search for associations between AEs and potential risk factors. Of the 127 patients, 81% had at least one AE. AEs concerned the genitourinary sphere in 80% of cases. The proportion of side effects classified as severe was 4%. BCG treatment was discontinued in 41 patients (32.2% of patients), the main reason being the occurence of AEs (21 out of 41 patients, i.e. 51%). Age, diabetes, active smoking, previous BCG instillations, residual tumor at 2nd look TURB, use of ofloxacin and non-negative urine culture were significantly associated to AEs. Conversely, gender, previous MMC instillation, stage, grade, 2nd look procedure and ASA score were not. Multivariate analysis showed that the presence of residual tumour at 2nd look and active smoking were independent predictive factors. However, these factors were not systematically found for all instillations. The analysis was also performed per instillation. Data on a total of 1498 BCG instillations were collected, with a median of 11 instillations per patient. Of these instillations, 29.6% resulted in AEs. In addition, 125 instillations (8%) were associated with more than one AE. A total of 569 AEs were recorded, with an average of 27.2% AEs per instillation. AEs led to the postponement of 16 instillations out of 93 (17%) in 15 patients. In our study, most patients who received endovesical instillations of BCG experienced AEs, mainly localized to the genitourinary sphere and of low severity. Discontinuation of BCG and serious AEs requiring more than monitoring or symptomatic treatment were not frequent during the first year of treatment. We found no robust predictor of AEs. The problems of predicting the efficacy of BCG on the one hand, and its tolerability on the other, remain unresolved and warrant a future sufficiently powered prospective study.

Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial

The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. Merck Sharp & Dohme.

The Efficacy and Safety of Hyperthermic Intravesical Chemotherapy Compared with Other Instillation Methods in Treating Intermediate- and High-Risk Non-Muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Background. In order to prevent the recurrence and progression of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), various bladder instillation therapies have been developed in recent years. Among these, device-assisted Hyperthermic Intravesical Chemotherapy (HIVEC) has received a great deal of attention. Objective. To identify the efficacy and safety of HIVEC, we conducted this meta-analysis. Methods. We identified relevant articles from PubMed, Embase, and Cochrane Library databases. All published randomized controlled trials (RCTs) describing the role of bladder instillation for the treatment of intermediate- and high-risk NMIBC were involved. Outcomes included 1–3 years Recurrence-Free Survival (RFS), 1–3 years Progression-Free Survival (PFS), 5 years Overall Survival (OS), Adverse Events (AEs), and relevant subgroup analyses. Result. Our study involved a total of 10 RCTs and 1360 patients. In subgroup analysis, we found that compared to MMC instillation, HIVEC decreased the 1–3 years RFS (OR = 0.51; p=0.009) while not increasing the incidence of AEs (OR = 0.86; p=0.30). Compared with BCG instillation, HIVEC reduced the incidence of serious AEs (OR = 0.21; p=0.04) while bringing the same efficacy (OR = 0.78; p=0.63). Conclusion. HIVEC combined the advantages of efficacy and safety compared with the two recommended instillation modalities. As a potential alternative therapy, its widespread clinical effect remains to be further evaluated.

Does intravesical Bacillus Calmette-Guérin for bladder cancer protect from COVID-19?

The study aimed to correlate the history of intravesical BCG as well as infantile BCG immunization with the incidence and severity of COVID-19 infection. Retrospective data collection of patients with high-risk non muscle invasive bladder cancer (NMIBC) from two Canadian centers. Data collection included a history of BCG instillation, infantile immunization, and the development of COVID-19 infection. Admission and/ or mortality because of COVID-19 was reported. We could include data from 348 patients: including 188 and 160 patients from Ontario and British Columbia respectively. COVID-19 affected 15% of these patients. Intravesical BCG was used in 44% of these patients. Intravesical BCG and/or infantile BCG immunization did not correlate with the incidence of COVID-19 infection. Previous intravesical BCG and/ or a history of infantile BCG vaccination were not more/ less frequent in patients who had COVID-19 infection.

Management of high-grade papillary Ta or T1 bladder cancer after restaging transurethral resection: A retrospective study comparing Bacillus Calmette–Guerin therapy upfront versus a third resection

PurposePerforming restaging transurethral bladder resection (reTURB) for high-risk non-muscle invasive bladder cancer (NMIBC) reduces the risk of recurrence and tumour understaging. Management of residual high-grade papillary Ta or T1 after reTURB has changed this last 10years in international recommendations. This study aimed to compare the recurrence free survival according to the different management procedures performed. Materials and methodsPatients who underwent reTURB for initial high-risk NMIBC between 2011 and 2020 were included. Patients with residual high-grade papillary Ta or T1 tumour after reTURB were divided into two groups: BCG instillations upfront versus BCG following a third-look resection (3TURB). Patient and tumour characteristics, BCG instillations, recurrence-free survival were retrospectively analysed. ResultsA total of 162 high-risk patients were included. Sixty-one (37.7%) had residual high-grade papillary Ta or T1 at reTURB: 35 (21.6%) had BCG instillations upfront, 18 (11.2%) had a 3TURB and 8 (5%) had other management. The mean follow-up was 34.2weeks±20.2. Recurrence-free survival was significantly better in patients who underwent BCG instillations upfront (P<0.0043). Recurrence after BCG therapy following reTURB was significantly lower in patients with no residual NMIBC at 6 (92.5% vs. 72.4%, P<0.004) and 12months (85% vs. 67.3%, P<0.03). ConclusionsThe efficacy of intravesical BCG is compromised in case of residual tumour following TURB. The role of a 3TURB following a positive reTURB is not yet determined. This study has confirmed that residual tumor following reTURB is a negative predictive factor but could not demonstrate the value of a 3TURB compared to upfront BCG. Level of evidence3.

No Association Between BCG Instillations and COVID-19 Incidence in a Dutch Non-Muscle Invasive Bladder Cancer Cohort.

No Association Between BCG Instillations and COVID-19 Incidence in a Dutch Non-Muscle Invasive Bladder Cancer Cohort.

The relationship between BCG immunotherapy and oxidative stress parameters in patients with nonmuscle invasive bladder cancer

IntroductionEnvironmental chemicals have been associated with the regulation of oxidative stress markers, which have the potential for the development of bladder cancer. However, limited studies on the function of oxidative stress parameters and nonmuscle invasive bladder cancer (NMIBC) in therapy response are available. Here we studied the oxidative stress parameters in response to BCG immunotherapy in NMIBC patients. Material and MethodsA total of 120 patients with NMIBC and treatment with BCG were enrolled and categorized into 2 groups on BCG response, 50 patients were BCG-responsive (BCG-R) and 70 were BCG-nonresponsive (BCG-N). BCG-R have no evidence of tumor recurrence or advancement after 1 year of BCG immunotherapy, but BCG-N has a recurrence of tumor after 3 to 6 months cycles of BCG instillation, as determined by cystoscopy. In all groups, we measured the levels of oxidative stress markers- malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). ResultsThe levels of oxidative stress markers viz. MDA, NO, and SOD in the BCG-N group were significantly higher (P < 0.001) than in the BCG-R group. Furthermore, the data demonstrated a significant correlation between oxidative stress marker and NMIBC T1 high grade and tumor size >2.5 cm. However, no statistically significant difference was found between studied groups with CAT. ConclusionThe findings suggest that the carcinogenesis of NMIBC is associated with oxidative damage of biomolecules and indicates the involvement of oxidative stress markers in the development and recurrence of NMIBC.; Therefore, it is critical to ensure the management for T1 high grade and tumor size of >2.5 cm for antioxidant protection.

The efficacy of hyperthermic intravesical chemotherapy in high-risk non-muscle-invasive bladder cancer patients with BCG intolerance.

Some patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are unable to receive adequate BCG instillations due to intolerance. In this study we aimed to investigate the efficacy and tolerability of hyperthermic intravesical chemotherapy (HIVEC®) treatment using Mitomycin C (MMC) in BCG-intolerant NMIBC patients. Retrospectively collected data from a total of 22 high-risk papillary NMIBC patients who received adjuvant HIVEC therapy for BCG intolerance were analyzed. The primary outcomes of the study were recurrence-free survival (RFS), time to recurrence, progression-free survival (PFS), and time to progression following initial TURB. Detection of histologically confirmed urothelial carcinoma during follow-up was considered as recurrence, while detection of muscle-invasive disease was defined as progression. The secondary outcome was adverse events of HIVEC treatment. The median follow-up was 32.2 (IQR: 17.8-42.8) months. The RFS and PFS rates were 81.8% and 95.4%, respectively. The mean time to tumor recurrence and progression was 29.2 ± 14.3 and 16.7 months, respectively. Adverse events occurred in 50% of patients, and 95% of adverse events were mild to moderate. This study demonstrated that adjuvant HIVEC with MMC is an effective and safe alternative bladder sparing treatment in BCG intolerant high risk papillary NMIBC patients.

Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.

Development of a dynamic risk system for predicting the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer after thulium laser resection of bladder tumor or transurethral resection of bladder tumor followed by intravesical BCG instillation.

The high recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after tumor resection brings huge physical and financial burdens for patients. Several predictive models that predict the recurrence of patients with NMIBC have drawbacks in clinical practice. With the rapid development of therapeutic methods, more factors should be taken into consideration when constructing predictive model. We retrospectively enrolled 90 patients who were diagnosed as intermediate- or high-risk NMIBC and received a Thulium laser resection of bladder tumor (TmLRBT) or transurethral resection of bladder tumor (TURBT) followed by BCG instillation. Univariate Cox regression analysis and multivariate Cox regression analysis were performed to screen out the independent prognostic factors of recurrence free survival (RFS). A nomogram and risk index were constructed using these prognostic factors. In this study, 22 patients suffered recurrence; 37 patients (41%) received TmLRBT, and over 90% patients completed intravesical BCG instillation for one year. The univariate Cox regression showed that surgery (TURBT vs TmLRBT), previous bladder tumor, tumor number, pathological stage, post-operative catheterization and number of BCG therapy were associated with RFS. The multivariate Cox regression revealed that surgery (TURBT vs TmLRBT) (HR = 3.16, 95%CI [1.02 - 9.83]); previous bladder tumor (HR = 4.03, 95%CI [1.41 - 11.54]); number of BCG therapy (HR = 0.89, 95%CI [0.84 - 0.95]) were independent prognostic factors. A nomogram was constructed and exhibited excellent capability in predicting the RFS with an AUC of 0.789, 0.848, 0.806 at 6-, 12- and 24-months respectively and a c-index of 0.822. Also, the calibration curve and decision curve analysis were performed to verify the predictive efficacy. The risk index was derived from the nomogram and also exhibited favorable capability in predicting the progression free survival (PFS) of patients. Patients who received TmLRBT, without previous bladder tumor history and had more intravesical BCG instillations are likely to have better RFS. The nomogram and the risk index which were constructed to predict the RFS and PFS of patients may help urologists to make clinical decisions and aid in precision medicine.

The natural course of bacillus Calmette-Guérin induced bladder lesions: A long-term follow-up study and systematic review

ObjectiveBacillus Calmette-Guérin (BCG) instillation is the standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer after transurethral resection. Nevertheless, its toxicity often causes bladder complications. On follow-up cystoscopy, post-BCG bladder lesions can be pathologically benign, urothelial carcinoma recurrence, or other types of bladder malignancy. Only a small number of case reports have been published on post-BCG bladder lesions. Their clinical features, natural course, and management remain unknown. MethodsWe retrospectively studied cystoscopic videos and medical records of BCG-treated bladder cancer patients at our center. During a long-term follow-up, we took biopsies on tumor-like lesions and described their changes. In addition, we summarized previous studies on post-BCG bladder lesions by systematic literature searching and review. ResultsWe described a series of three cases with post-BCG bladder lesions mimicking tumor recurrence from a total of 38 cases with follow-up data for more than 5 years. Those lesions could last, grow, or disappear spontaneously, and remain pathological benign for years. In systematic review, we identified and analyzed a total of 15 cases with post-BCG bladder lesions with detailed clinical information. Eleven of the 15 were benign and have a good prognosis with nephrogenic adenoma being the most common pathological type. ConclusionBased on previous studies and our experience, benign lesions after BCG instillation cannot distinguish with cancer recurrence by cystoscopy alone, even under narrow band imaging mode. Nonetheless, given most of them have a good prognosis, random biopsy or transurethral resection might be spared in the patients with long-term negative biopsy and urine cytology.

PD09-01 THE TOLERABILITY AND EFFICACY OF BCG ADMINISTRATION AFTER RECURRENCE IN BLADDER-PRESERVING THERAPY FOR MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD09-01 THE TOLERABILITY AND EFFICACY OF BCG ADMINISTRATION AFTER RECURRENCE IN BLADDER-PRESERVING THERAPY FOR MUSCLE-INVASIVE BLADDER CANCER Ruiyang Xie, Jie Wu, Honglei Cui, Ping Tang, Sijing Zhong, Hongzhe Shi, Youyan Guan, Aiping Zhou, Yueping Liu, and Jianzhong Shou Ruiyang XieRuiyang Xie More articles by this author , Jie WuJie Wu More articles by this author , Honglei CuiHonglei Cui More articles by this author , Ping TangPing Tang More articles by this author , Sijing ZhongSijing Zhong More articles by this author , Hongzhe ShiHongzhe Shi More articles by this author , Youyan GuanYouyan Guan More articles by this author , Aiping ZhouAiping Zhou More articles by this author , Yueping LiuYueping Liu More articles by this author , and Jianzhong ShouJianzhong Shou More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: For highly selected patients with muscle-invasive bladder cancer (MIBC), a multidisciplinary protocol of bladder-preserving therapy includes radiotherapy with concomitant chemotherapy. Some patients confer intravesical nonmuscle-invasive (NMIBC) recurrence. A retrospective study was carried out to explore the tolerability of BCG administration after chemo-radiotherapy in these patients. METHODS: Patients with clinical stage T2-T4aN0M0 urothelial carcinoma of the bladder were enrolled in the analysis (some were enrolled in the clinical trial, NCT02861196). The bladder-preserving strategies were described as follows: 1) cT2 patients underwent a maximal transurethral resection (TURBT), while cT3-T4a patients underwent a biopsy; 2) All patients received neoadjuvant chemotherapy with a gemcitabine/cisplatin regimen; 3) patients then completed maximal TURBT, and those who with pT0 or downstaging to pT1/pTa received concurrent chemo-radiotherapy; 4) patients with intravesical NMIBC recurrence were recommended with TURBT followed by BCG administration. The BCG instillation schedules were as follows: 1) the induction therapy- BCG 120mg weekly for 6 cycles; 2) a 3 mo gap; 3) the maintenance therapy- BCG 120mg weekly for 3 cycles; 4) repeat the maintenance therapy every 6 mo for 1 yr to 3 yr. RESULTS: Between 2012 and 2021, 19 patients with NMIBC recurrence underwent BCG administration after bladder-preserving therapy. All patients completed the BCG induction therapy, and 11 of 19 (57.9%) patients started maintenance therapy. Median follow-up since the recurrence was 36.2 mo. The 1 yr/3 yr probabilities of disease-free survival (DFS) and overall survival (OS) were 71.1%/65.2% and 88.8%/81.4% respectively. The most frequent BCG-related adverse events were bladder irritation (17/19, 89.5%), followed by hematuria (3/19, 15.8%), fever (1/19,5.3%), arthritis (1/19,5.3%), and bladder tuberculosis (1/19,5.3%). None of them had bladder contracture post BCG instillation. CONCLUSIONS: In summary, the tolerability and efficacy of BCG instillation after chemo-radiotherapy in NMIBC recurrence are acceptable and controllable. This study provides an alternative strategy rather than radical cystectomy in the comprehensive bladder-preserving therapy for MIBC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e239 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ruiyang Xie More articles by this author Jie Wu More articles by this author Honglei Cui More articles by this author Ping Tang More articles by this author Sijing Zhong More articles by this author Hongzhe Shi More articles by this author Youyan Guan More articles by this author Aiping Zhou More articles by this author Yueping Liu More articles by this author Jianzhong Shou More articles by this author Expand All Advertisement PDF downloadLoading ...

Bilateral Adrenal and testicular Tumours; When a Simple Diagnosis Becomes Complicated

A 78-year-old man with a BMI 28.7, a moon face and a medical history of diabetes mellitus, hypothyroidism, undefined adrenal insufficiency and history of cardiac ablation, had been in urological follow up for both prostate and bladder cancer. PSA remained low after radiation and adjuvant ADT. Cystoscopy revealed no recurrence after transurethral resection of bladder tumour and instillation of BCG. A routine CT scan as indicated by EAU guideline, showed bilateral enlargement of the adrenal glands as the only abnormality de novo. Patient had no other symptoms than already long-existing fatigue. Considering patient's medical history, subsequently a FDG PET scan was performed which showed intense FDG uptake not only bilaterally in the adrenal glands, but also in both testes. An ultrasound of the testes demonstrated hypodense lesions with increased flow. US imaging raised the suspicion of testicular adrenal rest tumours. Differential diagnoses were primary testis tumour, metastatic disease, BCG-itis, lymphoma or rare endocrine disorders. The combination of bilateral adrenal gland hyperplasia and testicular masses reminded us of seeking the rare diagnosis of ectopic adrenal remnant in both testis and a Cushing-like feature. Endocrinological evaluation could not establish an all-encompassing diagnosis to explain all of the clinical findings. Bilateral orchidectomy was performed. Histological examination showed localization of diffuse large B cell lymphoma (DLBCL) in both testes. Patient was referred to the haematologist and started with chemotherapy, R-CHOP. The diagnostic process in this case was challenging and misleading.

Systemic Interleukin-6 Response after Intravesical Instillation of Bacillus Calmette-Guérin and Mitomycin C in Superficial Bladder Cancer.

Interleukin-6 (IL-6) is proposed to play a significant role in pathogenesis of urinary bladder cancer (UBC). This role may be influenced by chemotherapy (mitomycin C; MMC) or immunotherapy (Bacillus Calmette-Guérin; BCG). A case-control study was conducted to determine IL-6 levels in serum of newly diagnosed cases (NDC) of superficial UBC, as well as in patients treated with MMC or BCG intravesical instillation. A total sample of 111 patients (36 NDC, 45 MMC and 30 BCG) was included, as well as a control group of 107 healthy controls (HC). IL-6 was detected by enzyme-linked immunosorbent assay. Results revealed that median levels of IL-6 were significantly elevated in NDC group (15.8 pg/mL; P<0.001) compared to MMC and BCG groups (7.5 and 5.3 pg/mL, respectively) or HC (4.4 pg/mL); while, there were no significant differences between the latter three groups (MMC, BCG and HC). Receiver operating characteristic curve analysis revealed that IL-6 is a very good predictor of UBC in NDC group versus HC (area under the curve=0.885; 95% confidence interval=0.828-0.942; P<0.001; cut-off value=10.5 pg/mL; Youden index=0.62; sensitivity=80.6%; specificity=81.3%). Logistic regression analysis confirmed this significance and IL-6 was associated with a higher risk of UBC (odds ratio=1.18; 95% confidence interval=1.11-1.26; P<0.001). In conclusion, this study indicated that IL-6 level was upregulated in serum of NDC of UBC. Further, IL-6 level was restored to normal levels after intravesical instillation of MMC or BCG.

Analysis of sex-based differences to Bacillus Calmette-Guérin for non-muscle invasive bladder cancer.

To evaluate whether differences exist between men and women in response to intravesical BCG treatments. The incidence of urothelial carcinoma of the bladder is lower in women but they tend to present with more aggressive and advanced disease. Some prior studies also suggest there are sex-based differences in response to treatment for non-muscle invasive bladder tumors. In this retrospective study, we reviewed all consecutive patients who received BCG at the CHU de Québec - Laval University from 2009-2019. Men and women were treated with intravesical BCG therapy following pathologic confirmation of urothelial carcinoma. Outcomes evaluated include recurrence, progression, and treatment tolerability. Recurrence was defined as a pathology confirmed cancer whereas progression was the new development of high-grade (recurrence) pathology or an increase of stage. Tolerability was defined according to the proportion of prescribed BCG received. All clinical details were obtained through review of the medical records, collaborated by pharmacy records for BCG administration. Competing-risk analysis was used to compare outcomes. Among 613 patients who received BCG at our institution between 2009-2019, 472 (77.0%) were men and 141 (23.0%) were women. The recurrence rate was not different between sexes, with a 5-year recurrence risk of 52% (95% CI: 36.93-65.4) among women compared to 57.5% (CI 95%: 51.9-62.6) among men. The overall non-progression rate at 1,3 and 5 years was 97.3% (95% CI: 95.6%-98.3%), 93.6% (95% CI: 91.2%-95.4%), and 91.7% (95% CI: 88.4%-94.1%), respectively. The completion of ≥5 induction BCG instillations and maintenance BCG use was similar in both genders. We report a contemporary NMIBC cohort treated with BCG and find no clear evidence for sex-based differences in response to BCG treatment in regard of progression, recurrence, and tolerability.

Secondary Haemophagocytic Lymphohistiocytosis Syndrome (HLH) After Intravesical Instillation of Bacillus Calmette-Guérin (BCG): A Case Report and Review of the Literature.

BCGitis after intravesical BCG instillation is a rare, but potentially fatal complication.HLH syndrome associated with BCGitis should be suspected in patients with systematic symptoms, cytopenias and elevated inflammation markers.Prompt diagnosis and early treatment is essential for reducing the mortality rates of this rare clinical entity.

Remodeling the bladder tumor immune microenvironment by mycobacterial species with changes in their cell envelope composition.

Intravesical BCG instillation after bladder tumor resection is the standard treatment for non-muscle invasive bladder cancer; however, it is not always effective and frequently has undesirable side effects. Therefore, new strategies that improve the clinical management of patients are urgently needed. This study aimed to comprehensively evaluate the bladder tumor immune microenvironment profile after intravesical treatment with a panel of mycobacteria with variation in their cell envelope composition and its impact on survival using an orthotopic murine model to identify more effective and safer therapeutic strategies. tumor-bearing mice were intravesically treated with a panel of BCG and M. brumae cultured under different conditions. Untreated tumor-bearing mice and healthy mice were also included as controls. After mycobacterial treatments, the infiltrating immune cell populations in the bladder were analysed by flow cytometry. We provide evidence that mycobacterial treatment triggered a strong immune infiltration into the bladder, with BCG inducing higher global absolute infiltration than M. brumae. The induced global immune microenvironment was strikingly different between the two mycobacterial species, affecting both innate and adaptive immunity. Compared with M. brumae, BCG treated mice exhibited a more robust infiltration of CD4+ and CD8+ T-cells skewed toward an effector memory phenotype, with higher frequencies of NKT cells, neutrophils/gMDSCs and monocytes, especially the inflammatory subset, and higher CD4+ TEM/CD4+ Treg and CD8+ TEM/CD4+ Treg ratios. Conversely, M. brumae treatment triggered higher proportions of total activated immune cells and activated CD4+ and CD8+ TEM cells and lower ratios of CD4+ TEM cells/CD4+ Tregs, CD8+ TEM cells/CD4+ Tregs and inflammatory/reparative monocytes. Notably, the mycobacterial cell envelope composition in M. brumae had a strong impact on the immune microenvironment, shaping the B and myeloid cell compartment and T-cell maturation profile and thus improving survival. Overall, we demonstrate that the bladder immune microenvironment induced by mycobacterial treatment is species specific and shaped by mycobacterial cell envelope composition. Therefore, the global bladder immune microenvironment can be remodelled, improving the quality of infiltrating immune cells, the balance between inflammatory and regulatory/suppressive responses and increasing survival.

Vδ2 T cells are associated with favorable clinical outcomes in patients with bladder cancer and their tumor reactivity can be boosted by BCG and zoledronate treatments

Background Bladder cancer is an important public health concern due to its prevalence, high risk of recurrence and associated cost of management. Although BCG instillation for urothelial cancer treatment is...

Frequency of Complications Post-Intravesical BCG Instillation in Patients with Superficial Urinary Bladder Carcinoma

Objectives: To analyze patients who underwent intravesical BCG instillation for non-muscle invasive bladder tumor and to determine the frequency of complications after intravesical BCG instillation. Study Design: Cross-sectional study. Place and Duration of Study: Departments of Urology and General Surgery, Pakistan Ordinance Factories Hospital Wah Cantt from 1st January 2019 till 31st December 2020. Methodology: Fifty patients; Results: The mean age was 57.06±7.93 years. Forty two patients (84%) were male and 8 patients (16%) were female. Four patients (8%) were Ta stage, 34 patients (68%) were Tis stage and 12 patients (24%) were T1 stage. Mean time interval between TURBT and BCG instillation was 28.68±5.07 days, mean number of BCG instillation cycles was 6.80±2.06 days. Ten (20%) patients had urinary tract infection, 19 (38%) patients had bladder TB, 9 (18%) patients had BCG sepsis, 5 (10%) patients had miliary TB, 2 (4%) patients had epidimo-orchitis, 2 (4%) patients developed ophthalmic complications, 1 (2%) patient had polyarthralgia, 1 (2%) patient had septic arthritis and 1 (2%) patient developed spinal Conclusion: Bacillus Calmette-Guérin is most commonly used drug as chemotherapeutic agent for superficial bladder tumors after TURBT. Repeated cycles of BCG i.e. 6-12 cycles have been administered to patients. Previously most of symptoms i.e. LUTS, dysuria, hematuria were being associated with presence of tumor but now many case reports and few studies have associated these symptoms with BCG administration. Keywords: Superficial bladder carcinoma, Intravesical BCG, Lower urinary tract symptoms

Robot-Assisted, Laparoscopic, and Open Radical Cystectomy: Pre-Operative Data of 1400 Patients From The Italian Radical Cystectomy Registry.

IntroductionThe Italian Radical Cystectomy Registry (RIC) is an observational prospective study aiming to understand clinical variables and patient characteristics associated with short- and long-term outcomes among bladder cancer (BC) patients undergoing radical cystectomy (RC). Moreover, it compares the effectiveness of three RC techniques - open, robotic, and laparoscopic.MethodsFrom 2017 to 2020, 1400 patients were enrolled at one of the 28 centers across Italy. Patient characteristics, as well as preoperative, postoperative, and follow-up (3, 6, 12, and 24 months) clinical variables and outcomes were collected.ResultsPreoperatively, it was found that patients undergoing robotic procedures were younger (p<.001) and more likely to have undergone preoperative neoadjuvant chemotherapy (p<.001) and BCG instillation (p<.001). Hypertension was the most common comorbidity among all patients (55%), and overall, patients undergoing open and laparoscopic RC had a higher Charlson Comorbidities Index (CCI) compared to robotic RC (p<.001). Finally, laparoscopic patients had a lower G-stage classification (p=.003) and open patients had a higher ASA score (p<.001).ConclusionThe present study summarizes the characteristic of patients included in the RIC. Future results will provide invaluable information about outcomes among BC patients undergoing RC. This will inform physicians about the best techniques and course of care based on patient clinical factors and characteristics.