Intravesical Bacillus Research Articles

Healthcare Resource Utilization and Cost Burden of BCG-Treated Non-Muscle Invasive Bladder Cancer Patients in Germany: A Retrospective Claims Analysis.

Intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection of the bladder tumour (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy; however, NMIBC patients can become refractory or unresponsive to BCG treatment, and/or progress to muscle-invasive bladder cancer (MIBC). Healthcare resource utilization (HCRU) and costs in these patient populations are high. A retrospective longitudinal cohort design of adult (≥18 years) patients with bladder cancer and BCG treatment (01/01/2012-31/12/2017) was conducted using data from a representative subset of the German statutory health insurance database. During the follow-up period after last BCG, patients were categorized into subgroups of No further NMIBC treatment, Continuous treatment for NMIBC, or MIBC evidence; HCRU and costs were tabulated for each subgroup and for the entire cohort. A total of 1049 patients met the study inclusion criteria (mean age, 70.9 years; 84.8% male). Across the different subgroups, patients showing MIBC evidence had more than two times higher hospitalization rates compared to the other subgroups. Overall, the entire BCG-treated cohort's total direct medical cost including hospitalizations, outpatient care and drugs was €33.9 million and €9250 per patient-year. Cost for patients with MIBC evidence was much higher, at €17,983 per patient-year, than patients with No further NMIBC treatment (€6617) and patients with Continuous treatment for NMIBC (€7786). Across the subgroups, hospitalization was the largest driver of cost and contributed the most to cost for those with MIBC evidence. The overall cost burden of this BCG-treated cohort of 1049 patients is high (€38 million whereof 4.1 million are indirect costs) over a mean follow-up of 3.9 years; economic burden is especially substantial for patients who fail BCG treatment and those who progress.

Evaluating the cost-utility of intravesical Bacillus Calmette-Guérin versus radical cystectomy in patients with high-risk non-muscle-invasive bladder cancer in the UK

AimsApproximately 75% of bladder cancer (BC) cases present as non-muscle-invasive BC (NMIBC). In patients with high-risk NMIBC, the mainstay treatment is intravesical Bacillus Calmette-Guérin (BCG), with immediate radical cystectomy (RC) as an alternative treatment option. The aim of the present study was to evaluate the cost-utility of BCG versus RC in patients with high-risk NMIBC from the UK healthcare payer perspective.Materials and methodsA six-state Markov model was developed that covered controlled disease, recurrence, progression to muscle-invasive BC, metastatic disease, and death. The model included adverse events of BCG and RC and monitoring and palliative care. Drug costs were obtained from the British National Formulary. Intravesical delivery, RC, and monitoring costs were sourced from the National Tariff Payment System and the literature. Utility data were obtained from the literature. Analyses were run over a 30-year time horizon, with future costs and effects discounted at 3.5% per annum. One-way and probabilistic sensitivity analyses were performed.ResultsThe base case analysis comparing BCG with RC showed that BCG would increase life expectancy by 0.88 years versus RC, from 7.74 to 8.62 years. BCG resulted in an increase of 0.76 quality-adjusted life years (QALYs) versus RC, from 5.63 to 6.39 QALYs. Patients incurred lower lifetime costs if treated with BCG (£47,753) than with RC (£64,264). Cost savings were mainly driven by the lower cost of BCG versus RC, and palliative care costs. Sensitivity analyses showed that results were robust to assumptions.LimitationsThe evidence base informing efficacy estimates of BCG is heterogeneous as different BCG administration schedules were reported in the literature, while incidence and cost data on some BCG-associated adverse events were sparse.ConclusionsIntravesical BCG led to increased QALYs and reduced costs versus RC for patients with high-risk NMIBC from the UK healthcare payer perspective.

Evaluating the Protective Effect of Intravesical Bacillus Calmette-Guerin against SARS-CoV-2 in Non-Muscle Invasive Bladder Cancer Patients: A Multicenter Observational Trial.

We aim to evaluate the potential protective role of intravesical Bacillus Calmette-Guerin (BCG) against SARS-CoV-2 in patients with non-muscle invasive bladder cancer (NMIBC). Patients treated with intravesical adjuvant therapy for NMIBC between January 2018 and December 2019 at two Italian referral centers were divided into two groups based on the received intravesical treatment regimen (BCG vs. chemotherapy). The study's primary endpoint was evaluating SARS-CoV-2 disease incidence and severity among patients treated with intravesical BCG compared to the control group. The study's secondary endpoint was the evaluation of SARS-CoV-2 infection (estimated with serology testing) in the study groups. Overall, 340 patients treated with BCG and 166 treated with intravesical chemotherapy were included in the study. Among patients treated with BCG, 165 (49%) experienced BCG-related adverse events, and serious adverse events occurred in 33 (10%) patients. Receiving BCG or experiencing systemic BCG-related adverse events were not associated with symptomatic proven SARS-CoV-2 infection (p = 0.9) nor with a positive serology test (p = 0.5). The main limitations are related to the retrospective nature of the study. In this multicenter observational trial, a protective role of intravesical BCG against SARS-CoV-2 could not be demonstrated. These results may be used for decision-making regarding ongoing and future trials.

Predictive Role of the Systemic Immune Inflammation Index for Intravesical BCG Response in Intermediate- and High-Risk Non-Muscle-Invasive Bladder Cancer

Introduction: In this study, we aimed to explore using the predictive role of systemic immune inflammation index (SII) for responses of intravesical Bacillus Calmette-Guérin (BCG) therapy in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: From 9 centers, we reviewed the data of patients treated for intermediate- and high-risk NMIBC between 2011 and 2021. All patients enrolled in the study presented with T1 and/or high-grade tumors on initial TURB had undergone re-TURB within 4–6 weeks after initial TURB and had received at least a 6-week course of intravesical BCG induction. SII was calculated with the formula SII = (P × N)/L, where P, N, and L refer to peripheral platelet, neutrophil, and lymphocyte counts, respectively. In patients with intermediate- and high-risk NMIBC, the clinicopathological features and follow-up data were evaluated to compare SII with other systemic inflammation-based prognostic indices. These included the neutrophil-to-lymphocyte ratio (NLR), platelet-to-neutrophil ratio (PNR), and platelet-to-lymphocyte ratio (PLR). Results: A total of 269 patients were enrolled in the study. Median follow-up time was 39 months. Disease recurrence and progression were observed in 71 (26.4%) and 19 (7.1%) patients, respectively. For groups with and without disease recurrence in terms of NLR, PLR, PNR, and SII calculated prior to intravesical BCG treatment, no statistically significant differences were observed (p = 0.470, p = 0.247, p = 0.495, and p = 0.243, respectively). Moreover, there were also no statistically significant differences between the groups with and without disease progression in terms of NLR, PLR, PNR, and SII (p = 0.504, p = 0.165, p = 0.410, and p = 0.242, respectively). SII did not show any statistically significant difference between early (<6 months) and late (≥6 months) recurrence (p = 0.492) and progression groups (p = 0.216). Conclusion: For patients with intermediate- and high-risk NMIBC, serum SII levels do not present as an appropriate biomarker for the prediction of disease recurrence and progression following intravesical BCG therapy. A possible explanation for the failure of SII to predict BCG response may be found in the impact of Turkey’s nationwide tuberculosis vaccination program.

Study EV-104: Phase 1 study of intravesical enfortumab vedotin for treatment of patients with non-muscle invasive bladder cancer (NMIBC)—Trial in progress.

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

Sarcopenia Predicts Disease Progression in Patients with T1 High-grade Non–muscle-invasive Bladder Cancer Treated with Adjuvant Intravesical Bacillus Calmette-Guérin: Implications for Decision-making?

BackgroundSkeletal muscle loss (sarcopenia) has been linked to cancer cachexia and can predict survival in several tumors, including advanced genitourinary malignancies. ObjectiveTo investigate the predictive and prognostic role of sarcopenia in patients with T1 high grade (HG) non-muscle invasive bladder cancer (NMIBC) treated with adjuvant intravesical Bacillus Calmette-Guerin (BCG). Design, setting, and participantsOncological outcomes were evaluated for 185 patients with T1 HG NMIBC treated with BCG at two European referral centers. Sarcopenia, identified from computed tomography scans performed within 2 mo after surgery, was defined as a skeletal muscle index of <39 cm2/m2 for women and <55 cm2/m2 for men. Outcome measurements and statistical analysisThe main endpoint was the association between sarcopenia and disease recurrence and progression. Kaplan-Meier curves and multivariable Cox models were built, and the clinical value of any association was assessed using Harrell’s C index and decision curve analysis (DCA). Results and limitationsSarcopenia was present in 130 patients (70%). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathological prognosticators, sarcopenia was independently associated with disease progression (hazard ratio 3.41; p = 0.02). Addition of sarcopenia to a standard model for prediction of disease progression improved the discrimination of the model from 62% to 70%. DCA revealed superior net benefits for the proposed model in comparison to the strategies of treating all or no patients with radical cystectomy, and in comparison to the existing predictive model. Limitations are inherent to the retrospective design. ConclusionsWe demonstrated the prognostic role of sarcopenia in T1 HG NMIBC. Pending external validation, this tool could be easily incorporated into existing nomograms for prediction of disease progression to improve clinical decision-making and patient counseling. Patient summaryWe looked at the role of loss of skeletal muscle (sarcopenia) as a factor in predicting prognosis for stage T1 high-grade non–muscle-invasive bladder cancer. We found that sarcopenia is a ready-to-use, cost-free marker that could be used to guide treatment and follow-up in this disease, although the results need to be confirmed in other studies.

A systematic review on the available treatment modalities for Bacillus Calmette-Guérin-unresponsive carcinoma in situ and tumors in patients who are ineligible for or decline radical cystectomy.

Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette-Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette-Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy. Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and Bacillus Calmette-Guérin-unresponsive urothelial bladder carcinoma. The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin. This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette-Guérin-unresponsive non-muscle invasive intravesical bladder cancer.

Mycobacterium Bovis-Related Abdominal Aortic Aneurysm after Intravesical Bacillus Calmette-Guérin Therapy for Non-Muscle Invasive Bladder Cancer

Background: Systemic infection after intravesical Bacillus Calmette- Guérin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) is a rare complication. Case

Laboratory predictors to intravesical BCG therapy response in patients with non-muscle invasive bladder cancer

Introduction. Transurethral resection of bladder tumor (TURBT) is the gold standard treatment for patients with non-muscle invasive bladder cancer (NMIBC). However, the high recurrence rate after TURBT makes necessary not only regular following to reveal recurrence disease timely, but it also talks about a necessity of adjuvant antitumor therapy in some cases, that allows to prevent disease recurrence and progression. In this regard, patients belonging to high- and sometimes intermediate- risk progression groups are shown to undergo postoperative adjuvant intravesical Bacillus Calmette–Guérin (BCG) therapy. Despite the long experience of using BCG therapy for NMIBC treatment the question of the existence of possible prognostic markers and response predictors to intravesical BCG therapy remains open.Objective. To review cutting-edge data on different markers that can be used as predictive response markers to ongoing intravesical BCG therapy in NMIBC-patients.Materials and methods. A literature search was conducted using PubMed/ Medline and Google Scholar databases. We used terms 'bladder cancer', 'non-muscle-invasive bladder cancer' in conjunction with 'recurrence', 'progression', 'BCG', 'intravesical therapy', 'immune response', 'molecular markers' to choose relevant articles published between 2000 and 2022.Results. Clinical and pathological characteristics of the tumor and the patient himself remain leading in predicting the response to intravesical BCG therapy in NMIBC-patients. However, to improve the effectiveness of assessing the risk of developing adverse BC outcomes and choosing the most appropriate strategy for monitoring and treatment in each case, it is necessary to introduce additional assessment parameters. Molecular and genetic markers could be considered as such parameters, make it possible to reveal differences between tumors at a deeper level.Conclusion. Currently, there are no markers that have high-evidence in predicting response to intravesical BCG therapy in NMIBC-patients compared with the cliniсal and pathological characteristics of the tumor and the patient himself. The clearer awareness of molecular genetic pathways of BC pathogenesis, the mechanism of BCG antitumor effect will make it possible to competently select markers that have the highest specificity for BC, which will increase the predictive ability of currently existing tools to assess the risks of BC recurrence and progression.

Sequential intravesical gemcitabine and docetaxel therapy in patients with nonmuscle invasive bladder cancer: a systematic review and meta-analysis.

Shortages in intravesical Bacillus Calmette-Guérin (BCG) immunotherapy represent a challenge in the management of high-risk nonmuscle invasive bladder cancer (HR-NMIBC). This study aimed to review the efficacy and safety of intravesical gemcitabine (GEM) and docetaxel (DOCE) for BCG-naive and unresponsive HR-NMIBC. We identified six studies eligible for quantitative analysis through a systematic search according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. In the two studies in the BCG-naive setting, 1-year and 2-year pooled recurrence-free survival (RFS) were 86 and 84%, respectively. In the two studies in the BCG unresponsive setting, 6-month, 1-year and 2-year pooled high-grade recurrence-free survival (HG-RFS) were 80, 66 and 51%, respectively. Cumulative data from four studies revealed that 2.3% of patients could not complete induction therapy and 6.9% experienced treatment delay or dose reduction due to adverse events. Despite the preliminary data and based on a small sample size, intravesical GEM/DOCE therapy is a highly promising combination yielding an effective and well tolerated alternative to BCG when indicated. Further large, well designed comparative studies with BCG are needed.

A Multicenter Study of 2-year Outcomes Following Hyperthermia Therapy with Mitomycin C in Treating Non-Muscle Invasive Bladder Cancer: HIVEC-E.

High grade, non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical Bacillus Calmette-Guérin. Chemohyperthermia therapy (CHT) may be a novel alternative therapy for the treatment of NMIBC. To evaluate the recurrence-free survival (RFS) of patients treated with CHT using the Combat bladder recirculation system (BRS) for NMIBC. This was a prospective multi-institutional study of 1,028 consecutive patients with NMIBC undergoing CHT between 2012 and 2020. A total of 835 patients were treated with CHT with Mitomycin C (MMC). Disease was confirmed on transurethral resection of bladder tumor (TURBT) prior to starting CHT. Follow-up included cystoscopy and subsequent TURBT if recurrence/progression was suspected. The primary endpoint was RFS. Secondary endpoints were progression-free survival (PFS) and adverse events from CHT. Median follow up was 22.4 months (Interquartile range (IQR): 12.8 -35.8). Median age was 70.4 years (IQR: 62.1 -78.6). A total of 557 (66.7%), 172 (20.6) and 74 (8.9%) of patients were classified to BCG naïve, BCG unresponsive and BCG failure, respectively. The RFS at 12 months and 24 months for BCG naïve was 87.6% (95% CI 85.0% - 90.4%) and 75.0% (95% CI 71.3% - 78.8%), respectively. The RFS at 12 months and 24 months for BCG unresponsive cohort was 78.1% (95% CI 72.0% - 84.7%) and 57.4% (95% CI 49.7% - 66.3%), respectively. The RFS at 24 months for the BCG unresponsive cohort for CIS with/without papillary disease and papillary only disease were 43.6% (95% CI 31.4% -60.4%) and 64.5% (95% CI 55.4% - 75.1%), respectively. Minor adverse events occurred in 216 (25.6%) patients and severe events occurred in 17 (2.0%) patients. CHT with MMC using the Combat BRS is effective in the medium term and has a favorable adverse event profile.

Efficacy of outpatient surveillance in post-intravesical BCG management of high-risk bladder cancer

Background: Intravesical Bacillus Calmette–Guérin (BCG) instillation is an established form of immunotherapy for intermediate and high-risk bladder cancers. Mandatory cystoscopic surveillance is commonly performed under general anaesthesia (GA) to facilitate biopsy or other procedures. However, it is resource-intensive with unclear clinical benefit. Methods and patients: We performed a two-cycle audit, before and after changing post-BCG surveillance policy, from GA cystoscopy to local anaesthetic flexible cystoscopy (LAFC) on trans urethral laser ablation (TULA) lists, where patients may undergo a tumour biopsy or laser ablation. In the first cycle, we audited 53 patients undergoing 114 post-BCG rigid cystoscopies from January 2018 to December 2019. In the second cycle, there were 56 patients undergoing 99 post-BCG LAFCs on TULA lists in 2020. Results: In the first audit cycle cohort, the mean patient age was 72.29 ± 8.98 years and 48 were men; malignant histology was identified only on five occasions (three grade progressions). Fourteen patients required overnight admission. In the second audit cycle cohort, the mean patient age was 70.44 ± 9.17 years and 47 were men. Four had a grade progression, while another a stage progression. Out of 99 LAFCs, 47 confirmed normal bladder appearance. A biopsy was taken during other 52 cystoscopies: 17 (33%) confirmed malignancy. Fifteen patients showed findings that were labelled as recurrence, but only two required a further GA procedure to deal with recurrence. One patient was admitted for post-procedure bleeding, which settled with irrigation. Conclusion: Local anaesthetic TULA procedure is a safe and effective alternative for a GA rigid cystoscopy to survey bladders of patients on intravesical BCG therapy. Level of evidence: 3

Effects of acupuncture to decrease adverse events in patients with high-risk non-muscle invasive bladder cancer receiving induction intravesical BCG therapy: Study protocol for a randomized, controlled pilot and feasibility study

BackgroundTreatment-related serious adverse events (SAEs) are common in patients receiving intravesical Bacillus Calmette-Guerin (BCG) for the treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC). Here we describe the protocol of a randomized, attention/waitlist-controlled feasibility pilot study testing the use of acupuncture to decrease SAEs and treatment interruptions in this population. The primary objectives are to evaluate the feasibility and efficacy of conducting pre-procedure acupuncture in a Urology Clinic. MethodsA total of 45 patients will be recruited and randomized in a 2:1 ratio (treatment arm: attention/waitlist control). Eligibility criteria include 1) age 18 years or older, 2) English-speaking, 3) high-risk NMIBC, 4) no acupuncture in the previous 3 months, and 5) willing and able to participate in trial activities. Patients in the treatment arm will receive acupuncture prior to weekly BCG for a total of six weeks. Methods were developed to train and monitor research acupuncturists and included online and in-person training, study manuals, and monthly meetings throughout the study period. Feasibility assessments include evaluation of the recruitment, retention and protocol adherence to acupuncture treatment, and measurement of CTCAE v5.0 adverse events specific to acupuncture, and clinic staff surveys regarding the intervention impact on clinic workflow. Efficacy measures will be compared between treatment and control groups including: EORTC-QLQ-NMIBC-24, EORTC-QLQ-C30, CTCAE v5.0, medication journal, healthcare utilization, current use of complementary, alternative, and integrative therapies, and acupuncture expectancy and treatment preference. Trial results will inform the design of a multi-center trial to expand testing of the protocol to a larger patient cohort.

PCR97 Patient and Caregiver Insight Into the Impact of Non-Muscle Invasive Bladder Cancer and Its Treatments: A Social Media Review

To gain insights into patient/caregiver experience of non-muscle invasive bladder cancer (NMIBC) and its treatments (e.g., intra-vesical Bacillus Calmette-Guerin [BCG]/cystectomy) using social media (SM) data.

EE563 Evaluating the Cost-Utility of Intravesical Bacillus Calmette-Guérin Versus Radical Cystectomy in Patients With High-Risk Non-Muscle-Invasive Bladder Cancer in the UK

EE563 Evaluating the Cost-Utility of Intravesical Bacillus Calmette-Guérin Versus Radical Cystectomy in Patients With High-Risk Non-Muscle-Invasive Bladder Cancer in the UK

Novel Therapeutic Strategies for BCG-unresponsive Non-muscle Invasive Bladder Cancer

Development of therapeutic strategies for non-muscle-invasive bladder cancer (NMIBC) that failed intravesical Bacillus Calmette - Guerin (BCG) therapy remains an urgent priority for clinicians. Currently, radical cystectomy is the recommended standard of care treatment options for these patients. Intravesical chemotherapy using gemcitabine and docetaxel are regarded as the most effective treatment options for unresponsive NMIBC, however, these options are ineffective in the control of bladder cancer. In this review, we present the definition of BCG unresponsive NMIBC and discuss about the recent management options that include immunotherapy, intravesical chemotherapy, gene therapy, and targeted individualized therapy. Notably, immunotherapy is the most recent strategy utilizing the PD-1/PD-L1 and other immune checkpoint inhibitors (ICIs). Pembrolizumab (KEYNOTE-057), Atezolizumab (SWOG S1605) and Nivolumab were developed and are efficacious in BCG –unresponsive NMIBC. In summary, ICIs are considered as the most promising agent for BCG unresponsive NMIBC in the future.

Translocation of nuclear chromatin distribution to the periphery reflects dephosphorylated threonine-821/826 of the retinoblastoma protein (pRb) in T24 cells treated with Bacillus Calmette-Guérin.

The standard treatment for non-muscle-invasive bladder cancer is intravesical Bacillus Calmette-Guérin (BCG) therapy, which is considered the only intravesical therapy that reduces the risk of progression to muscle-invasive cancer. BCG unresponsiveness, in which intravesical BCG therapy is ineffective, has become a problem. It is thus important to evaluate the effectiveness of BCG treatment for patients as soon as possible in order to identify the optimal therapy. Urine cytology is a noninvasive, easy, and cost-effective method that has been used during BCG treatment, but primarily only to determine benign or malignant status; findings concerning the efficacy of BCG treatment based on urine cytology have not been reported. We investigated the relationship between BCG exposure and nuclear an important criterion in urine cytology, i.e., nuclear chromatin patterns. We used three types of cultured cells to evaluate nuclear chromatin patterns and the cell cycle, and we used T24 cells to evaluate the phosphorylation of retinoblastoma protein (pRb) in six-times of BCG exposures. The results revealed that after the second BCG exposure, (i) nuclear chromatin is distributed predominantly at the nuclear periphery and (ii) the dephosphorylation of threonine-821/826 in pRb occurs. This is the first report of a dynamic change in the nuclear chromatin pattern induced by exposure to BCG. Molecular findings also suggested a relationship between this phenomenon and cell-cycle proteins. Although these results are preliminary, they contribute to our understanding of the cytomorphological changes that occur with BCG exposure.

ODP079 BCG-Osis, a Rare Cause of 1,25 Hydroxy Vitamin D Mediated Hypercalcemia

Abstract Background Non-parathyroid hormone (PTH) mediated hypercalcemia is mostly related to malignancy and less commonly caused by granulomatous diseases. We report a rare case of severe hypercalcemia caused by systemic granulomatous disease after intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer (BCGosis). Clinical Case 74-year-old male with history of bladder cancer treated with intravesical BCG a year ago, was hospitalized with confusion, weakness, recurrent falls and polyuria for a few days. He had night sweats and 50 lb weight loss over 6 months. Lab evaluation showed hypercalcemia with calcium 10.9 mg/dL, albumin 3.6 g/dL, corrected calcium 11.2 mg/dL, PTH 12 pg/ml, and 25 OH vitamin D 44ng/ml. He had normal thyroid hormone levels, serum electrophoresis and PTHrP &amp;lt;2 pmol/L. CT chest/abdomen/pelvis without contrast revealed sub-cm pulmonary nodules and non-obstructive renal calculi and bone scan showed no evidence of osseous metastases. He was treated with intravenous (IV) hydration and pamidronate 60 mg infusion, and his corrected calcium improved to 9.7 mg/dL. He was admitted again 3 weeks later with hypercalcemia, calcium 11.9 mg/DL, albumin 3.2 g/dL, corrected calcium 12.5 mg/dL, 25 OH vitamin D 24 ng/ml, PTH 14.6 pg/ml, and PTHrP &amp;lt;2 pmol/L. He received IV hydration and zoledronic acid 4 mg infusion. 3 weeks later he was hospitalized for the third time for recurrent hypercalcemia and worsening renal failure, calcium 13.2, albumin 2.6 g/dL, corrected calcium 14.2 mg/dL, PTH 19.2 pg/ml. 1,25 OH vitamin D checked this time was elevated at 113 pg/mL. He received another infusion of zoledronic acid 4 mg infusion and 10 days later required denosumab 120 mg for resistant hypercalcemia. PET CT scan showed multiple hypermetabolic foci in right neck, right anterior 4th rib, scrotum, and around left kidney and aorta. He underwent biopsy of the right rib lesion which demonstrated + AFB on smear and histiocytic inflammation, which led to diagnosis of BCGosis, with subsequent cultures positive for Mycobacterium bovis. He was started on multi drug regimen with rifampin, isoniazid and ethambutol. Follow up labs at 4 weeks showed normalization of calcium 8.9 mg/dL, albumin 3.2 g/dL, corrected calcium 9.78 mg/dL, PTH 54 pg/ml and low 1,25 OH vitamin D 17 pg/mL. Calcium and 1,25 OH vitamin D levels were stable at 4 months follow up. Conclusion Intravesical BCG treatment can be associated with systemic reactions in 1- 5% of patients. Granulomas associated with disseminated BCG infection can lead to hypercalcemia due to increased 1-alpha-hydroxylase activity in macrophages, causing elevated 1,25 OH vitamin D levels. Therefore, evaluation of 1,25 OH vitamin D levels is critical to determine the etiology of hypercalcemia. Treatment of underlying BCGosis with anti-tuberculosis treatment is key in management of hypercalcemia along with supportive treatments that may include IV hydration, bisphosphonates and/or glucocorticoids. Presentation: No date and time listed

Preoperative systemic inflammation response index is an independent prognostic marker for BCG immunotherapy in patients with non-muscle-invasive bladder cancer.

The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients. A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non-response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan-Meier method was used to compare recurrence-free survival (RFS) and progression-free survival (PFS) between the two groups. Multivariable logistic regression analysis revealed that high SIRI (p=0.001), high MLR (p=0.015), and high tumor pathological T stage (p=0.015) were significantly correlated with non-response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p < 0.05). Collectively, our results indicate that the combination of tumor pathological T staging and the SIRI can enhance the predictive power of BCG response. Pretreatment peripheral blood SIRI can be employed to predict the response to BCG immunotherapy and the prognosis of NMIBC patients. Taken together, the combination of T stage and SIRI demonstrated robust performance in predicting the response to BCG immunotherapy in NMIBC patients.

Preoperative sarcopenia and systemic immune-inflammation index can predict response to intravesical Bacillus Calmette-Guerin instillation in patients with non-muscle invasive bladder cancer.

BackgroundTo explore the prognostic significance of sarcopenia and systemic immune-inflammation index (SII) for response to intravesical Bacillus Calmette-Guerin (BCG) in patients with intermediate-, and high-risk non-muscle invasive bladder cancer (NMIBC).MethodsWe retrospectively analyzed 183 consecutive patients treated in Qilu hospital of Shandong University for a first diagnosis of intermediate and high risk NMIBC. Using computed tomography scans at the third lumbar vertebra level, we calculated skeletal muscle index (SMI). Sarcopenia was defined as SMI <43 cm2/m2 for males with BMI < 25 kg/m2, <53 cm2/m2 for males with BMI ≥ 25 kg/m2, and <41 cm2/m2 for females. The response to intravesical BCG immunotherapy and relapse-free survival (RFS) were analyzed.ResultsCompared with BCG responders, BCG non-responders were associated with sarcopenia (P < 0.001), carcinoma in situ (P < 0.001), T1 stage (P < 0.001), multiple tumor (P < 0.001), tumor diameter >=3cm (P < 0.001), and have a significant increase of neutrophil-to-lymphocyte ratio (NLR) (P < 0.001), platelet to lymphocyte ratio (PLR) (P = 0.004), SII (P < 0.001). The area under the ROC curve (AUC) of the BMI, NLR, PLR, and SII for response to intravesical BCG immunotherapy were 0.425, 0.693, 0.631, and 0.702 respectively. Logistic regression analysis demonstrated that sarcopenia and SII were predictors of response to intravesical BCG immunotherapy. The Kaplan-Meier survival analysis showed that the RFS of patients with BCG response, lower SII and no sarcopenia was significantly increased compared with that of patients with BCG non-response, higher SII and sarcopenia, respectively. Subgroup analysis demonstrated that the RFS of patients with high SII and sarcopenia was significantly decreased compared with those with low SII and no sarcopenia in Ta stage subgroup, T1 stage subgroup, non-Cis subgroup, multiple tumor subgroup, single tumor subgroup, tumor diameter≥3cm subgroup and tumor diameter<3cm subgroup, respectively (P < 0.05). However, there was no significant difference in RFS for patients in CIS subgroup (P > 0.05). Multivariate Cox analysis shown that sarcopenia (p=0.005) and high SII (p = 0.003) were significantly associated with poor RFS.ConclusionsBoth sarcopenia and high SII are useful predictors of response to intravesical BCG in intermediate- and high-risk NMIBC patients. Patients with intermediate- and high-risk NMIBC that had sarcopenia or high SII at diagnosis were associated with poor RFS, and the combination of sarcopenia and SII may be a better predictor of RFS.