Intravesical Bacillus Calmette-Guerin Instillation Research Articles

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Peritoneal and pulmonary tuberculosis following intravesical administration of Bacillus Calmette-Guérin for bladder cancer.

We report a rare case of peritoneal and pulmonary tuberculosis after intravesical instillation of Bacillus Calmette-Guérin (BCG). A 76-year-old man diagnosed as high-grade urothelial carcinoma (UC) with carcinoma in situ (CIS) was treated with intravesical BCG instillation and transurethral resection of bladder tumor (TUR-BT). Three months later, TUR-BT for recurrent tumors and multiple site biopsy of bladder mucosa were performed. During TUR-BT, near perforation in the posterior wall was observed, and was disappeared after observation with urethral catheterization for 1 week. Two weeks later, he was admitted with a complaint of abdominal distention, and a computed tomography (CT) showed ascites. One week later, CT showed pleural effusion and worsening of ascites. Drainage of pleural effusion and ascites puncture was performed, and elevated adenosine deaminase (ADA) and lymphocytes count were subsequently found. In laparoscopic examination, numerous white nodules were observed in the peritoneum and omentum, and Langhans giant cells were pathologically identified in biopsy specimens. Mycobacterium culture confirmed Mycobacterium tuberculosis complex. The patient was then diagnosed with pulmonary and peritoneal tuberculosis. Anti-tuberculous agents consisting of isoniazid (INH), rifampicin (RFP), and ethambutol (EB) were administered. Six months later, a CT scan showed no evidence of pleural effusion or ascites. There has been no recurrence of either urothelial cancer or tuberculosis during follow-up for 2 years.

Bladder Preservation With Transurethral Tumor Resection and Intravesical BCG Instillation in Superficial Muscle-Invasive Bladder Cancer: A 10-Year Follow-up

Purpose: The aim of this study was to evaluate the 10-year oncological outcomes of bladder preservation with transurethral resection of bladder tumor (TURBT) and intravesical bacillus Calmette-Guérin (BCG) instillation in selected patients with superficial muscle-invasive bladder cancer (MIBC).Materials and Methods: Patients diagnosed with superficial MIBC (stage T2a) by TURBT between 2001 and 2009 were included. Cystectomy-free survival, recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to identify predictors of each type of survival.Results: Of 145 patients, 135 underwent bladder preservation and 10 underwent immediate radical cystectomy (RC). Among the latter, 9 patients showed downstaging. During a median follow-up of 132 months (interquartile range, 96–161 months), 13 patients underwent RC, with a 10-year cystectomy-free survival rate of 83.9%. Seventy patients (48.3%) had recurrence, and the 10-year RFS rate was 48.9%. Progression occurred in 12 patients (8.3%), with a 10-year PFS rate of 90.1%. Death occurred only in patients who exhibited progression; 5 patients (3.4%) died of bladder cancer, and the 10-year CSS rate was 96.5%. Tumors greater than 3 cm were associated with RC, and a high tumor grade predicted recurrence. RC was related to progression and cancer-specific mortality.Conclusions: Although high-grade tumors require careful follow-up, bladder preservation with TURBT and intravesical BCG instillation can enable the successful management of selected patients with stage T2a MIBC less than 3 cm, without carcinoma in situ or tumor-associated hydronephrosis, in a nonmetastatic setting.

Intravesical instillation of bacillus Calmette-Guerin for non-muscle invasive bladder cancer: outcomes of 421 patients in a single center

To assess the therapeutic effect and adverse effect of intravesical instillation of bacillus Calmette-Guerin (BCG) for treatment of non-muscle invasive bladder cancer (NMIBC) and analyze the independent predictors of patient survival. We retrospectively collected the clinical data from 421 patients (mean age 61.79±11.51 years) with NMIBC, who received intravesical instillation of BCG after surgery in Sun Yat-sen University Cancer Center from September, 2015 to September, 2021. Recurrence-free survival (RFS), progression-free survival (PFS), and disease specific survival (DSS) of the patients were analyzed, and the adverse effects were assessed using Common Terminology Criteria for Adverse Events 5.0. Kaplan-Meier analysis, univariate and multivariate COX regression analyses were used to identify the independent predictors of the patients' survival outcomes. The median follow-up of the patients was 17 months, during which 88 (20.9%) patients experienced recurrence (median time to recurrence of 10 months, range 3-58 months); 40 (9.5%) patients showed tumor progression (median time to progression of 18 months, range 3-50 months); and 14 (3.3%) patients died (median survival time of 30 months, range 8-52 months). Adverse events of grade 1, 2, and 3 occurred in 69, 110, and 23 of the patients, respectively. Survival analysis indicated that an age below 67.5 years (P=0.013), first tumor onset (P < 0.001), solitary tumor (P= 0.010), time to recurrence over one year (P=0.042), low levels of neutrophils (P=0.005), monocytes (P=0.005) and neutrophil/lymphocyte ratio (NLR; P=0.014), and cytokeratin 19 fragment 21-1 (CyFra21-1; P=0.002) were all associated with a higher PFS rate. Multivariate COX analysis suggested that the time of tumor recurrence (P=0.007, HR=2.669, 95% CI: 1.316-5.414), monocyte counts (P=0.015, HR=0.376, 95% CI: 0.171-0.829), and serum CyFra21-1 level (P=0.002, HR=0.312, 95% CI: 0.151-0.647) were independent predictors of RFS; primary tumor or tumor relapse (P=0.003, HR=0.301, 95% CI: 0.138-0.660), neutrophil counts (P=0.028, HR=0.302, 95% CI: 0.103-0.882), and CyFra21-1 level (P=0.029, HR=0.358, 95% CI: 0.142-0.903) were independent predictors of PFS following BCG instillation. Intravesical instillation of BCG is effective for treatment of intermediate or high-risk NMIBC, and the adverse effects are tolerable in most cases. The time of tumor recurrence, monocyte counts, and serum CyFra21-1 level are independent predictors of RFS, and primary tumor or tumor relapse, neutrophil counts, and CyFra21-1 level are independent predictors of PFS.

Peripheral tuberculin purified protein derivative specific T cell immunoreactivity dynamics in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin instillation treatment.

Intravesical bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt) with nearly 70% reoccurrence. In the present study, we investigated the dynamics of peripheral purified protein derivative (PPD)-specific immune responses along the treatment. Intravesical BCG instillation caused a significant increase in peripheral PPD-specific IFN-γ release of NMIBC patients, when compared to those receiving chemo-drug instillation. Through a follow-up study, we detected rapid increase in PPD-specific IFN-γ, IL-2, and IL-17A producing CD4+ and CD8+ T cells in the induction phase. Interestingly, the frequencies of PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells decreased dramatically after induction treatment and were restored after BCG re-instillation, whereas IL-17A-producing T cells remained at the maintenance phase. However, we only observed that the percentages of peripheral CD8+ T cells were significantly higher in BCG responder patients than those in BCG refractory patients at the baseline with the potential of predicting the recurrence. A more dramatic increase in PPD-specific IFN-γ and IL-2 producing CD4+ and CD8+ T cells after one and two dose BCG instillations was observed in refractory NMIBC patients. Therefore, regional BCG instillation induced transient peripheral PPD-specific T cell responses, which could be restored through repetitive BCG instillation. Higher proportions of peripheral CD8+ T cells at baseline were associated with better responses to BCG instillation for the prevention of recurrence of bladder cancer.

Muscular pseudotumor revealing a mycobacterial granuloma after bacillus Calmette-Guérin therapy

IntroductionThe Bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis. Intravesical therapy with BCG has long been proved to be effective in treating early-stage bladder carcinoma. Case reportA 81-year-old male patient with former history of BCG instillations for bladder cancer two years ago was admitted in February 2020 to our department for a pulsatile and painful tumefaction of the right thigh that lasted for 6 months, due to a muscular M. bovis granuloma leading to femoral artery erosion. Emergency vascular surgery associated with prolonged antibiotherapy provided full recovery. DiscussionLate infectious complications of intravesical BCG instillations are classical but rare. Isolated muscular involvement is exceptional. ConclusionMycobacterial infection should be carefully screened face to a granuloma presenting as muscular pseudotumor. A history of BCG therapy, even decades earlier, enhances this hypothesis and should lead to enforce microbiological testing, especially molecular test.

Cytokeratin 5/6 expression in pT1 bladder cancer predicts intravesical recurrence in patients treated with bacillus Calmette–Guérin instillation

Bacillus Calmette-Guérin (BCG) instillation is the gold standard for the treatment of patients with pT1 bladder cancer but causes severe adverse effects. Few predictive factors have been established for intravesical recurrence and/or stage progression in bladder cancer. We analysed 138 patients who underwent transurethral resection of bladder tumour and were pathologically confirmed to have stage pT1 bladder cancer. Of these, 72 patients (52.2%) received intravesical BCG instillation, 12 patients (8.7%) demonstrated stage progression, and five patients (3.6%) died of the disease. The number of patients who received BCG instillation was more in the group with multifocal tumours than that in the group with unifocal tumours (p=0.0034). Among 53 patients (38.4%) who demonstrated cytokeratin 5/6 (CK5/6) expression, 15 patients (28.3%) showed CK5/6 expression in more than 10% of tumour cells and 38 patients (71.7%) showed CK5/6 expression in 1-10% of tumour cells. CK5/6 expression was observed in both invasive and non-invasive components in 15 patients (28.3%), only in invasive components in 30 patients (56.6%), and only in non-invasive components in eight patients (15.1%). Furthermore, CK5/6 expression was observed in tumour cells only in front of the invasive component and stroma in 24 patients. The proportion of CK5/6-expressing tumour cells in the invasive component was significantly higher than that in the non-invasive component (p<0.001). The follow-up period for patients who received BCG tended to be shorter than that in the non-BCG patients. The CK5/6-positive group displayed significantly shorter recurrence-free survival (RFS) than the CK5/6-negative group (p=0.0412). Importantly, CK5/6 expression was a significant predictive factor of inferior RFS in the BCG instillation group (p=0.0197). In contrast, CK5/6 expression was not significantly associated with RFS in the non-BCG instillation group (p=0.841). Thus, CK5/6 expression can be a predictive marker for RFS in patients with pT1 bladder cancer and can provide critical information for patient care.

Can Bacillus Calmette-Guérin (BCG) treat localized prostate cancer?

The Bacillus Calmette-Guérin (BCG) vaccine has been used for a century to prevent tuberculosis and non-specific effects of BCG vaccination have provided a degree of protection from other non-mycobacterial pathogens and even some cancers. As such, intravesical BCG instillation is an accepted and well tolerated immunotherapy for non-muscle-invasive bladder cancer. Notably, during BCG instillations there is commonly reflux of urine from the prostatic urethra into the prostatic ducts and most men develop an asymptomatic granulomatous prostatitis in the peripheral zone of the prostate, typically where prostate cancer occurs. In the United States, prostate cancer is the most common diagnosed cancer in men; and most men are diagnosed over age sixty. There are several treatment options for localized intermediate-risk prostate cancer; they include active surveillance, radical prostatectomy, radiotherapy, and androgen deprivation therapy. However, these treatments can cause urinary, sexual, and rectal toxicities; as such, some older men defer treatment and instead choose watchful waiting, which is associated with a worse survival outcome compared to treatment options. We posit that intravesical BCG can target prostate cancer directly by refluxing from the prostatic urethra via ducts into the peripheral zone of the prostate and at that location initiate a robust immunologic anti-tumor response. Moreover, there is evidence that a prior BCG vaccination will augment the immune response from intravesical BCG therapy. Hence, we hypothesize that BCG vaccination followed by intravesical BCG instillation might be a treatment option for localized intermediate-risk prostate cancer, will have limited side effects, and be particularly suited for older men who have chosen watchful waiting. We have suggested how this hypothesis can be safely tested.

The Paris system classification for urinary cytology in patients under bacillus Calmette-Guerin treatment.

The role of urinary cytology as a diagnostic test for the detection and surveillance of urothelial cancer is crucial. Intravesical bacillus Calmette-Guerin (BCG) is the appropriate therapeutic strategy for patients with high-grade urothelial carcinoma (HGCU) or in situ carcinoma. We investigate how applicable is the Paris System for reporting urinary cytology (TPS) and how accurate is urinary cytology, in patients who undergo intravesical BCG instillations. Our study contains urine samples from patients during the period January 1, 2017 to December 31, 2019. The inclusion criteria were patients with history of urothelial bladder carcinoma who had been treated with intravesical BCG instillation and cytology was followed by histology. We report our results and estimate the risk of high-grade malignancy (ROHM) for each TPS category and cytology accuracy. Four hundred thirty-eight samples corresponding to 146 patients fulfilled the criteria to be included in the study. There were 2 inadequate, 118 negative for high-grade urothelial carcinoma (NHGUC), 14 atypical urothelial cells (AUC), 6 suspicious for high-grade urothelial carcinoma (SHGUC), and 6 cases HGUC. Corresponding histology assessment has shown that the ROHM amounted to 0 for inadequate, 3.4% for NHGUC, 57% for AUC, 100% for SHGUC and HGUC. Sensitivity was 50%, specificity 100%, PPV 100%, NPV 91%, and accuracy 91.7%, considering inadequate, NHGUC and AUC as negative and SHGUC and HGUC as positive result. However, considering AUC a positive result, the accuracy parameters were different; sensitivity 83.3%, specificity 95%, PPV 76.9%, NPV 96.67%, and accuracy 93%. The Paris system for reporting urinary cytology can be safely applied to patients during follow-up after BCG intravesical administration.

Severe hemophagocytic syndrome after intravesical BCG instillation with a fatal outcome

Introduction. Hemophagocytic syndrome (HS) after Bacillus Calmette-Guerin (BCG) immunotherapy is extremely rare in everyday practice. Only three times HS have been reported on in the world until now. BCG is used for preventing the recurrence of superficial tumors of the urinary bladder. The first extensive research was conducted by Morales, since when his treatment protocol has been in use. Severe complications are rarely seen. Case report. A 55 year-old patient in bad condition was transferred to Clinic for urology after second round of BCG immunotherapy (Morales protocol) after transurethral electroresection of bladder tumor (TURBT). Computed tomography (CT) of the abdomen and lesser pelvis was performed, which didn?t indicate any clear signs of organ failure or disease. Hemophagocytic syndrome (HS) after BCG immunotherapy was suspected. During further hospitalization, the patien?s already severe condition further deteorited and became more complicated, in the form of the multiorgan disfunction syndrome (MODS). Death occurred on the sixth day of hospitalization. Conclusion. Secondary HS after BCG immunotherapy is an extremely rare disease that is accompanied by a severe general condition of the patient, with many life-threatening complications that can lead to death. We have presented a case of severe HS after BCG immunotherapy that caused death of the patient. This case was unique because, for the first time, the possible causative agent was isolated-Mycobacteria.

Impact of bacillus Calmette-Guerin intravesical therapy on the diagnostic efficacy of The Paris System for Reporting Urinary Cytology in patients with high-grade bladder cancer.

In high-grade urothelial carcinoma (UC) of the bladder, bacillus Calmette-Guerin (BCG) therapy is a therapeutic mainstay, and urinary cytology is recommended to detect recurrences. However, intravesical BCG instillations can induce morphologic changes in urothelial cells. The authors investigated the impact of BCG therapy on the efficacy of urinary cytology. Matched pathology and cytology samples from patients undergoing transurethral resection of the bladder after BCG therapy were assessed. Cytology samples were graded according to The Paris System for Reporting Urinary Cytology. Diagnostic quality criteria were tested for different cutoff definitions, and the results were compared between those obtained <100 versus ≥100 days after the last BCG instillation. In addition, the oncologic outcome of false-positive results was assessed. In total, 389 matched cases from 197 patients who had a history of high-grade UC (HGUC) were identified. Sixty cases (15.7%) were diagnosed as high-grade urothelial bladder cancer. The cytology diagnoses were as follows: non-HGUC, 191 cases (49.1%); atypical urothelial cells, 80 cases (20.6%); suspicious for HGUC, 56 cases (14.4%); and HGUC, 56 cases (14.4%). Interrater reliability was substantial (κ = 0.660). Sensitivity increased from 45% to 75% when cases diagnosed as suspicious for HGUC were also counted as positive. Notably, sensitivity was reduced within the first 100 days after BCG therapy (61.9%) compared with sensitivity at longer intervals (82.1%). Reactive atypia (odds ratio, 4.155; 95% confidence interval, 2.136-8.085; P < .001) and cellular degeneration (odds ratio, 5.050; 95% CI, 2.094-12.175; P < .001) of urothelial cells were associated with false-positive rates, and 44.7% of patients who had a false-positive cytology classification presented with HGUC during follow-up. BCG therapy has a short-term adverse impact on the efficacy of urinary cytology. After BCG therapy, cases classified as suspicious for HGUC should be considered positive. Importantly, patients with false-positive cytology findings should be closely monitored.

Aortic Complications Related to Mycobacterium bovis after Intravesical Bacille Calmette-Guérin Therapy - a Systematic Review

Aortic complications after intravesical Bacillus Calmette-Guérin (BCG) application are a rare complication of the treatment of non-muscle invasive bladder cancer. The aim of this systematic review was to perform a descriptive analysis of previously published studies and to discuss the particular challenges of diagnosis and treatment of this rare complication. A literature search was performed in PubMed (1949-2021) and Web of Science (1900-2021) using the search terms "mycobacterium" OR "bovis" OR "BCG" AND "aorta" OR "aneurysm". In a staged review process, publications with the following inclusion criteria were included in data analysis: original paper, full-text availability in English or German and aortic complication after intravesical BCG instillation. We focused on the analysis of BCG-specific medical history data as well as treatment strategies in relation to patient outcome and the occurrence of graft infections during follow-up. A total of 60 individual cases were described in 55 published articles. BCG-induced mycotic aortic aneurysms can occur in all segments of the thoracoabdominal aorta, but the infrarenal aortic segment was most commonly affected (65% of cases). The most common configuration was saccular outpouchings (65%). Concomitant infections in other tissues were typical (65%). Patients with mycotic aneurysm presented with or without consecutive aortic rupture in 28% and 63%, respectively. Diagnosis was based on a combination of pathological and microbiological examinations. A common treatment algorithm was surgical infection treatment (85%) and antitubercular therapy (83%). Performed simultaneously, they resulted in a long-term survival of 81%. Graft infection after initial aortic repair with alloplastic material (n=40) developed in ten patients (25%) during follow-up. Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. Diagnosis is based on obtaining sample material of affected regions and the combination of patient's history, clinical presentation and pathological or microbiological examinations. Currently, no consensus guideline for optimal medical treatment options of aortic complications secondary to BCG instillation exists. The combination of surgical treatment and supportive antitubercular therapy seems to achieve the best results. Since the risk of prosthetic infection after the use of alloplastic materials remains high (25%), we strongly suggest evaluating autologous or allogenic aortic replacement during initial aortic repair.

Sporotrichoid distributed tuberculous panniculitis as a late complication of intravesical bacillus Calmette–Guérin (BCG) immunotherapy

An 82-year-old man presented with unilateral oedema of the right lower limb overlaid with multiple sporotrichoid distributed panniculitis lesions. These symptoms appeared in a context of immunodepression and were associated with significant weight loss and a deterioration in general condition. The patient’s medical history, the histological findings, PCR testing, and bacterial culture led to a diagnosis of cutaneous tuberculosis due to Mycobacterium bovis. This infection occurred as a late complication of intravesical bacillus Calmette–Guérin (BCG) instillations that the patient had received as an adjunctive immunotherapy for bladder cancer. This is an unusual clinical presentation and aetiology of cutaneous tuberculosis. Indeed, the observed sporotrichoid pattern is uncommon for tuberculous mycobacteria. Moreover, the occurrence of tuberculous skin lesions after intravesical BCG instillations is extremely rare, with only a few cases described, and, to the authors’ knowledge, none with such a clinical presentation. This case report suggests that a medical history of BCG immunotherapy should always be considered when assessing any infectious-type cutaneous lesions and that skin should be regarded as a possible late localization of infectious complications of this treatment.

Comparison of Single Monthly Instillations of Intra-Vesical Bacillus Calmette-Guerin Maintenance Therapy with Southwest Oncology Group Regimen in Non-Muscle Invasive Bladder Cancer Patients-A Retrospective Analysis In a Single Institute.

To compare the efficacy and complication rate of monthly instillations of Bacillus Calmette-Guerin (BCG) as maintenance therapy in intermediate and high risk Non-Muscle Invasive Bladder Cancer (NMIBC) patients with the current standard Southwest Oncology Group (SWOG) protocol. In this observational retrospective study, 40 intermediate and high risk NMIBC patients, receiving standard BCG maintenance regimen, were compared with another 40 NMIBC patients, undergoing monthly intra-vesical instillations of BCG with regard to recurrence, progression and major and minor adverse effects. The two groups were similar in their basic characteristics except for the older age in the monthly instillation group ( 70.95 ± 9.66 years vs. 64 ± 8.8, p = 0.001). Study objectives between the monthly instillation group and the standard group, including recurrence ( 17.5 % vs. 25%, p = 0.34) and progression rate ( 7.5% vs. 10%, p = 0.54) did not show statistically significant difference. Major and minor complication rate also did not show any difference between the two groups. In addition to the currently recommended standard protocol of BCG maintenance therapy, our study shows that the monthly regimen can be recommended in intermediate and high risk NMIBC patients without compromising the efficacy of the treatment.

Peripheral Purified Protein Derivate Specific T Cell Immunoreactivity Dynamics in Non-Muscle Invasive Bladder Cancer Patients Receiving Bacillus Calmette-Guerin Instillation Treatment

Background : Intravesical Bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt). The aim of this study was to investigate peripheral immune responses induced by intravesical BCG instillation and to figure out the putative indicators for predicting the recurrence of NMIBC. Methods: Thirty-six NMIBC patients receiving BCG instillation were recruited in the study among which 19 patients were followed up from the start of the instillation. Whole blood was collected before BCG instillation. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with purified protein derivate (PPD) in vitro. PPD-specific cellular responses were evaluated by an IFN-γ releasing assay. Cytokines-secreting CD4+ and CD8+ T cells were detected by flow cytometry. Findings: Intravesical BCG instillation evoked a dramatic increase in IFN-γ producing spot-forming units (SFUs) in PBMCs upon PPD stimulation when compared to those without BCG instillation, together with higher percentages of IFN-γ, IL-2 and IL-17A producing T cells in the periphery. In the follow-up study, IFN-γ producing SFUs elevated rapid after one instillation of BCG and maintained later. However, PPD-specific cytokine producing CCD4+ and CD8+ T cells reached the plateau after two times of BCG instillation. Interestingly, the frequencies of PPD-specific cytokine secreting CD4+ and CD8+ T cells decreased dramatically after induction treatment and restored after BCG re-instillation except IL-17A at the maintenance phase. Of note, more dramatic increase in PPD-specific IFN-γ and IL-2 releasing CCD4+ and CD8+ T cells after one and two BCG instillations was observed in refractory NMIBC patients. Interpretation: Regional BCG instillation can induce peripheral PPD-specific immune responses whereas attenuated after the termination of the instillation. The rapid and transient increase in peripheral PPD-specific Th1-type cytokine producing T cells, however, might be unfavorable indicators associated with the refractory of NMIBC. Funding Information: This work was supported by grants from Chinese National Mega Science and Technology Program on Infectious Diseases (2018ZX10731301-001-004, 2018ZX10302301-002-002 and 2013ZX10003007-003-003) and Shanghai Academic Research Leader Project (18XD1403300). Declaration of Interests: The authors report no conflict of interest. Ethics Approval Statement: All the patients have signed the informed consent forms. The study was approved by the Ethical Committee of Xinhua Hospital. The procedures performed in this study were in accordance with the 1964 Helsinki declaration.

A Randomized Controlled Study of Intravesical Instillation Therapy of Bacillus Calmette-Guérin vs. Epirubicinin Treating Non-muscular Invasive Bladder Cancer

To explore the best treatment plan of intravesical instillation for patients with non-muscular invasive bladder cancer (NMIBC), to explore recurrence-related clinicopathological factors after intravesical instillation, and to evaluate the value of the prognosis and prediction models currently used for NMIBC patients. Starting from 2016, patients who underwent transurethral resection of bladder tumor (TURBT) in our hospital and who received post-surgery diagnosis of having intermediate or high risks for NMIBC were enrolled in the study. They were randomly assigned to different group sat a ratio of 2∶2∶1 for receiving intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) for 19 times, BCG for 15 times, and epirubicin (EPI) for 18 times. The clinicopathological data of the patients were recorded before, during and after instillation therapy, and survival curves were drawn to evaluate the effects of the three regimens, using recurrence-free survival as the endpoint. Clinicopathological data were analyzed to study the associations between various factors and post-instillation recurrence. The consistency index (c-index) was used to evaluate the predictive accuracy of the scoring model of the Spanish Urological Club for Oncological Treatment (CUETO) and the risk tables of European Organization for Research and Treatment of Cancer (EORTC). A total of 93 NMIBC patients (35 in the 19-time BCG group, 37 in the 15-time BCG group, and 21 in the EPI group) were included, with a median follow-up time of 33.46 months. Twenty-two patients experienced tumor recurrence and eight, tumor progression. The survival curve showed that the BCG group had better recurrence-free survival than the EPI group ( P=0.002), while the difference in recurrence-free survival between 19-time BCG and 15-time BCG groups was not statistically significant. Higher general complication rate was seen in the BCG groups compared with the EPI group (84.7% vs. 61.9%, P=0.022), but there was no grade 3-5 adverse events in any group. The c-index of CUETO scoring model and EORTC risk tables was higher than that of the prediction based solely on T stage, nuclear grade, or EAU risk stratification. In addition, the c-index in the BCG group was higher than that in the whole cohort. Among the subjects of this study, the recurrence rate of bladder cancer in the intravesical BCG instillation groups was lower than that of the epirubicin group. EORTC risk tables and CUETO scoring model exhibited higher predictive accuracies in BCG-treated patients than its performance for the whole NMIBC cohort.

Beware of Drug Interactions Treating Iatrogenic Mycobacterium bovis Endocarditis from Intravesical BCG Instillation.

To consider endocarditis as an extra-pulmonary manifestation of Mycobacterium bovis infection, especially in the presence of predisposing heart conditions and risk factors.To be careful of drug interactions among warfarin, rifampin and amiodarone.

Role of immunotherapy in Bacillus Calmette-Guérin unresponsive: non-muscle invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is recommended as the first-line treatment option for intermediate to high risk non-muscle invasive bladder cancer (NMIBC) by current clinical guidelines. However, despite the intravesical instillation of BCG, a significant proportion of patients with intermediate to high risk NMIBC develop intravesical recurrence. Moreover, the treatment of BCG-unresponsive NMIBC is currently challenging. There are no reliable treatment options for these patients with BCG-unresponsive NMIBC except radical cystectomy, which reported to show acceptable oncological outcomes. In this regards, reliable and safe non-invasive or less-invasive treatment options with acceptable oncological outcomes are awaited for the treatment of BCG-unresponsive NMIBC. The treatment of advanced or metastatic urothelial carcinoma has greatly advanced following the recent introduction of immunotherapeutic agents. These advancements have triggered an increasing interest in the use of immunotherapeutic agents for NMIBC, and especially for BCG-unresponsive NMIBC. The current review article aims to introduce and discuss the cutting-edge knowledge on the role of immunotherapy in BCG-unresponsive NMIBC and the currently available therapeutic strategies for its treatment. In addition, this article also summarizes the ongoing studies in this field.