ß-glucan: a potent adjuvant in immunotherapy for digestive tract tumors.

The immunotherapy for gastrointestinal tumors, as a significant research direction in the field of oncology treatment in recent years, has garnered extensive attention due to its potential therapeutic efficacy and promising clinical application prospects. Recent advances in immunotherapy notwithstanding, challenges persist, such as side effects, the complexity of the tumor immune microenvironment, variable patient responses, and drug resistance. Consequently, there is a pressing need to explore novel adjunctive therapeutic modalities. ß-glucan, an immunomodulatory agent, has exhibited promising anti-tumor efficacy in preclinical studies involving colorectal cancer, pancreatic cancer, and gastric cancer, while also mitigating the adverse reactions associated with chemotherapy and enhancing patients' quality of life. However, further clinical and fundamental research is warranted to comprehensively evaluate its therapeutic potential and underlying biological mechanisms. In the future, ß-glucan holds promise as an adjunctive treatment for gastrointestinal tumors, potentially bringing significant benefits to patients.

Developments in conservative treatment for BCG-unresponsive non-muscle invasive bladder cancer.

INTRODUCTION: To reduce the risk of disease recurrence and progression of intermediate and high-risk Non-Muscle Invasive Bladder Cancers (NMIBCs), intravesical adjuvant treatment with Bacillus Calmette-Guerin (BCG) represents the standard of care, although up to 50% of patients will eventually recur and up to 20% of them will progress to Muscle Invasive Bladder Cancer (MIBC). Radical Cystectomy (RC) is the treatment of choice in this setting; however, this represents a major and morbid surgery, thus meaning that not all NMIBCs patient could undergo or may refuse this procedure or may refuse. The search for effective bladder sparing strategies in NMIBCs BCG-unresponsive patients is a hot topic in the urologic field. AREAS COVERED: We aimed to review the most important bladder-preserving strategies for BCG unresponsive disease, from those used in the past, even though rarely used nowadays (intravesical chemotherapy with single agents), to current available therapies (e.g. intravesical instillation with Gemcitabine-Docetaxel), and to future upcoming treatments (Oportuzumab Monatox). EXPERT OPINION: At present, bladder-preserving treatments in BCG-unresponsive patients are represented by the use of intravesical instillations, systemic immunotherapies, both with good short-term and modest mid-term efficacy, and numerous clinical trials ongoing, with encouraging initial results, in which patients could be recruited.

Small molecule inhibitors as adjuvants in cancer immunotherapy: enhancing efficacy and overcoming resistance.

Adjuvant therapy is essential in cancer treatment to enhance primary treatment effectiveness, reduce adverse effects, and prevent recurrence. Small molecule inhibitors as adjuvants in cancer immunotherapy aim to harness their immunomodulatory properties to optimize treatment outcomes. By modulating the tumor microenvironment, enhancing immune cell function, and increasing tumor sensitivity to immunotherapy, small molecule inhibitors have the potential to improve patient responses. This review discusses the evolving use of small molecule inhibitors as adjuvants in cancer treatment, highlighting their role in enhancing the efficacy of immunotherapy and the opportunities for advancing cancer therapies in the future.

Preoperative blood-based nutritional biomarkers as significant prognostic factors after intravesical BCG therapy in patients with non-muscle-invasive bladder cancer.

The aim of this study was to investigate the prognostic role of blood-based nutritional biomarkers, including red blood cell (RBC count), hemoglobin (Hb), total protein (TP), albumin, the serum albumin to globulin ratio (AGR) and the prognostic nutritional index (PNI) in patients who underwent intravesical treatment for non-muscle invasive bladder cancer (NMIBC). A total of 501 NMIBC patients who received intravesical Bacillus Calmette-Guerin (BCG) treatment following transurethral resection of bladder tumor (TURBT) were included. The optimal cutoff values for these nutrition-based indicators were determined using receiver operating characteristic curve analysis. We observed a significantly higher recurrence-free survival (RFS) rate in patients with elevated levels of RBC count, Hb, TP, and albumin. Cox univariate and multivariate Cox regression analyses demonstrated that serum albumin (P = 0.002, HR = 0.51, 95%CI: 0.33-0.78), RBC count (P = 0.002, HR = 0.50, 95%CI: 0.32-0.77), TP (P = 0.028, HR = 0.62, 95%CI: 0.41-0.95), Hb (P = 0.004, HR = 0.53, 95%CI: 0.33-0.84), AGR (P = 0.003, HR = 0.46, 95%CI: 0.27-0.76) and PNI (P = 0.019, HR = 0.56, 95%CI: 0.35-0.91) were significant independent factors predicting RFS. These cost-effective and convenient blood-based nutritional biomarkers have the potential to serve as valuable prognostic indicators for predicting recurrence in NMIBC patients undergoing BCG-immunotherapy.

Make it a combo.

Adjuvants that combine TLR agonists and inflammatory agonists promote robust and durable vaccine responses (Bechtold et al. and Arunachalam et al.).

A critical analysis of the effect of OM-85 for the prevention of recurrent respiratory tract infections or wheezing/asthma from systematic reviews with meta-analysis.

Acute respiratory tract infections (RTIs) are one of the most common causes of pediatric consultations/hospitalizations and a major trigger for asthma exacerbations. Some consensus statements have recommended the use of immunostimulants to boost natural defenses against severe or repeated infections. One of the most common immunostimulants is OM-85; while several randomized clinical trials (RCTs) have evaluated its efficacy in preventing acute RTIs and wheezing/asthma exacerbations, results have been conflicting. Similarly, various systematic reviews with meta-analyses (SRMs) on OM-85 have used different strategies, populations, and outcomes; moreover, SRM conclusions are limited when the original studies are highly heterogeneous or have a low quality, hindering the generalizability of the findings. Here we summarize the evidence on the effect of OM-85 to prevent acute RTIs, wheezing/asthma episodes, or loss of asthma control in children, by including and critically evaluating all SRMs published to date. We searched for SRMs on OM-85 in three publication databases and found nine SRMs (seven for RTI, and two for wheezing/asthma). Among those, one had a high confidence evaluation of quality (AMSTAR-2 tool) and found a reduction in the total number of acute RTIs among the OM-85 group. Overall, no strong recommendations can be derived from the existing literature, mainly due to the high heterogeneity among included RCTs and SRMs. Further, large, high-quality RCTs are needed to confirm the true efficacy of OM-85 for the prevention of acute RTIs, asthma development, and asthma exacerbations.

Programming of in Situ Tumor Vaccines via Supramolecular Nanodrug/Hydrogel Composite and Deformable Nanoadjuvant for Cancer Immunotherapy.

The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANPMTO/ALCD) and a deformable nanoadjuvant (PPER848). The ANPMTO/ALCD composite consisted of ß-cyclodextrin-decorated alginate (Alg-g-CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANPMTO) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPER848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.

Immune Stimulation with Imiquimod to Best Face SARS-CoV-2 Infection and Prevent Long COVID.

Through widespread immunization against SARS-CoV-2 prior to or post-infection, a substantial segment of the global population has acquired both humoral and cellular immunity, and there has been a notable reduction in the incidence of severe and fatal cases linked to this virus and accelerated recovery times for those infected. Nonetheless, a significant demographic, comprising around 20% to 30% of the adult population, remains unimmunized due to diverse factors. Furthermore, alongside those recovered from the infection, there is a subset of the population experiencing persistent symptoms referred to as Long COVID. This condition is more prevalent among individuals with underlying health conditions and immune system impairments. Some Long COVID pathologies stem from direct damage inflicted by the viral infection, whereas others arise from inadequate immune system control over the infection or suboptimal immunoregulation. There are differences in the serum cytokines and miRNA profiles between infected individuals who develop severe COVID-19 or Long COVID and those who control adequately the infection. This review delves into the advantages and constraints associated with employing imiquimod in human subjects to enhance the immune response during SARS-CoV-2 immunization. Restoration of the immune system can modify it towards a profile of non-susceptibility to SARS-CoV-2. An adequate immune system has the potential to curb viral propagation, mitigate symptoms, and ameliorate the severe consequences of the infection.

An emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria.

Fusobacterium nucleatum (F. nucleatum), an oral anaerobe, is prevalent in colorectal cancer and is closely related to increased cancer cell growth, metastasis, and poor treatment outcomes. Bacterial vaccines capable of selectively eliminating bacteria present a promising approach to targeting intratumor F. nucleatum, thereby enhancing cancer treatment. Although adjuvants have been employed to enhance the immune response, the vaccine's effectiveness is constrained by inadequate T-cell activation necessary for eradicating intracellular pathogens. In this study, we developed a minimalistic, biomimetic nanovaccine by integrating highly immunostimulatory adjuvant cholesterol-modified CpG oligonucleotides into the autologously derived F. nucleatum membranes. Compared to the traditional vaccines consisting of inactivated bacteria and Alum adjuvant, the nanovaccine coupled with bacterial membranes and adjuvants could remarkably improve multiple antigens and adjuvant co-delivery to dendritic cells, maximizing their ability to achieve effective antigen presentation and strong downstream immune progress. Notably, the nanovaccine exhibits outstanding selective prophylactic and therapeutic effects, eliminating F. nucleatum without affecting intratumoral and gut microbiota. It significantly enhances chemotherapy efficacy and reduces cancer metastasis in F. nucleatum-infected colorectal cancer. Overall, this work represents the rational application of bacterial nanovaccine and provides a blueprint for future development in enhancing the antitumor effect against bacterial-infected cancer.

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Comparison of PDD-TURBT alone versus white light TURBT plus intravesical BCG therapy: A propensity-score matching study.

BACKGROUND: Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. METHODS: We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. RESULTS: In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. CONCLUSIONS: PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.

No clinical benefit from sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) than BCG alone in the adjuvant treatment of high risk non muscle invasive bladder cancer: result of a planned interim analysis of a prospective randomized trial.

BACKGROUND: The aim of this study was to evaluate whether the sequential use of Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) is superior to BCG alone in reducing the risk of disease recurrence in patients with non-muscle invasive bladder cancer (NMIBC) with high risk of progression. METHODS: Prospective randomized trial was conducted from March 2021 to March 2023 and included 72 patients with high risk NMIBC. Trial registration number: NCT03790384; EUDRACT Number: 2017-004540-37. Thirty-one patients underwent to BCG alone and forty-one to MMC plus BCG during the induction course. The BCG schedule comprised six weekly instillation of 81 mg Connaught strain BCG as the induction course, followed by a further three-monthly instillation at three, six and twelve months, as the maintenance course. Forty mg of MMC were administered the day prior to each weekly BCG instillation in BCG plus MMC arm. A planned interim analysis was carried out in June 2023, at the end of the 12mo follow-up period. RESULTS: Six out of thirteen 6/31(19.3%) and 10/41 (24.4%) patients experienced recurrence in BCG and BCG plus MMC group (P=0.611), respectively. BCG plus MMC did not improve Disease Free Interval (HR: 1.23 95% CI:0.46-3.50; P=0.640). Patients receiving sequential treatment experienced similar AEs (P>0.05) and more urinary symptoms (P<0.05). CONCLUSIONS: This interim pre-planned analysis suggested absence of clinical advantages in terms of disease recurrence rate when MMC is administered one day prior to BCG during induction course.

BCG and bladder cancer. Forty-eight years after Morales report.

Although BCG use as an anticancer drug was nearly abandoned due to the poor results in most tumors, in 1976 Morales reported a relevant reduction in recurrence with intravesical BCG in few patients affected by NMIBC. Since then BCG was globally accepted as an empirical and effective therapy in treating Tis and preventing recurrence of intermediate and high risk NMIBC. Forty-eight years after Morales' report, although some open questions remain object of debate, we have been able to find answers to many doubts improving BCG activity and toxicity. We better select patients undergoing BCG and many trials have indicated the best dosage and schedule. Moreover, we are able to better identify the patient unresponsive to BCG who might benefit of a timely radical cystectomy. We are also aware of the difficulties and toxicities that can be encountered with BCG use in every-day clinical practice. Research is ongoing to obtain genetically modified BCG to increase its efficacy and reduce toxicity. Moreover, the combination of BCG with other immunotherapeutic drugs given intravesically or systemically, first immune checkpoint inhibitors, is under study to obtain a response in patients unresponsive or intolerant to BCG. Almost 50 years after Morales publication, intravesical BCG remains an inalienable tool against NMIBC.

The impact of purified protein derivative prior to intravesical bacillus Calmette-Guérin for the treatment of patients with non-muscle invasive bladder cancer.

BACKGROUND: The aim of this study is to investigate the impact of the intradermal injection of purified protein derivative (PPD) and PPD skin test reactions on the oncological outcomes of patients with non-muscle invasive bladder cancer (NMIBC) treated by trans-urethral resection of bladder tumor (TURBT) and adjuvant intravesical BCG. METHODS: The study included 100 consecutive patients with NMIBC prospectively given intradermal PPD 1-2 weeks before starting BCG therapy. Another 100 patients with NMIBC not given intradermal PPD before starting BCG were chosen as a historical control. The control group was chosen to be matching with the study group regarding baseline characteristics. The study group was divided into 2 subgroups with positive and negative reaction to PPD skin test. Oncological outcomes, immunological markers (TNF-α and IL-6) changes and BCG side effects were evaluated. RESULTS: There were no significant differences between patients who received PPD or not regarding the 2-year recurrence free survival (RFS) rates and progression-free survival (PFS) rates and immunological markers changes. The 2-year RFS and PFS rates were significantly higher in patients with positive reactions. Post-induction values of immunological markers increased in all patients with a significant increase in patients with positive reactions. BCG side effects were significantly higher in patients with positive reactions. CONCLUSIONS: The intradermal injection of PPD before intravesical BCG has no impact on oncological outcomes of patients with NMIBC treated with TURBT and intravesical BCG. However, the PPD skin test reactions before BCG therapy can predict the oncological outcomes, BCG side effects and the immunological outcomes of patients.

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy?

PURPOSE: We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. RESULTS: Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. CONCLUSIONS: The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

Vaccimel immunization is associated with enhanced response to treatment with anti-PD-1 monoclonal antibodies in cutaneous melanoma patients - a case reports study.

Cancer vaccines are gaining ground as immunotherapy options. We have previously demonstrated in cutaneous melanoma (CM) patients that adjuvant treatment with VACCIMEL, a mixture of four irradiated CM cell lines co-adjuvanted with BCG and GM-CSF, increases the cellular immune response to melanocyte differentiation antigens, cancer-testis antigens and neoantigens, with respect to basal levels. On the other hand, it is also known that treatment with anti-PD-1 monoclonal antibodies (MAbs), acting on pre-existing tumor-reactive lymphocytes, induces clinical responses in CM patients, albeit in a fraction of treated patients. A combination of both treatments would appear therefore desirable. In this paper, we describe CM patients who, having progressed even years after vaccination, were treated with anti-PD-1 MAbs. In 5/5 of such progressor patients, complete responses were obtained which lasted between 3 and 65+ months. Three of the patients remain disease-free and two recurred. One of the patients passed away after a recurrence of brain metastases. We suggest that clonally expanded reactive lymphocytes induced by VACCIMEL partially remain as memory cells, which may be recalled after tumor recurrence and may foster ulterior activity of anti-PD-1 MAbs.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Efficacy of BCG for non-muscle invasive bladder cancer following nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the efficacy of intravesical (IVe) Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer (NMIBC) recurrences in patients who have previously undergone nephroureterectomy for upper tract urothelial carcinoma (UTUC). METHODS: We performed a single institution retrospective review of patients who underwent nephroureterectomy for UTUC from 2009 to 2021. Patients who subsequently developed NMIBC treated with transurethral resection followed by IVe BCG were included in the study group. A control cohort was formed by retrospective review of patents with primary NMIBC treated with BCG during the same period. Patients in the control cohort were matched by stage of bladder cancer at a 2:1 ratio of control to study subjects. Demographic data, pathology of bladder tumors prior to and following BCG, use of maintenance BCG (mBCG), time to recurrence, time to progression, progression to cystectomy, and progression to metastatic disease were collected on all patients. Descriptive statistics were utilized to compare the 2 groups. The primary outcome was progression to muscle invasive disease. Secondary outcomes included intravesical recurrence free survival, disease free survival, and progression to metastatic disease. Univariable and multivariable logistic regression analysis was performed to elucidate independent variables associated with bladder tumor recurrence. Multivariable Cox regression analysis was used to assess the impact of prior UTUC on time to bladder tumor recurrence. RESULTS: One-hundred and ninety-one patients underwent nephroureterectomy at our institution from 2009 to 2021 for UTUC. Twenty-five patients were identified to have subsequently developed NMIBC recurrences treated with inductions BCG. The control group was comprised of 50 patients with primary NMIBC matched by stage of bladder cancer for which BCG was indicated in the study group. Median (interquartile range [IQR]) follow-up was significantly longer in the control group relative to the study group (64.8 [50.1-85.6] vs 25 months [17-35]; P = 0.001). There were no significant differences in demographics between the study and control groups. The rate of progression to muscle invasive disease was 17% vs 0% in the study group and control group respectively (P = 0.0521). History of UTUC was associated with increased risk of intravesical bladder tumor recurrence post BCG on multivariable analysis (HR 2.5; P = 0.017) and Kaplan Meier survival analysis (P = 0.039). The mean time to bladder tumor recurrence after treatment with BCG was significantly worse in the study group at (7.9 vs. 23.9 months; P = 0.0322). Similarly, the rate of progression to metastatic disease was worse in the study group (24% vs 2%; P = 0.0047). Overall disease-free survival was also noted to be significantly worse on Kaplan Meier survival analysis in the study group (P = 0.0074). No statistically significant differences in the stage grade of bladder tumor recurrence, grade of bladder tumor recurrence, or rate of progression to cystectomy were identified. CONCLUSIONS: Our study suggests reduced efficacy of BCG for NMIBC in patients with a history of UTUC. Patients in this population should be counseled accordingly. Research into alternative treatments for bladder tumor recurrence and more aggressive prophylactic regimens after nephroureterectomy for prevention of bladder tumor recurrence in this population is encouraged.

Increased risk of bladder cancer recurrence due to bacillus Calmette-Guérin shortage in Brazil.

OBJECTIVE: Our study aimed to evaluate the impact of bacillus Calmette-Guérin shortage on recurrence and progression in patients with non-muscle invasive bladder cancer in a Brazilian cohort. METHODS: We retrospectively reviewed the clinicopathological data of 409 patients who had their first transurethral resection of the bladder tumor for intermediate or high-risk non-muscle invasive bladder cancer between June 2014 and May 2021 in a tertiary public hospital in Brazil. Patients included had non-muscle-invasive urothelial carcinoma of the bladder resected completely for the first time, regardless of bacillus Calmette-Guérin use. Low-risk disease patients were excluded from the analysis. Demographic, clinicopathological, and bacillus Calmette-Guérin use data were collected from our database. Recurrence and progression data were obtained from patient records or through telephone interviews. Recurrence-free survival and progression-free survival were calculated from the date of transurethral resection of the bladder tumor until the events of recurrence, progression, last office visit, or phone interview. RESULTS: Within a median follow-up period of 26.7 months, 168 (41.1%) patients experienced a recurrence in a median time of 27 months (95%CI 16.1-38). Bacillus Calmette-Guérin was administered to 57 (13.9%) individuals after transurethral resection of the bladder tumor. Patients with ≥3 lesions (p<0.001), those with lesions >3 cm (p=0.02), and those without bacillus Calmette-Guérin treatment (p<0.001) had shorter recurrence-free survival. According to a Cox multivariate regression model, bacillus Calmette-Guérin use was independently associated with a reduced recurrence rate, with an HR of 0.43 (95%CI 0.25-0.72). Out of the patients studied, 26 (6.4%) experienced progression. T1 stage (p<0.001) and high-grade (p<0.001) were associated with shorter progression-free survival. Bacillus Calmette-Guérin did not influence bladder cancer progression. In the Cox multivariate analysis, high-risk disease was independently associated with progression (p<0.001). CONCLUSION: Our study confirms that non-muscle invasive bladder cancer exhibits a high recurrence rate. The use of adjuvant bacillus Calmette-Guérin in intermediate and high-risk patients significantly reduces this rate. Furthermore, the bacillus Calmette-Guérin shortage could have negatively impacted these patients.