Search Results (147)

Bladder cancer worldwide has seen a sharp rise, making it a significant global health concern. Recurrence monitoring is the main concern in treating the disease, and drug resistance follows suit. Treatment options include first-line medications, adjuvant therapy with BCG (Bacillus Calmette–Guérin) instillations, and combination therapies targeting the PD-1/PD-L1 axis. It has varying 5-year relative survival rates depending on the stage at diagnosis. Despite initial treatment success, resistance often develops, leading to relapse. Resistant to standard treatment is often due to immune landscape changes that are controlled by the most aberrant genes in bladder cancer, which also have a hold in the immune environment of the bladder. Dysregulation of FGFR3 (Fibroblast Growth Factor Receptor 3) in bladder cancer contributes to cell proliferation and metastasis. Simultaneously, the alterations in EGFR (Epidermal Growth Factor Receptor) regulation are linked to cell migration and resistance to treatment. FGFR3 in non-muscle invasive bladder cancer and EGFR in muscle-invasive bladder cancer are central elements in triggering various signaling pathways that contribute to chemoresistance. Concentrating the roles of both genes within the bladder tumour, they present opportunities not only as therapeutic targets but also as potential points of resistance and monitoring for recurrence. Exploring FGFR3 and EGFR to enhance treatment efficacy when combined with ICIs and developing markers into reliable diagnostic tools for recurrence, ultimately aiming for improved patient well-being, is the key aspect we propose to target from this narrative. Full article

Background/Objectives: Although intravesical Bacillus Calmette–Guérin (BCG) is an established adjuvant therapy for non-muscle-invasive bladder cancer (NMIBC), chronic global shortages and adverse events (AEs) can occur. Thus, intravesical gemcitabine has been used as an alternative. We compared the long-term oncological outcomes and safety profiles of BCG and gemcitabine in treatment-naïve patients with intermediate- and high-risk NMIBC. Methods: Patients with intermediate- and high-risk NMIBC (n = 477) received adjuvant intravesical induction and maintenance therapy with intravesical BCG (n = 361) or gemcitabine (n = 116) and their data were collected retrospectively. Results: Compared with the gemcitabine group, the BCG group had significantly higher proportions of patients with T1 stage, high-grade tumors, high-risk tumors, and longer median follow-up duration. Over a median 36-month observation period, the BCG group exhibited significantly better recurrence-free survival (RFS) and high-grade RFS (HG-RFS) than the gemcitabine group. In the propensity score–matched high-risk population, BCG also outperformed gemcitabine in RFS and HG-RFS. BCG therapy was identified as a potent protective predictor, reducing the risk of recurrence and high-grade recurrence by 65% and 66%, respectively, in the total cohort, and by 69% and 71%, respectively, in the propensity score-matched high-risk subgroup. No significant differences were observed in the frequency of grade ≥ 3 AEs between BCG and gemcitabine. Conclusions: Intravesical BCG is strongly associated with superior oncological outcomes over gemcitabine in intermediate- and high-risk NMIBC. The results of this study offer pivotal practice-based insights to guide clinical strategies for managing NMIBC. Full article

Intravesical Bacillus Calmette–Guérin (BCG) is a recommended therapy approach for non-muscle invasive bladder cancer (NMIBC) to prevent disease progression and eliminate tumor cells. Nevertheless, some patients have shown resistance to BCG therapy, exhibiting disease recurrence and progression to MIBC, thereby necessitating radical cystectomy as the best-recommended treatment option. However, radical cystectomy greatly affects postoperative morbidity and quality of life, rendering many patients hesitant or surgically unsuitable for this invasive therapy. The concept of bladder preservation has emerged as an alternative, employing a diverse array of therapeutic agents and interventions to improve therapeutic efficacy to retain the bladder for as long as possible. In this review, we explore various established therapeutic agents and ongoing clinical trials involving new potential agents and interventions. This study was undertaken to determine the advantage of each agent and their combined therapeutic regimens in improving prognostic efficacy, offering an alternative to radical cystectomy for BCG-unresponsive NMIBC. Full article

Introduction: Non-muscle-invasive bladder cancer (NMIBC) represents approximately 78% of newly diagnosed bladder cancers and is characterized by high recurrence rates and variable progression risk. While transurethral resection of bladder tumor (TURBT) followed by intravesical therapy remains standard management, optimal treatment of high-risk and Bacillus Calmette-Guerin (BCG)-unresponsive disease remains controversial. Radiotherapy (RT), particularly in combination with chemotherapy, has been explored as a bladder-preserving alternative. Material and Methods: We conducted a narrative review of published literature evaluating the role of definitive RT in high-risk NMIBC, with emphasis on T1 disease. Retrospective series, prospective trials, meta-analyses, and contemporary guideline recommendations were examined. For each included study, we extracted data on the extent of TURBT (maximal vs. incomplete/non-specified), use and type of concurrent chemotherapy, radiotherapy technique (3D-conformal, IMRT, or proton), treatment volume (bladder only vs. whole pelvis), and dose/fractionation schedule. Results: Early studies evaluating RT alone demonstrated modest complete response rates. More recent approaches incorporating maximal TURBT followed by concurrent chemoradiotherapy report improved outcomes, with complete response rates of approximately 80–88% and 5-year overall survival comparable to surgical series. The phase II NRG/RTOG 0926 trial in recurrent high-risk T1 disease after intravesical therapy failure demonstrated an 81% complete response rate and favorable bladder preservation outcomes. Meta-analytic data suggest 5-year recurrence-free survival around 54% and overall survival near 70%, although evidence remains limited and largely non-randomized. Advances in image-guided and hypofractionated RT may further improve therapeutic outcomes while limiting toxicity. Conclusions: while definitive chemoradiotherapy is a promising option for selected patients, it remains investigational and should be considered only in those who are unfit for or decline radical cystectomy. Prospective randomized studies are needed to better define its role in contemporary management. Full article

Background/Objectives: Tuberculosis remains one of the preventable causes of mortality among liver transplant recipients. The prevalence of tuberculosis in solid organ transplant recipients is higher than in the general population. The aim of this study was to evaluate the incidence of latent tuberculosis infection (LTBI) and active tuberculosis after liver transplantation. Methods: This is a retrospective, single-center, case–control study. Adult liver transplant candidates who were evaluated between 1 January 2016 and 31 December 2022 were retrospectively assessed. Patients with pre-transplant tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) results who underwent transplantation were included in this study. Results: A total of 111 liver transplant recipients with available IGRA and/or TST results were included; 70 were men (63.1%) and 41 were women (36.9%), with a mean age of 53.5 ± 11.3 years. Demographic, clinical, and laboratory characteristics were evaluated. The most common indication for liver transplantation was viral hepatitis (33.3%), followed by cryptogenic cirrhosis (19.8%) and hepatocellular carcinoma (10.8%). All patients had a Bacillus Calmette–Guérin (BCG) vaccination scar. Ten patients received grafts from deceased donors, while 101 underwent living-donor liver transplantation. No patient received LTBI treatment before transplantation, whereas LTBI treatment was initiated in four patients after transplantation. None of the patients had a diagnosis of active tuberculosis prior to transplantation. Thoracic computed tomography revealed findings compatible with tuberculosis sequelae in 11 patients (9.9%). During a median follow-up period of 49 [27–64] months after transplantation, no cases of active tuberculosis were observed among patients with positive TST and/or IGRA results. Patients were divided into two groups according to their TST and IGRA results. Group 1 consisted of patients with IGRA positivity and/or a TST ≥ 5 mm, while Group 2 included patients with a TST < 5 mm and negative IGRA results. The only statistically significant difference between the groups was the administration of LTBI treatment (p = 0.027); four patients in Group 1 received LTBI therapy. None of these patients were able to continue prophylaxis due to treatment-related adverse effects. Conclusions: Prophylaxis with hepatotoxic agents poses a substantial risk in liver transplant candidates. Since the hepatotoxicity may cause early cessation of LTBI treatment, the risk–benefit ratio of post-transplant LTBI therapy should be carefully assessed. In situations where LTBI treatment is deferred, close clinical monitoring is strongly recommended. Full article

Background/Objectives: Early recurrence after complete initial transurethral resection of bladder tumor (TUR-BT) may indicate biologically aggressive non-muscle-invasive bladder cancer (NMIBC). This study aimed to identify clinicopathological predictors of ER and its independent impact on progression and survival outcomes. Methods: Clinical data of 335 primary NMIBC patients who underwent TUR-BT between 2012 and 2024 were retrospectively analyzed. Patients with non-primary tumors, incomplete resection, or follow-up <6 months were excluded from the study. Patients were categorized into recurrence-free, early recurrence, and late recurrence groups. Logistic regression was used to identify predictors of early recurrence. Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) were analyzed using the Kaplan–Meier method and Cox regression. A 36-month landmark analysis was conducted to adjust for heterogeneity in follow-up duration. Results: Early recurrence occurred in 118 patients (35.2%). Independent predictors of early recurrence were tumor size (OR = 1.012, p = 0.038), T1 stage (OR = 2.57, p = 0.004), high-grade pathology (OR = 1.933, p = 0.030), and absence of single-dose intravesical chemotherapy (IVC) (OR = 3.642, p = 0.025). Additionally, adjuvant IVC (OR = 0.279, p = 0.015) and intravesical BCG (OR = 0.427, p = 0.006) independently reduced the risk of early recurrence. Early recurrence independently predicted worse PFS (HR = 6.053), CSS (HR = 2.052), and OS (HR = 1.961) (all p < 0.001). The landmark analysis confirmed these results (all p < 0.05). Conclusions: Early recurrence after initial and complete TUR-BT is an independent predictor of adverse oncological outcomes. Identifying high-risk patients and applying early intravesical therapy may improve outcomes by preventing early recurrence. Full article

Background: Tuberculous meningitis (TBM) is the most severe manifestation of tuberculosis in children, with high mortality rates and long-term neurological sequelae. Early diagnosis is challenging due to its nonspecific symptoms and insidious onset. Case Presentation: An 8-year-old previously healthy male, fully vaccinated, presented with a two-week history of fever, headache, vomiting, and abdominal pain. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, elevated protein, and low glucose levels, while multiplex polymerase chain reaction (PCR) testing for bacteria and viruses yielded negative results. Brain computed tomography (CT) revealed mild ventricular dilation and pansinusitis. Empirical antibacterial and antiviral therapy were initiated; however, the patient subsequently experienced neurological deterioration, including cranial nerve deficits and hemiparesis. Brain magnetic resonance imaging (MRI) demonstrated acute infarctions of the basal ganglia, raising suspicion for TBM. Repeated CSF sampling and Xpert MTB/RIF assay confirmed infection with Mycobacterium tuberculosis. Anti-tuberculosis treatment was initiated in combination with adjunctive corticosteroids, anticonvulsant and anticoagulant therapies, and supportive care, including neurosurgical intervention for hydrocephalus. After 16 months of treatment, the patient showed clinical improvement but sustained left-sided hemiparesis, visual impairment, and cognitive deficits. Conclusions: This case highlights the diagnostic challenges of pediatric TBM in immunocompetent and Bacillus Calmette–Guérin (BCG)-vaccinated children, particularly in the presence of initially negative microbiological findings. It emphasizes the importance of maintaining a high index of clinical suspicion and the crucial supportive role of neuroimaging findings, as well as the earlier initiation of empirical TB therapy especially when epidemiological plausibility exists. Early recognition and intervention remain critical to reducing morbidity and mortality associated with this devastating disease. Full article

Background/Objectives: High recurrence rates and intensive lifelong surveillance make bladder cancer among the costliest malignancies to treat. Although Bacillus Calmette–Guérin (BCG) immunotherapy is the standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), up to 50% of patients fail to respond, and predictive biomarkers are lacking. Molecular profiling has established three BCG response subtypes (BRS1–3), with BRS3 characterized by an immunosuppressive, BCG-resistant phenotype; however, these features have not been validated at single-cell spatial resolution. Methods: We applied imaging mass cytometry (IMC) to 82 BCG-treated high-risk NMIBC samples and performed (i) single-cell IMC with unsupervised clustering to identify phenotypic cell clusters and quantify cluster abundances and (ii) a convolutional neural network-based gated attention multiple instance learning model trained on IMC images (IMC-GA-MIL) to predict BCG response. Cluster abundances were summarized using II (immune composition within the immune compartment), TT (tumor phenotypic composition), and IT (immune/stromal abundance relative to tumor cells) indices. Results: Single-cell IMC identified 18 distinct phenotypic cell clusters. In BCG responders, immune cells localized within the tumor compartment were enriched and independently protective (HR 0.67, 95% CI 0.49–0.92). BCG nonresponse was associated with a higher abundance of fibroblast-dominant clusters relative to tumor cells (IT index). Plasma cell-dominant clusters were the strongest predictors of progression (II index HR 2.28, 95% CI 1.37–3.79; IT index HR 1.25, 95% CI 1.06–1.48). The IMC-GA-MIL model predicted BCG response with 90% accuracy (9/10) and identified myeloid- and T-cell-associated marker patterns involving CD14, CD11b, CD68, CD8, and FOXP3 as the most informative contributors. Conclusions: Spatial single-cell profiling and IMC-GA-MIL identify spatial immune and stromal features associated with BCG failure. However, findings from both analyses should be considered exploratory and will require validation in larger, independent cohorts. Full article

Background and Clinical Significance: Bladder cancer is common, with urothelial carcinoma (UC) comprising most cases in Western countries. Metastases usually involve pelvic structures, lymph nodes, and organs such as the liver, lungs, bones, and adrenal glands. Identifying unusual metastatic sites is critical for accurate diagnosis and treatment planning. Case Presentation: A 65-year-old man with a history of high-grade (G3) UC and carcinoma in situ, previously treated with TURBT, second-look resection, and SWOG-protocol BCG, presented with a new bladder lesion (pT1). Staging CT revealed extravesical spread and a 1.5 cm pancreatic body nodule. EUS-guided biopsy confirmed metastatic UC with concordant immunohistochemistry (GATA3+), excluding primary pancreatic cancer. The patient was referred for systemic therapy with immune checkpoint inhibitors and Enfortumab Vedotin. Conclusions: This case demonstrates the rare occurrence of pancreatic metastasis from bladder UC. EUS-guided biopsy with immunohistochemistry is essential to distinguish secondary lesions from primary pancreatic tumors. Accurate diagnosis is crucial to guide systemic therapy, particularly with emerging immunotherapy and antibody–drug conjugates. Full article

Evidence on modifiable post-diagnosis factors influencing outcomes after intravesical Bacillus Calmette–Guérin (BCG) therapy for high-risk non-muscle-invasive bladder cancer (NMIBC) is limited. In this exploratory, feasibility-focused prospective multicenter cohort (March 2023–November 2024), BCG-naïve patients completed repeated interviewer-administered 24 h dietary recalls; prespecified food groups, selected foods, and nutrients were screened for associations with 1-year intravesical recurrence using Firth’s penalized logistic regression adjusted a priori for age, sex, and total energy intake, with false discovery rate control within each exposure family. Forty-six patients were enrolled; 41 had evaluable recurrence status, including 8 recurrences (19.5%). Participants were predominantly overweight (mean body mass index (BMI) 28.4 kg/m²) and had low adherence to a Mediterranean dietary pattern (median Mediterranean Adequacy Index 2.25). No dietary exposure met the within-family false discovery rate threshold; the smallest q-value was 0.361. Nominal inverse associations were observed for leafy green vegetables (OR per 1 SD 0.385; 95% CI 0.101–0.972) and for energy-adjusted zinc (OR 0.280; 95% CI 0.069–0.802) and magnesium intakes (OR 0.260; 95% CI 0.045–0.872), but these did not remain significant after FDR adjustment. These exploratory signals warrant replication in larger, biomarker-informed cohorts incorporating dietary biomarkers and immune profiling during BCG. Given the limited sample size and low number of recurrence events, these findings are strictly hypothesis-generating and should not be interpreted as evidence of definitive protective or risk dietary factors. Full article

Latent tuberculosis infection (LTBI) represents a major global health concern as it constitutes the principal reservoir for future tuberculosis (TB) disease. Its identification is particularly important in Bacille Calmette–Guérin (BCG)-vaccinated populations, where cross-reactivity of purified protein derivative limits the specificity of the tuberculin skin test and hampers targeted preventive therapy. Early Mycobacterium tuberculosis antigens encoded within the RD1 region, especially ESAT-6, CFP-10 and TB7.7, have enabled the development of antigen-specific interferon-gamma release assays (IGRAs) and recombinant skin tests with improved BCG-independent specificity. This narrative review integrates and critically appraises current evidence on the immunobiological properties of early and latency-associated antigens, the cellular mechanisms underlying T-cell-dependent immune reactivity, and the diagnostic performance of IGRAs and ESAT-6/CFP-10-based skin tests, rather than merely summarizing individual studies. Although these platforms rely on different assay principles (in vitro cytokine release versus in vivo delayed-type hypersensitivity), both measure antigen-specific T-cell memory and do not define the biological stage of infection or reliably distinguish latent from incipient or active TB. Across most adult populations, IGRAs demonstrate high specificity and acceptable sensitivity, whereas reduced sensitivity and higher rates of indeterminate results are observed in young children and immunocompromised individuals. ESAT-6/CFP-10-based skin tests show diagnostic accuracy comparable to IGRAs and may offer operational advantages in resource-limited settings. Latency-associated antigens and host biomarkers such as IP-10, together with multi-analyte immune signatures, represent promising avenues for improving diagnostic sensitivity and prognostic stratification but currently lack sufficient validation for routine clinical use. Overall, RD1-encoded antigens remain central to LTBI immunodiagnosis, while future research should focus on developing stage-resolving and prognostic biomarkers, optimized antigen panels, and standardized interpretive frameworks. Full article

Background: In high-risk non-muscle-invasive bladder cancer (NMIBC), adjuvant therapies, such as intravesical Bacillus Calmette–Guérin (BCG) instillation, are widely employed; however, BCG treatment poses challenges due to potential adverse effects and ongoing supply limitations. This study aimed to evaluate treatment patterns, therapeutic efficacy, incidence of adverse events, and clinical predictors of recurrence and progression in patients with high-grade pT1 urothelial carcinoma (HG-T1 UC) of the bladder. Methods: This retrospective cohort study included 204 patients diagnosed with HG-pT1 UC who underwent transurethral resection of bladder tumor (TURBT) at Toho University Sakura Medical Center between 2010 and 2021. Clinical data encompassing treatment modalities (BCG or intravesical chemotherapy), complications, and oncological outcomes were collected. Recurrence-Free Survival (RFS), Progression-Free Survival, and Cancer-Specific Survival were analyzed using Kaplan–Meier analyses and multivariate regression models. Results: Maintenance BCG therapy was significantly associated with prolonged RFS compared to other treatments, including among ‘very high-risk’ patients. However, 52.4% of patients receiving BCG maintenance experienced adverse events, with dose reductions required in 59% of cases. Notably, recurrence rates did not significantly differ based on dose reduction or the total number of BCG instillations. Tumor multiplicity emerged as an independent risk factor for recurrence. Conclusions: Although maintenance BCG therapy remains essential for managing HG-T1 UC, especially in high-risk patients, treatment should be individualized due to concerns about tolerability and availability. The study results support the importance of personalized strategies based on risk stratification as outlined in clinical guidelines for preventing recurrence in NMIBC. Full article

Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancer cases but exhibits significant clinical heterogeneity in treatment response and progression risk. While intravesical bacillus Calmette–GuérinCa (BCG) therapy remains the gold standard for high-risk disease, approximately 30–50% of patients experience BCG failure, creating a critical decision point between additional bladder-sparing therapy (BST) and early radical cystectomy (RC). Recent clinical data from the CISTO study suggest that, in appropriately selected patients, RC may be associated with higher 12-month recurrence-free survival while maintaining comparable cancer-specific survival and physical functioning. In this narrative review, we synthesize contemporary evidence on NMIBC genomic and transcriptomic subtypes, immune contexture, and clinicopathologic features associated with BCG response and progression risk, with emphasis on clinically oriented classification systems such as BCG Response Subtypes (BRS1–3) and UROMOL21. We highlight how tumor-intrinsic biology (e.g., EMT-associated programs), immune phenotypes (inflamed vs. immune-cold microenvironments), and genomic alterations may help refine risk stratification beyond traditional clinicopathologic models. To facilitate clinical integration, we propose a conceptual decisional framework that combines molecular subtype assignment, immune profiling, key pathologic risk factors, and patient considerations to generate probabilistic risk tiers that support selection among early RC, BST, and clinical trial strategies. Standardized multicenter cohorts and prospective evaluation are needed to validate integrated models and define their clinical utility for the precision timing of cystectomy in BCG-unresponsive NMIBC. Full article

Pediatric tuberculosis (TB) remains a critically underrecognized contributor to global childhood morbidity and mortality, with the highest burden concentrated in low-resource settings. Although children comprise a minority of overall TB cases, mortality is disproportionately high, particularly among those under five years of age, driven largely by delayed diagnosis, inadequate linkage to care, and limited access to effective treatment. The continued rise of pediatric multidrug-resistant TB (MDR-TB), especially in regions with low sociodemographic development, further highlights persistent gaps in current control strategies. This review synthesizes key aspects of pediatric TB pathogenesis and host immune responses that predispose young children to rapid disease progression and severe outcomes, including immune immaturity and paucibacillary infection. We summarize pulmonary and extrapulmonary disease manifestations and identify populations at heightened risk, including children with HIV, malnutrition, type 1 diabetes mellitus, and congenital or treatment-related immunosuppression. Ongoing challenges in diagnosis and treatment are discussed, including limitations of existing microbiologic and immunologic tests, specimen collection constraints, regimen toxicity, and barriers to adherence. Prevention remains central to reducing pediatric TB mortality. We highlight the sustained importance of bacille Calmette–Guérin (BCG) vaccination in preventing severe disease and death, the context-dependent variability in vaccine effectiveness, and the structural and socioeconomic determinants of vaccine coverage. We conclude that integrating equitable vaccine delivery, scalable preventive therapy, and child-adapted diagnostic strategies is essential to meaningfully reduce the global pediatric TB burden. Full article

Background/Objectives: Non-muscle invasive bladder cancer (NMIBC) management is increasingly complex due to conflicting guideline-based risk classifications, ongoing Bacillus Calmette–Guérin (BCG) shortages, and emerging alternative therapies. Computational Histology Artificial Intelligence (CHAI) tests are clinically available, providing insights from tumor specimens including predicting BCG responsiveness and individualized recurrence and progression risks, which may support precision medicine. This technology features biomarkers purpose-built for clinically unmet needs and has practical advantages including a fast turnaround time and no need for consumption of tissue or other specimens. We assessed the impact of such tests on physicians’ decision-making in routine, real-world NMIBC management. Methods: Physicians at six centers ordered CHAI tests (Vesta Bladder) at their discretion during routine NMIBC care. Tumor specimens were processed by a CLIA/CAP-accredited laboratory (Valar Labs, Houston, TX, USA) where H&E-stained slides were analyzed with the CHAI assay to extract histomorphic features of the tumor and microenvironment, which were algorithmically assessed to generate biomarker test results. For each case from 24 June 2024 to 18 July 2025, ordering physicians were surveyed to assess pre- and post-test management plans and post-test result usefulness. Results: Among 105 high-grade NMIBC cases with complete survey results available, primary management changed in 67% (70/105). Changes included modality shifts (n = 7; three to radical cystectomy with high prognostic risk scores; four avoiding cystectomy with low scores) and intravesical agent change (n = 63). Surveillance was intensified in 7%, predominantly among those with ≥90th percentile risk scores. The therapeutic agent changed in 80% (40/50) of predictive biomarker-present (indicative of poor response to BCG) tumors vs. 48% (23/48) of biomarker-absent tumors. Conclusions: In two thirds of cases, CHAI biomarker results influenced clinical decision-making during routine care. BCG predictive biomarker results frequently guided intravesical agent selection. These results have implications for optimizing clinical outcomes, especially in the setting of ongoing BCG shortages. Prognostic risk stratification results guided treatment escalation vs. de-escalation, including surveillance intensification and surgical vs. bladder-sparing decisions. CHAI biomarkers are currently utilized in routine clinical care and informing precision NMIBC management. Full article