Prostate cancer therapy using immune checkpoint molecules to target recombinant dendritic cells.

PURPOSE: We developed immune checkpoint molecules to target recombinant dendritic cells (DCs) and verified their anti-tumor efficacy and immune response against prostate cancer. MATERIALS AND METHODS: DCs were generated from mononuclear cells in the tibia and femur bone marrow of mice. We knocked down the programmed death ligand 1 (PD-L1) on monocyte-derived DCs through siRNA PD-L1. Cell surface antigens were immune fluorescently stained through flow cytometry to analyze cultured cell phenotypes. Furthermore, we evaluated the efficacy of monocyte-derived DCs and recombinant DCs in a prostate cancer mouse model with subcutaneous TRAMP-C1 cells. Lastly, DC-induced mixed lymphocyte and lymphocyte-only proliferations were compared to determine cultured DCs' function. RESULTS: Compared to the control group, siRNA PD-L1 therapeutic DC-treated mice exhibited significantly inhibited tumor volume and increased tumor cell apoptosis. Remarkably, this treatment substantially augmented interferon-gamma and interleukin-2 production by stimulating T-cells in an allogeneic mixed lymphocyte reaction. Moreover, we demonstrated that PD-L1 gene silencing improved cell proliferation and cytokine production. CONCLUSIONS: We developed monocyte-derived DCs transfected with PD-L1 siRNA from mouse bone marrow. Our study highlights that PD-L1 inhibition in DCs increases antigen-specific immune responses, corroborating previous immunotherapy methodology findings regarding castration-resistant prostate cancer.

Comparative analysis of recurrence rates between intravesical gemcitabine and bacillus Calmette-Guérin induction therapy following transurethral resection of bladder tumors in patients with intermediate- and high-risk bladder cancer: A retrospective multicenter study.

PURPOSE: This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS: Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. RESULTS: In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p<0.001). There were no consistent significant differences observed between the two groups in the 3-month (gemcitabine, 98.4% vs. BCG, 95.3%; p=0.848), 6-month (94.9% vs. 90.0%, respectively; p=0.793) and 1-year CR rates (84.2% vs. 83.3%, respectively; p=0.950). Also, there was no significant statistical difference in progression-free survival between the two groups (p=0.953). The occurrence rates of adverse events were similar between the groups (22.2% vs. 22.1%; p=0.989); however, the rate of Clavien-Dindo grade 2 or higher was significantly higher in the BCG group (1.6% vs. 16.3%, respectively; p<0.001). CONCLUSIONS: Intravesical gemcitabine demonstrated efficacy comparable to BCG therapy for the first year in patients with intermediate- and high-risk NMIBC. However, long-term follow-up studies are warranted.

Availability of ChatGPT to provide medical information for patients with kidney cancer.

ChatGPT is an advanced natural language processing technology that closely resembles human language. We evaluated whether ChatGPT could help patients understand kidney cancer and replace consultations with urologists. Two urologists developed ten questions commonly asked by patients with kidney cancer. The answers to these questions were produced using ChatGPT. The five-dimension SERVQUAL model was used to assess the service quality of ChatGPT. The survey was distributed to 103 urologists via email, and twenty-four urological oncologists specializing in kidney cancer were included as experts with more than 20 kidney cancer cases in clinic per month. All respondents were physicians. We received 24 responses to the email survey (response rate: 23.3%). The appropriateness rate for all ten answers exceeded 60%. The answer to Q2 received the highest agreement (91.7%, etiology of kidney cancer), whereas the answer to Q8 had the lowest (62.5%, comparison with other cancers). The experts gave low assessment ratings (44.4% vs. 93.3%, p = 0.028) in the SERVQUAL assurance (certainty of total answers) dimension. Positive scores for the overall understandability of ChatGPT answers were assigned by 54.2% of responders, and 70.8% said that ChatGPT could not replace explanations provided by urologists. Our findings affirm that although ChatGPT answers to kidney cancer questions are generally accessible, they should not supplant the counseling of a urologist.

Changes in patient perceptions regarding ChatGPT-written explanations on lifestyle modifications for preventing urolithiasis recurrence.

Purpose: Artificial Intelligence (AI) imitating human-like language, such as ChatGPT, has impacted lives throughout various multidisciplinary fields. However, despite these innovations, it is unclear how well its implementation will assist patients in clinical situations. We evaluated changes in patient perceptions regarding AI before and after reading a ChatGPT-written explanation. Materials and methods: In total, 24 South Korean patients receiving urolithiasis treatment were surveyed through questionnaires. The ChatGPT explanatory note was provided between the first and second questionnaires, detailing lifestyle modifications for preventing urolithiasis recurrence. The study questionnaire was the Korean version of the General Attitudes toward Artificial Intelligence Scale, including positive and negative attitude items. Wilcoxon signed-rank tests were accomplished to compare questionnaire scores before and after receiving the explanatory note. A linear regression analysis with stepwise elimination was used to assess variable (demographic data) accuracy in predicting outcomes. Results: There were significant differences between total negative questionnaire scores pre- and post-surveys of ChatGPT, but not in the positive scores. Among variables, only education level significantly influenced mean score differences in the negative questionnaires. Conclusions: The negative perception change among urolithiasis patients after receiving the explanatory note provided by the AI chatbot program was observed, evidencing that patients with lower education levels expressed a more negative response. The explanatory note provided by the AI chatbot program could provoke an adverse change in AI perception. Negative human responses must be considered to improve and adapt new technology in health care. Only through changing patient perspectives will upgraded AI technology integrate into medical healthcare.

Dose Optimization Using a Deep Learning Tool in Various CT Protocols for Urolithiasis: A Physical Human Phantom Study.

Background and Objectives: We attempted to determine the optimal radiation dose to maintain image quality using a deep learning application in a physical human phantom. Materials and Methods: Three 5 × 5 × 5 mm3 uric acid stones were placed in a physical human phantom in various locations. Three tube voltages (120, 100, and 80 kV) and four current-time products (100, 70, 30, and 15 mAs) were implemented in 12 scans. Each scan was reconstructed with filtered back projection (FBP), statistical iterative reconstruction (IR, iDose), and knowledge-based iterative model reconstruction (IMR). By applying deep learning to each image, we took 12 more scans. Objective image assessments were calculated using the standard deviation of the Hounsfield unit (HU). Subjective image assessments were performed by one radiologist and one urologist. Two radiologists assessed the subjective assessment and found the stone under the absence of information. We used this data to calculate the diagnostic accuracy. Results: Objective image noise was decreased after applying a deep learning tool in all images of FBP, iDose, and IMR. There was no statistical difference between iDose and deep learning-applied FBP images (10.1 ± 11.9, 9.5 ± 18.5 HU, p = 0.583, respectively). At a 100 kV-30 mAs setting, deep learning-applied FBP obtained a similar objective noise in approximately one third of the radiation doses compared to FBP. In radiation doses with settings lower than 100 kV-30 mAs, the subject image assessment (image quality, confidence level, and noise) showed deteriorated scores. Diagnostic accuracy was increased when the deep learning setting was lower than 100 kV-30 mAs, except for at 80 kV-15 mAs. Conclusions: At the setting of 100 kV-30 mAs or higher, deep learning-applied FBP did not differ in image quality compared to IR. At the setting of 100 kV-30 mAs, the radiation dose can decrease by about one third while maintaining objective noise.

Oral chemotherapeutic agents in metastatic hormone-sensitive prostate cancer: A network meta-analysis of randomized controlled trials.

Background: Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents. Materials and methods: We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate. Results: We identified 18 RCTs (n = 13,509). Concerning OS, ADT + abiraterone, ADT + abiraterone + docetaxel, ADT + apalutamide, ADT + bicalutamide, ADT + darolutamide + docetaxel, ADT + enzalutamide, ADT + orteronel, and ADT + rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT + bicalutamide, nilutamide, flutamide, ADT + bicalutamide + palbociclib, and ADT + nilutamide. ADT + docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis. Conclusions: Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT + docetaxel SOC. Even so, ADT + docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.

Animal models of bone metastatic prostate cancer.

Metastatic disease is a main cause of mortality in prostate cancer and remains to be incurable despite emerging new treatment agents. Development of novel treatment agents are confined within the boundaries of our knowledge of bone metastatic prostate cancer. Exploration into the underlying mechanism of metastatic tumorigenesis and treatment resistance will further expose novel targets for novel treatment agents. Up to date, many of these researches have been conducted with animal models which have served as classical tools that play a pivotal role in understanding the fundamental nature of cancer. The ability to reproduce the natural course of prostate cancer would be of profound value. However, currently available models do not reproduce the entire process of tumorigenesis to bone metastasis and are limited to reproducing small portions of the entire process. Therefore, knowledge of available models and understanding the strengths and weaknesses for each model is key to achieve research objectives. In this article, we take an overview of cell line injection animal models and patient derived xenograft models that have been applied to the research of human prostate cancer bone metastasis.

Efficacy of recombinant Bacillus Calmette-Guérin containing dltA in in vivo three-dimensional bio-printed bladder cancer-on-a-chip and ex vivo orthotopic mouse model.

PURPOSE: We investigated the efficacy and optimal dosage of recombinant Bacillus Calmette-Guérin-dltA (rBCG-dltA) in a high-throughput 3D bio-printed bladder cancer-on-a-chip (BCOC) and orthotopic bladder cancer mouse model. MATERIALS AND METHODS: We fabricated high-throughput BCOC with microfluidic systems, enabling efficient drug screening. The efficacy of rBCG-dltA was evaluated using BCOC by the cell viability assay, monocyte migration assay, and measuring cytokine levels. The anti-tumor effect was compared using the orthotopic bladder cancer mouse model. RESULTS: The cell proliferation rates of T24 and 253J bladder cancer cell lines (mean±standard error) were measured at three days after treatment. In T24 cell line, there was significantly decreased T24 cells compared to control at rBCG 1 multiplicity of infection (MOI) and 10 MOI (30 MOI: 63.1±6.4, 10 MOI: 47.4±5.2, 1 MOI: 50.5±7.5, control: 100.0±14.5, p<0.05). In 253J cell line, a statistically significant decrease in 253J cell count compared to control and mock BCG 30 MOI (30 MOI: 11.2±1.3, 10 MOI: 22.5±2.3, 1 MOI: 39.4±4.7, Mock: 54.9±10.8, control: 100.0±5.6, p<0.05). The migration rates of THP-1 cells showed increased patterns after rBCG-dltA treatment in BCOC. The concentration of tumor necrosis factor-α and interleukin-6 after rBCG-dltA 30 MOI treatment was higher than control in T24 and 253J cell line. CONCLUSIONS: In conclusion, rBCG-dltA has the potential to have better anti-tumor activity and immunomodulatory effects than BCG. Furthermore, high-throughput BCOCs have potential to reflect the bladder cancer microenvironment.

Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study.

BACKGROUND: We aimed to assess the trends in urinary tract infections (UTIs) and prognosis of patients with prostate cancer after radical prostatectomy (RP) and radiation therapy (RT) as definitive treatment options. METHODS: The data of patients diagnosed with prostate cancer between 2007 and 2016 were collected from the National Health Insurance Service database. The incidence of UTIs was evaluated in patients treated with RT, open/laparoscopic RP, and robot-assisted RP. The proportional hazard assumption test was performed using the scaled Schoenfeld residuals based on a multivariable Cox proportional hazard model. Kaplan-Meier analysis were performed to assess survival. RESULTS: A total of 28,887 patients were treated with definitive treatment. In the acute phase (< 3 months), UTIs were more frequent in RP than in RT; in the chronic phase (> 12 months), UTIs were more frequent in RT than in RP. In the early follow-up period, the risk of UTIs was higher in the open/laparoscopic RP group (aHR, 1.63; 95% CI, 1.44-1.83; p < 0.001) and the robot-assisted RP group (aHR, 1.26; 95% CI, 1.11-1.43; p < 0.001), compared to the RT group. The robot-assisted RP group had a lower risk of UTIs than the open/laparoscopic RP group in the early (aHR, 0.77; 95% CI, 0.77-0.78; p < 0.001) and late (aHR, 0.90; 95% CI, 0.89-0.91; p < 0.001) follow-up periods. In patients with UTI, Charlson Comorbidity Index score, primary treatment, age at UTI diagnosis, type of UTI, hospitalization, and sepsis from UTI were risk factors for overall survival. CONCLUSIONS: In patients treated with RP or RT, the incidence of UTIs was higher than that in the general population. RP posed a higher risk of UTIs than RT did in early follow-up period. Robot-assisted RP had a lower risk of UTIs than open/laparoscopic RP group in total period. UTI characteristics might be related to poor prognosis.

Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study.

This study assessed the trends in methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine-cisplatin (GC) regimens in Korean patients with metastatic urothelial carcinoma (UC) and compared the side effects and overall survival (OS) rates of the two regimens using nationwide population-based data. The data of patients diagnosed with UC between 2004 and 2016 were collected using the National Health Insurance Service database. The overall treatment trends were assessed according to the chemotherapy regimens. The MVAC and GC groups were matched by propensity scores. Cox proportional hazard analysis and Kaplan-Meier analysis were performed to assess survival. Of 3108 patients with UC, 2,880 patients were treated with GC and 228 (7.3%) were treated with MVAC. The transfusion rate and volume were similar in both the groups, but the granulocyte colony-stimulating factor (G-CSF) usage rate and number were higher in the MVAC group than in the GC group. Both groups had similar OS. Multivariate analysis revealed that the chemotherapy regimen was not a significant factor for OS. Subgroup analysis revealed that a period of ≥ 3 months from diagnosis to systemic therapy enhanced the prognostic effects of the GC regimen. The GC regimen was widely used as the first-line chemotherapy in more than 90% of our study population with metastatic UC. The MVAC regimen showed similar OS to the GC regimen but needed greater use of G-CSF. The GC regimen could be a suitable treatment option for metastatic UC after ≥ 3 months from diagnosis.

Shifting role of cytoreductive nephrectomy according to type of systemic therapy: A nationwide cohort study.

PURPOSE: The best protocol of cytoreductive nephrectomy (CN) and systemic therapy (ST) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear. We sought to evaluate overall survival (OS) in patients with mRCC treated with ST with or without CN. METHODS: We collected data from the National Health Insurance Service database. We excluded 2 years of washout period, 2 years of follow-up period, other cancer diagnoses within 2 years, and ≥4 months interval between ST and CN. The patients were divided into two groups according to whether CN was performed. Kaplan-Meier, propensity score matching, Cox regression model, and incremental survival analyses were conducted. Additionally, we performed subgroup analysis according to whether cytokine therapy or targeted therapy was used as first-line ST. RESULTS: Of 6478 patients, 1707 (26.4%) underwent CN. The CN group showed significantly better OS than the no CN group (p < 0.001). In the cytokine therapy subgroup, patients who underwent CN had significantly higher OS than those who did not (p < 0.001). In the targeted therapy subgroup, no significant difference was found (p = 0.867). In multivariate analysis, CN was associated with better OS in the total cohort (hazard ratio 0.819, p < 0.001). The incremental OS benefit of CN ranged from +0.98 in patients who survived for <24 months to +2.13 in those who survived during all periods. CONCLUSION: About a quarter patients with mRCC from a nationwide database were treated with CN and ST. CN was beneficial in specific patients with mRCC. Patient selection is crucial for obtaining the benefits of CN.

Neoadjuvant versus adjuvant chemotherapy in upper tract urothelial carcinoma: A nationwide cohort study.

PURPOSE: This study aimed to evaluate the trend of adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC) in patients who underwent radical nephroureterectomy with bladder cuff excision (NUx) for upper tract urothelial carcinoma (UTUC) to compare the perioperative outcomes and overall survival (OS) between AC and NAC using nationwide population-based data. MATERIALS AND METHODS: We collected data on patients diagnosed with UTUC and treated with NUx between 2004 and 2016 using the National Health Insurance Service database, and evaluated the overall treatment trends. The AC and NAC groups were propensity score-matched. Cox proportional hazard and Kaplan-Meier analyses were used to assess survival. RESULTS: Of the 8,705 enrolled patients, 6,627 underwent NUx only, 94 underwent NAC, and 1,984 underwent AC. The rate of NUx without perioperative chemotherapy increased from 70.8 to 78.2% (R2 = 0.632; p < 0.001). The rates of dialysis (p = 0.398), TUR-BT (p = 1.000), and radiotherapy (p = 0.497) after NUx were similar. In the Kaplan-Meier curve, the NAC and AC groups showed no significant difference (p = 0.480). In multivariate analysis, treatment with AC or NAC was not associated with OS (hazard ratio 0.83, 95% confidence interval 0.49-1.40, p = 0.477). CONCLUSION: The use of NUx without perioperative chemotherapy has tended to increase in South Korea. Dialysis, TUR-BT, and radiotherapy rates after NUx were similar between the NAC and AC groups. There was no significant difference in OS between the NAC and AC groups. Proper perioperative chemotherapy according to patient and tumor conditions should be determined by obtaining more evidence of UTUC.

Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis.

AIMS: Mechanical forces surrounding solid tumors are pervasive in the tumor microenvironment (TME) and abnormally altered as solid tumors progress. Although it has been reported that biomechanical forces, including wall shear stress (WSS), enhance the metastatic features of cancer cells, its mechanism remains unknown. Here, we investigate how cancer cells sense mechanical stress and propagate signals in the TME. MAIN METHODS: Using a microfluidic device, interstitial fluid-mimicking flow (0.05 dyne cm-2) was applied to the human prostate cancer cell line PC3. Piezo1 siRNA and shRNA lentivirus were applied to PC3 cells to ablate Piezo1 expression. PC3-Luc2 cells expressing control shRNA or shPiezo1 lentivirus were administered into the prostate of BALB/c mice for orthotopic injection. KEY FINDING: Here, we show that Piezo1, a mechanosensitive ion channel, is activated by WSS in microfluidic channels. Moreover, Yoda1, a Piezo1 agonist, synergistically potentiates cancer cell motility and nuclear retention of YAP/TAZ via WSS. Also, Piezo1 increases Src phosphorylation, which activates YAP. Conversely, silencing Piezo1 significantly reduces cell motility and YAP/TAZ activity induced by WSS, and finally retards tumor growth and metastasis of administered PC3 cells in BALB/c mice. SIGNIFICANCE: Taken together, these results demonstrate that Piezo1 allows cancer cells to sense mechanical stimuli by altering the microenvironment during tumor progression and is a critical player in modulating cancer metastasis through the Piezo1-Src-YAP axis.

A novel strategy for treatment of bladder cancer: Antibody-drug conjugates.

In the past, there was no second-line chemotherapeutic agent suitable for use when urothelial carcinoma (UC) progressed to platinum-resistant UC. However, recently, several new treatment options, such as immune checkpoint inhibitors or targeted therapy have shifted the treatment paradigm regarding second-line therapeutic modalities. A novel class of therapeutic agents includes an antibody-drug conjugate (ADC). ADCs consist of three characteristics: a monoclonal antibody, linker, and payload. The specificity of the monoclonal antibody facilitates the delivery of a linked cytotoxic drug directly into the target tumor cell. Although various ADCs have been developed and approved for use in treating several solid tumors, almost all ADCs for the treatment of UC are still in the testing phase. Here, we review the key points about ADCs and summarize the novel ADCs that are approved or are involved in ongoing studies in UC.

Low-dose versus standard-dose bacille Calmette-Guérin for non-muscle-invasive bladder cancer: Systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Intravesical BCG (bacille Calmette-Guérin) instillation in patients with non-muscle-invasive bladder cancer decreases the risk for tumor recurrence and progression. After one BCG product was discontinued, a chronic global BCG shortage occurred. We focused on identifying a reduced dose of BCG that could maintain efficacy and reduce adverse effects. MATERIALS AND METHODS: We conducted a comprehensive literature search of PubMed, Embase, the Cochrane Library, CINAHL, Web of Science, and Scopus to identify randomized controlled trials through April 2021. The odds ratios (ORs) and 95% confidence intervals (CIs) for the low and standard doses in nine studies were compared. A low dose was defined as a low volume of BCG compared with the standard BCG dose (Armand Frappier, 120 mg; Connaught, 81 mg; Danish 1331, 120 mg; modified Danish 1331, 120 mg; Tokyo 172, 80 mg). RESULTS: The low-dose group experienced aggravated recurrence (OR, 1.45; 95% CI, 1.09-1.94; p=0.01) but similar progression (OR, 1.11; 95% CI, 0.76-1.62; p=0.59), similar cancer-specific survival (OR, 1.02; 95% CI, 0.60-1.75; p=0.93), similar overall survival (OR, 1.09; 95% CI, 0.76-1.56; p=0.65), favorable adverse effects (OR, 0.41; 95% CI, 0.28-0.62; p<0.0001), and favorable withdrawal (OR, 0.42; 95% CI, 0.25-0.71; p=0.001). CONCLUSIONS: Low-dose BCG had more unfavorable outcomes than did standard-dose BCG in terms of recurrence. Tumor progression, cancer-specific survival, and overall survival were similar between the doses. Low-dose BCG improved adverse effects and withdrawal. In the setting of BCG shortage, low-dose BCG may have strong potential as an alternative.

Immunotherapeutic effects of recombinant Bacillus Calmette-Guérin containing sic gene in ex vivo and in vivo bladder cancer models.

PURPOSE: The recombinant Bacillus Calmette-Guérin (BCG) containing the streptococcal inhibitor of the complement gene (rBCG-sic) may be more resistant to antimicrobial peptides and improve internalization; therefore, it can enhance the immunotherapeutic effect of the BCG. Here we determined the optimal dose of rBCG-sic and compared its effectiveness with that of BCG. MATERIALS AND METHODS: We fabricated a high-throughput 3D-bioprinted bladder cancer-on-a-chip (BCOC) and used it to evaluate the effectiveness of the rBCG-sic in terms of cell viability, cell migration, and cytokine concentrations. Using an orthotopic mouse model, we evaluated its anticancer effect and toxicity via bioluminescence imaging. RESULTS: T24 cell viability was decreased after treatment with rBCG-sic 30 multiplicities of infection (MOI) versus the same dosage of mock BCG (42.8%±6.4% vs. 75.7%±6.6%, p<0.05). THP-1 cell migration was positively correlated with rBCG-sic concentration (2.42-fold at 30MOI, p<0.01). The interleukin-6 concentration of rBCG-sic 30MOI was significantly higher than that of mock BCG 30MOI (11.2±1.3 pg/mL vs. 6.7±0.6 pg/mL, p<0.05). In the orthotopic bladder cancer mouse model, lower tumor volume was observed in the rBCG-sic 30MOI group than in the BCG 30MOI group after 10 days of treatment (p<0.05). CONCLUSIONS: We concluded that rBCG-sic is a useful tool for overcoming BCG unresponsiveness in non-muscle invasive bladder cancer. Additionally, high-throughput BCOC with a microfluidic system can successfully reflect the bladder cancer microenvironment.

Neoadjuvant versus adjuvant chemotherapy in bladder cancer: a nationwide cohort study.

PURPOSE: Radical cystectomy is the standard of care for muscle-invasive bladder cancer. However, the 5-year survival rate is only about 50%. Therefore, additional treatments are needed. We compared the perioperative outcomes, overall survival, and treatment trends in patients with bladder cancer who underwent radical cystectomy and either neoadjuvant or adjuvant chemotherapy using nationwide population-based data. MATERIALS AND METHODS: We collected the data of patients diagnosed with bladder cancer treated with radical cystectomy between 2004 and 2016 using the National Health Insurance Service database. We evaluated overall treatment trends. The neoadjuvant chemotherapy and adjuvant chemotherapy groups were matched by propensity score. Cox proportional hazard analysis and Kaplan-Meier analysis were used to assess survival. RESULTS: Of 6134 patients, 1379 underwent adjuvant chemotherapy and 389 underwent neoadjuvant chemotherapy. The utilization rate of neoadjuvant chemotherapy increased from 6.4 to 12.2% from 2004 to 2016 (p = 0.018). The administration rate and number of granulocyte colony-stimulating factor cycles were lower in the neoadjuvant chemotherapy group than in the adjuvant chemotherapy group (p < 0.001 and p = 0.027, respectively). After propensity score matching, the neoadjuvant chemotherapy group had significantly better overall survival than the adjuvant chemotherapy group (p = 0.004). In multivariate analysis, neoadjuvant chemotherapy was associated with better overall survival (hazard ratio 0.77, 95% confidence interval 0.65-0.92, p = 0.003). CONCLUSIONS: Neoadjuvant chemotherapy was associated with lower granulocyte colony-stimulating factor administration and better overall survival than adjuvant chemotherapy. Neoadjuvant chemotherapy should be considered for patients with bladder cancer who undergo radical cystectomy.

Establishment of Three-Dimensional Bioprinted Bladder Cancer-on-a-Chip with a Microfluidic System Using Bacillus Calmette-Guérin.

Immunotherapy of bladder cancer is known to have favorable effects, although it is difficult to determine which patients will show a good response because of the different tumor microenvironments (TME). Here, we developed a bladder cancer-on-a-chip (BCOC) to mimic the TME using three-dimensional (3D) bioprinting and microfluidic technology. We fabricated a T24 and a 5637-cell line-based BCOC that also incorporated MRC-5, HUVEC, and THP-1 cells. We evaluated the effects of TME and assessed the immunologic reactions in response to different concentrations of Bacillus Calmette-Guérin (BCG) via live/dead assay and THP-1 monocytic migration, and concentrations of growth factors and cytokines. The results show that cell viability was maintained at 15% filling density in circle-shaped cell constructs at 20 µL/min microfluidic flow rate. A 3D co-culture increased the proliferation of BCOCs. We found that the appropriate time to evaluate the viability of BCOC, concentration of cytokines, and migration of monocytes was 6 h, 24 h, and three days after BGC treatment. Lastly, the immunotherapeutic effects of BCOC increased according to BCG dosage. To predict effects of immunotherapeutic agent in bladder cancer, we constructed a 3D bioprinted BCOC model. The BCOC was validated with BCG, which has been proven to be effective in the immunotherapy of bladder cancer.

Optimization of a floating poloxamer 407-based hydrogel using the Box-Behnken design: in vitro characterization and in vivo buoyancy evaluation for intravesical instillation.

Intravesical instillation of a poloxamer 407 (PLX)-based hydrogel offers advantages such as thermo-sensitivity and sol-to-gel transition, but its utility is limited by urinary obstruction and insufficient bladder residence time. To overcome these obstacles, a floating PLX-hydrogel (FPH) was developed using sodium bicarbonate (BC) as a floating agent and hyaluronic acid (HA) as a gel strength modulator. The FPH composition was optimized using the Box-Behnken design with three independent variables: X1 [PLX concentration, 23.91%], X2 [BC concentration, 5.15%], and X3 [HA concentration, 3.49%]. The quadratic model was the best fit (desirability function, 0.623), resulting in response parameters of Y1 [floating time, 53.7 s], Y2 [gelation temperature gap, 20.3°C], and Y3 [duration time of gel, 396.7 min]. Rheological observations revealed the mechanical rigidity (storage modulus > loss modulus at elevated temperature) of the optimized FPH (phase transition temperature, 15.08°C). Gel erosion and drug release studies were performed using the gravimetric method; the remaining FPH fraction decreased exponentially with time, and gemcitabine release was biphasic and surface erosion-controlled. In vivo buoyancy was evaluated in rats using ultrasonography; these results were similar to those of the in vitro floating behavior. Thus, optimized FPH for intravesical instillation is a prospective option for bladder cancer treatment.