Bladder Cancer最新文献

Background: The rationale for ethnic differences in bladder cancer (BCa) susceptibility is an important open question. In this study, we raised the hypothesis that the APOBEC3-rs1014971 variant associated with BCa risk and APOBEC-mutagenesis probably contribute to ethnic differences.

Methods: We calculated the ethnicity-stratified 5-year age-adjusted incidence rates of BCa using the US SEER database. We performed somatic mutational-signature analyses and compared the APOBEC-related mutational contribution across BCa tumors in patients of different ethnicities. We analyzed the allele frequency distribution of APOBEC3-related rs1014971 in contemporary populations of different ethnicities and in ancient human genomes. We also analyzed the natural selection profiles and ages of the investigated SNPs.

Results: We validated the ethnic difference in BCa risk using US SEER data, revealing Caucasians to be at >2-fold greater risk than Asians / Pacific islanders. In contemporary populations, we observed a coherent ethnic distribution in terms not only of the allele frequency of APOBEC3-related rs1014971, but also the mutational contribution of APOBEC-mediated mutagenesis in BCa tumors. Population genetics and ancient genome analyses further suggested that the diverse ethnic distribution of rs1014971 could be rooted in human evolution.

Conclusions: It is possible that APOBEC3-related rs1014971 is involved in the different BCa incidence across ethnic groups, and this difference is potentially derived from human evolution. Our findings suggested an evolutionary link between contemporary population-level variations in malignancy susceptibility and pathogen-driven selection in the past, not unlike previously reported cases of certain autoimmune and metabolic disorders.

Background: Bacillus Calmette-Guerin (BCG) is the standard adjuvant treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) following transurethral resection of the bladder (TURB). However, the optimal dose, strain, and schedule of BCG remain unclear.

Objective: To evaluate the impact of BCG dose reduction on oncological outcomes and toxicity in patients with non-muscle invasive bladder cancer.

Methods: We performed a systematic review of the literature in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Selected studies were analyzed for Meta Analysis using PRISMA criteria. The study focused on disease recurrence, progression, and toxicity. We also compared the oncological outcomes of the different BCG strains.

Results: A total of 2963 patients in 13 randomized controlled trials were included. In recurrence analysis, we found a non-significant difference between the full dose and any dose reduction of BCG (RR = 1.17, [1.06-1.28], I2 = 0%, p = 0.7). In terms of progression, the difference was also non-statistically significant (RR: 1.12 [0.89 - 1.41], I2 = 0%, p = 0.93). In the toxicity analysis, there were more local (RR: 0.81 [0.67-0.99] I2 = 76%; p < 0.01) and systemic (RR: 0.53 [0.34-0.82] I2 = 83%; p < 0.01) side effects in the full dose group than in the dose reduction group. There were no statistically significant differences in oncological outcomes between the analyzed BCG strains.

Conclusions: Dose reduction did not affect the oncological outcomes of patients with NMIBC who received adjuvant therapy with BCG. On the other hand, dose reduction showed a significant trend towards fewer systemic and local side effects. Further studies comparing oncological and toxicity outcomes using different strains are needed.

Background: With the exception of the FDA-approved valrubicin and pembrolizumab, there are no standard second-line treaments for BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC).

Objectives: To provide a systematic review of the novel intravesically administered therapeutic agents for the salvage treatment of BCG-unresponsive NMIBC.

Methods: Online search of the PubMed, EMBASE and Web of Science databases was performed. The endpoints of this review were to evaluate the efficacy of the agents in terms of complete response rates (CR) and durability of CR, overall survival, recurrence-free survival and cancer-specific survival and to report on their toxicity profile. A search on Clinicaltrials.gov was performed to identify ongoing clinical trials.

Results: 14 studies were included in this review. The critical clinical need for the development of an effective, safe and durable intravesical drug for the salvage treatment of high-risk NMIBC seems to be met mainly by intravesical gene therapy; in fact, data support the FDA-approved nadofaragene firadenovec as a potentially important therapeutic advancement in this context. Promising results are also being obtained by the combination of N-803/BCG and by innovative drug delivery systems.

Conclusions: Considering the plethora of novel intravesical treatments that have completed phase II evaluation, one can reasonably expect that clinicians will soon have at their disposal new agents and treatment options for BCG-unresponsive NMIBC. In the near future, it will be up to the urologist to identify, for each specific patient, the right agent to use, based on safety, results and cost-effectiveness.

The introduction of T-cell targeted immunomodulators blocking the PD-1 and PD-L1 axis is unquestionably one of the most notable advancements in the treatment of advanced or metastatic solid malignancies, including bladder cancer. Immune checkpoint antibodies are now widely utilized as monotherapies or in combination with other systemic therapies in the first or subsequent lines of treatment in approximately 50 cancer types. Deep and durable responses and long tails of survival curves are hallmarks of patients treated with immune checkpoint inhibitors. However, treatment can have negative impacts, including serious treatment-related side effects as well as a high financial burden to individual patients and the healthcare system. There is increasing data that the benefit of immune checkpoint treatment may persist after treatment is discontinued for reasons other than progressive disease, particularly in patients who have achieved a durable complete response. However, the optimal treatment duration and activity after treatment reinitiation remains undefined and will likely be influenced by disease biology (histology and genomics), treatment (monotherapy or combination therapy), and disease context (depth and duration of response). Well-designed prospective clinical trials and the development and validation of biomarkers that predict outcomes after treatment cessation are needed to move the field forward.

Background: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors.

Objective: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer.

Methods: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies.

Results: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies.

Conclusions: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.