Biocompatible gold nanoparticles designed to absorb light at wave-lengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles ...to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance–ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function.
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related ...gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.
Objective
To describe the natural history of untreated muscle‐invasive bladder cancer (MIBC) and compare the oncological outcomes of treated and untreated patients.
Patients and Methods
We utilised a ...database encompassing all patients with newly diagnosed bladder cancer in Stockholm, Sweden between 1995 and 1996. The median follow‐up for survivors was 14.4 years. Overall, 538 patients were diagnosed with bladder cancer of whom 126 had clinically localised MIBC. Patients were divided into two groups: those who received radical cystectomy or radiation therapy, and those who did not receive any form of treatment. Multivariable Cox or competing‐risks regressions were adopted to predict metastasis, overall survival (OS), and cancer‐specific mortality (CSM), when appropriate. Analyses were adjusted for age at diagnosis, sex, tumour stage, clinical N stage, and treatment.
Results
In all, 64 (51%) patients did not receive any definitive local treatment. In the untreated group, the median (interquartile range) age at diagnosis was 79 (63–83) vs 69 (63–74) years in the treated group (P < 0.001). Overall, 109 patients died during follow‐up. At 6 months after diagnosis, 38% of the untreated patients had developed metastatic disease and 41% had CSM. The 5‐year OS rate for untreated and treated patients was 5% (95% confidence interval CI 1, 12%) vs 48% (95% CI 36, 60%), respectively. Patients not receiving any treatment had a 5‐year cumulative incidence of CSM of 86% (95% CI 75, 94%) vs 48% (95% CI 36, 60%) for treated patients. Untreated patients had a higher risk of progression to metastatic disease (hazard ratio HR 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and CSM (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004).
Conclusions
Untreated patients with MIBC are at very high risk of near‐term CSM. These findings may help balance the risks vs benefits of integrating curative intent therapy particularly in older patients with MIBC.
To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer.
We pursued an unbiased approach using bulk RNA sequencing data from ...two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M
2IR) score. Single myeloid phagocytic cells with low M
2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer.
The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
.
Given that randomized trials exploring adjuvant chemotherapy for bladder cancer have been underpowered and/or terminated prematurely, yielding inconsistent results and creating an evidence gap, we ...sought to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients.
We conducted an observational study to compare the effectiveness of adjuvant chemotherapy versus observation postcystectomy in patients with pathologic T3-4 and/or pathologic node-positive bladder cancer using the National Cancer Data Base. We compared overall survival using propensity score (-adjusted, -stratified, -weighted, and -matched) analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to examine the impact of performance status.
A total of 5,653 patients met study inclusion criteria; 23% received adjuvant chemotherapy postcystectomy. Chemotherapy-treated patients were younger and more likely to have private insurance, live in areas with a higher median income and higher percentage of high school-educated residents, and have lymph node involvement and positive surgical margins (P < .05 for all comparisons). Stratified analyses adjusted for propensity score demonstrated an improvement in overall survival with adjuvant chemotherapy (hazard ratio, 0.70; 95% CI, 0.64 to 0.76), and similar results were achieved with propensity score matching and weighting. The association between adjuvant chemotherapy and improved survival was consistent in subset analyses and was robust to the effects of poor performance status.
In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively.
To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.
We ...prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.
With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB,
and
were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively;
< 0.001), whereas
and
were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively;
< 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in
and
. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.
UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic ...molecular alterations.
To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC.
A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.
A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies.
Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC.
We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type.
Recent data obtained by high-throughput molecular profiling technologies underscore the distinct molecular alterations found in upper tract urothelial carcinoma (UTUC). UTUC biology shares many features with bladder cancer, but there are important specific distinctions that support the need for UTUC-targeted therapeutic strategies.
With advancements in molecular biology techniques, great progress has been made in the understanding of urothelial carcinoma pathogenesis.
To examine the historic description of molecular alterations ...in bladder cancer and their evolution towards our current comprehension of the biology of the disease.
Historically, a two-pathway model was described from histological and cytogenetic studies: low-grade papillary non-muscle invasive bladder cancers (NMIBC) were described to arise from epithelial hyperplasia with loss of chromosome 9 as an early event, whereas muscle-invasive bladder cancers (MIBC) were considered to develop from dysplasia, associated with genetic instability. Although there could be connections between the 2 pathways, NMIBC and MIBC were largely believed to develop secondary to different molecular alterations.
Next-generation sequencing has allowed important insights into cancer biology and a better understanding of the pathways involved in bladder cancer pathogenesis and heterogeneity. Urothelial carcinoma has been found to have a high frequency of somatic mutations compared to other solid tumors, including several mutations in multiple signaling pathways, such as cell cycle regulators (TP53, RB1), RTK/RAS/RAF pathway, PI3K/AKT/mTOR pathway and TERT gene promoter. Epigenetic changes and mutations in chromatin remodeling genes are especially frequent in bladder cancer. Mutations in FGFR3 and KDM6A are more common in NMIBC than in MIBC, whereas mutations in TP53 and KMT2D are more common in MIBC, suggesting the previously hypothesized 2 different pathways, with a subset of tumors progressing from NMIBC to MIBC.
Using comprehensive RNA expression profiling studies, at least 5 subtypes of bladder cancer have been identified, the most fundamental division being Basal/Squamous-like and Luminal. These subtypes have different prognoses, natural histories and responses to systemic treatments: Luminal subtypes are enriched with papillary histology and have a better prognosis, while Basal/Squamous-like subtypes are enriched with squamous features, are associated with advanced stage at presentation, and portend a worse prognosis.
This new understanding of bladder cancer will optimistically translate into better understanding of this heterogeneous disease and lead to improvement in patient outcome and quality of life through better tailored treatments.
•Two pathways of pathogenesis were historically described: papillary NMIBC and MIBC.•Urothelial carcinoma has a high degree of molecular heterogeneity and a high mutational load.•Next-generation sequencing can identify potential targets for personalized therapy.•Molecular subtypes based on expression profiles can provide prognostic and predictive value.
Muscle-invasive bladder cancer is an aggressive disease, for which neoadjuvant chemotherapy followed by radical cystectomy remains the gold standard treatment. Although great efforts have been ...invested in developing and advancing urinary diversion methods, none has yet to approach those of a fully functional native bladder.Currently, the only bladder-sparing approach recommended for optimal candidates is concurrent chemoradiation (trimodal therapy). In the future, a risk-adapted approach, which includes transurethral resection of bladder tumor followed by systemic neoadjuvant treatment and stringent surveillance, could be offered to patients.Optimal patient selection remains the cornerstone of these approaches. Novel biomarkers, such as circulating tumor DNA, and the integration of multiparametric MRI with a standardized scoring system, may aid in better assessing clinical complete response, reducing misclassifications, and leading to improved oncological outcomes.
The pursuit of surgeons and oncologists in fulfilling the inherent desire of patients to retain their urinary bladder despite having muscle-invasive bladder cancer (MIBC) has sparked years of research and multiple debates, given its aggressive nature and the high risk of fatal metastatic recurrence. Historically, several approaches to bladder-sparing treatment have been explored, ranging from radical transurethral resection to concurrent chemoradiation. A less well-established approach involves a risk-adapted approach with local therapy deferred based on the clinical response to transurethral resection followed by systemic therapy. Each approach is associated with potential risks, benefits, and trade-offs. In this review, we aim to understand, navigate, and suggest future perspectives on bladder-sparing approaches in patients with MIBC.
The pursuit of surgeons and oncologists in fulfilling the inherent desire of patients to retain their urinary bladder despite having muscle-invasive bladder cancer (MIBC) has sparked years of research and multiple debates, given its aggressive nature and the high risk of fatal metastatic recurrence. Historically, several approaches to bladder-sparing treatment have been explored, ranging from radical transurethral resection to concurrent chemoradiation. A less well-established approach involves a risk-adapted approach with local therapy deferred based on the clinical response to transurethral resection followed by systemic therapy. Each approach is associated with potential risks, benefits, and trade-offs. In this review, we aim to understand, navigate, and suggest future perspectives on bladder-sparing approaches in patients with MIBC.
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