Biocompatible gold nanoparticles designed to absorb light at wavelengths 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.

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Tumor heterogeneity is common in cancer, however recent studies have applied single gene expression signatures to classify bladder cancers into distinct subtypes. Such stratification assumes that a predominant transcriptomic signature is sufficient to predict progression kinetics, patient survival and treatment response. We hypothesize that such static classification ignores intra-tumoral heterogeneity and the potential for cellular plasticity occurring during disease development. We have conducted single cell transcriptome analyses of mouse and human model systems of bladder cancer and show that tumor cells with multiple lineage subtypes not only cluster closely together at the transcriptional level but can maintain concomitant gene expression of at least one mRNA subtype. Functional studies reveal that tumor initiation and cellular plasticity can initiate from multiple lineage subtypes. Collectively, these data suggest that lineage plasticity may contribute to innate tumor heterogeneity, which in turn carry clinical implications regarding the classification and treatment of bladder cancer.

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Objective To evaluate the ability to detect clinically significant prostate cancer (PCa) using a novel electromagnetically (EM) tracked transperineal magnetic resonance imaging (MRI)/ultrasonography (US) fusion‐guided targeted biopsy (transperineal TBx) platform and the impact of inter‐reader variability on cancer detection. Materials and Methods A total of 176 patients with suspicious lesions detected on multiparametric MRI (mpMRI) underwent a systematic modified Barzel template biopsy (12‐core) transperineal biopsy (transperineal SBx) and transperineal TBx with EM tracking (UroNav; Philips Healthcare, Best, the Netherlands) in the same setting. Cancer detection rates (CDRs) were stratified by Prostate Imaging Reporting and Data System (PI‐RADS) v2 scores and compared with Fisher’s exact test. Area under the curve (AUC) was calculated for prostate‐specific antigen (PSA), PSA density (PSAD), PI‐RADS score, and subgroup analysis of individual readers' PI‐RADS scores with respect to overall CDR and clinically significant CDR. Results The overall CDR was 76.7% (135/176), of which 76.3% (103/135) was clinically significant PCa. Among the 135 patients with PCa, transperineal TBx detected 90.4% of cases (122/135), either alone or in combination with transperineal SBx. The remaining 9.6% of cases (13/135) missed by transperineal TBx were diagnosed by transperineal SBx alone, of which three were clinically significant. Conversely, transperineal SBx missed 14% of cases (19/135), 14 of which were clinically significant PCa. Sensitivities for transperineal TBx and transperineal SBx were 90.4% and 85.9%, respectively. On a per‐lesion basis, PI‐RADS score (AUC 0.74) outperformed both PSA (AUC 0.59) and PSAD (AUC 0.63) in discriminating clinically significant from non‐clinically significant PCa on transperineal TBx. Although not formally statistically tested, AUCs amongst different mpMRI readers appeared to display considerable variability. There were no adverse events, including sepsis. Conclusions Electromagnetically tracked transperineal TBx of MRI‐visible lesions enhanced the ability of transperineal SBx to detect PCa, with greater sensitivity for clinically significant disease. These findings suggest transperineal TBx is a safe, alternative fusion platform for patients with a suspicious lesion on prostate MRI. The assessment of inter‐reader variability, in conjunction with prediction of clinically significant PCa and CDR, is an important first step for quality control in implementing an MRI‐based screening programme.

The immune phenotype of PBMC from patients with high-risk NMIBC was significantly different from HD, regardless of the presence of disease or the initiation of BCG. Peripheral CD8 T cells could play a role in response to BCG.

Purpose: To characterize the evolution of Natural Killer (NK) and T cell exhaustion in peripheral blood and tumor tissue of patients representing the spectrum of human bladder cancer (BC), and to identify molecules for which therapeutic modulation enhances the anti-tumor immune response. Experimental Procedures: PBMC and freshly resected primary tumors were analyzed by FACS to determine phenotype. NK function was assessed via activation with IL-2 or IL-15 followed by co-culture with K562 cells to induce cytokine production and degranulation. For blockade studies, X-Tim-3 and X-TIGIT mAbs were added prior to K562 stimulation. Results: T cells undergo a process of exhaustion in the context of chronic inflammatory pathologies such as cancer that is characterized by diminished effector functionality and subsequent tumor outgrowth. Inhibition of signaling through certain mediators of this process (e.g. CTLA-4 and PD-(L)1) have shown clinical benefit in subsets of patients with a wide array of malignancies. However, it is unknown whether NK exhaustion occurs, and what molecules define it. We found that NK undergo an analogous process of exhaustion based on analysis of PBMC and tumor from 59 individuals with non, and muscle-invasive BC. NK exhaustion is marked by significant up-regulation of Tim-3 and TIGIT in both PBMC and tumor. T cells demonstrated a similar expression pattern but with a lower frequency of positive cells. The magnitude of NK Tim-3 expression is a barometer of tumor invasiveness on cells in both PBMC and tumor tissue, while TIGIT is induced equivalently in BC patients. Importantly, both molecules are expressed at similar frequencies on NK isolated from blood or tumor, independent of the magnitude of overall expression, yet define NK with different functional potential. NK in PBMC from BC patients are functionally comparable to NK from healthy donors in their ability to produce IFNγ/TNFα and degranulate in response to target cells, while tumor NK are refractory to both stimuli. NK from tumor tissue are not terminally exhausted as effector functions are restored after “resting” ex vivo prior to stimulation. Ex vivo blockade of Tim-3, but not TIGIT, enhances effector function in peripheral NK and T cells from BC patients, but is ineffective for NK in tumor tissue, implicating suppressive factors specific to tumor in mediating NK dysfunction. Tim-3 blockade was most efficient in peripheral NK from BC patients that were activated with IL-15 versus IL-2, suggesting that local cytokine milieu can affect responsiveness to subsequent checkpoint inhibition. Conclusions: NK and T cell acquisition of Tim-3 and TIGIT are indicators of BC and detectable in peripheral blood and tumor, but mark effector dysfunction only in tumor tissue. Blockade of Tim-3 enhances NK IFNγ/TNFα production in PBMC of BC patients and represents a new strategy to modulate innate, anti-tumor immunity. Citation Format: Adam M. Farkas, Francois Audenet, Harry Anastos, William K. Oh, Matthew D. Galsky, John P. Sfakianos, Nina Bhardwaj. Tim-3 and TIGIT mark NK and T cells susceptible to effector dysfunction in human bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4745.

The ACS NSQIP risk calculator poorly predicted and discriminated which patients would experience complications after robot-assisted partial nephrectomy. These findings suggest the need for a more tailored outcome prediction model to better assist urologists risk stratify patients undergoing robot-assisted partial nephrectomy and counsel them on individual surgical risks.