A combination of optical imaging technologies with cancer-specific molecular imaging agents is a potentially powerful strategy to improve cancer detection and enable image-guided surgery. Bladder cancer is primarily managed endoscopically by white light cystoscopy with suboptimal diagnostic accuracy. Emerging optical imaging technologies hold great potential for improved diagnostic accuracy but lack imaging agents for molecular specificity. Using fluorescently labeled CD47 antibody (anti-CD47) as molecular imaging agent, we demonstrated consistent identification of bladder cancer with clinical grade fluorescence imaging systems, confocal endomicroscopy, and blue light cystoscopy in fresh surgically removed human bladders. With blue light cystoscopy, the sensitivity and specificity for CD47-targeted imaging were 82.9 and 90.5%, respectively. We detected variants of bladder cancers, which are diagnostic challenges, including carcinoma in situ, residual carcinoma in tumor resection bed, recurrent carcinoma following prior intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), and excluded cancer from benign but suspicious-appearing mucosa. CD47-targeted molecular imaging could improve diagnosis and resection thoroughness for bladder cancer.

Purpose Bladder cancer presents as a spectrum of different diatheses. Accurate assessment for individualized treatment depends on initial diagnostic accuracy. Detection relies on white light cystoscopy accuracy and comprehensiveness. Aside from invasiveness and potential risks, white light cystoscopy shortcomings include difficult flat lesion detection, precise tumor delineation to enable complete resection, inflammation and malignancy differentiation, and grade and stage determination. Each shortcoming depends on surgeon ability and experience with the technology available for visualization and resection. Fluorescence cystoscopy/photodynamic diagnosis, narrow band imaging, confocal laser endomicroscopy and optical coherence tomography address the limitations and have in vivo feasibility. They detect suspicious lesions (photodynamic diagnosis and narrow band imaging) and further characterize lesions (optical coherence tomography and confocal laser endomicroscopy). We analyzed the added value of each technology beyond white light cystoscopy and evaluated their maturity to alter the cancer course. Materials and Methods Detailed PubMed® searches were done using the terms “fluorescence cystoscopy,” “photodynamic diagnosis,” “narrow band imaging,” “optical coherence tomography” and “confocal laser endomicroscopy” with “optical imaging,” “bladder cancer” and “urothelial carcinoma.” Diagnostic accuracy reports and all prospective studies were selected for analysis. We explored technological principles, preclinical and clinical evidence supporting nonmuscle invasive bladder cancer detection and characterization, and whether improved sensitivity vs specificity translates into improved correlation of diagnostic accuracy with recurrence and progression. Emerging preclinical technologies with potential application were reviewed. Results Photodynamic diagnosis and narrow band imaging improve nonmuscle invasive bladder cancer detection, including carcinoma in situ. Photodynamic diagnosis identifies more papillary lesions than white light cystoscopy, enabling more complete resection and fewer residual tumors. Despite improved treatment current data on photodynamic diagnosis do not support improved high risk diathetic detection and characterization or correlation with disease progression. Prospective recurrence data are lacking on narrow band imaging. Confocal laser endomicroscopy and optical coherence tomography potentially grade and stage lesions but data are lacking on diagnostic accuracy. Several emerging preclinical technologies may enhance the diagnostic capability of endoscopic imaging. Conclusions New optical imaging technologies may improve bladder cancer detection and characterization, and transurethral resection quality. While data on photodynamic diagnosis are strongest, the clinical effectiveness of these technologies is not proven. Prospective studies are needed, particularly of narrow band imaging, confocal laser endomicroscopy and optical coherence tomography. As each technology matures and new ones emerg...

Objective To investigate the modified frailty index (mFI) as a pre-operative predictor of post-operative complications following radical cystectomy in bladder cancer patients. Materials and Methods Patients undergoing radical cystectomy (RC) were identified from the National Surgical Quality Improvement Program (NSQIP) participant use files (2011-2013). The mFI was defined in prior studies with 11 variables based on mapping the Canadian Study of Health and Aging Frailty Index to NSQIP comorbidities and activities of daily living (ADL)s. Modified frailty index groups were determined by the number of risk factors per patient (0, 1, 2, ≥3). Univariate, χ2, independent sample t-test, and logistic regression analyses were performed when appropriate. A sensitivity analysis was performed to determine the mFI value at which Clavien 4 and 5 complications would reach significance. Results Of the 2679 cystectomy patients identified, 31% percent of patients had a mFI of 0, 44% had a mFI of 1, 21% had a mFI of 2, and 4% had a mFI ≥ 3. Overall, 59% of patients experienced a Clavien complication. When stratified at a cutoff of mFI >=2, the overall complication rate was not different (61.7% vs. 58.3%, p=0.1319), but the mFI2 or greater group had a significantly higher rate of Clavien grade 4 or 5 complications (14.6% vs. 8.3%, p<0.001) and overall mortality rate (3.5% vs. 1.8%, p=0.0128) in the 30-day post-operative period. The multivariate logistic regression model showed independent predictors of Clavien grade 4 or 5 complications were age >80 years old (OR, 1.58 [1.11-2.27]), mFI2 (odds ratio [OR], 1.84 [1.28-2.64]), and mFI3 (OR, 2.58 [1.47-4.55]). Conclusions Among patients undergoing radical cystectomy, the mFI can identify those patients at greatest risk for severe complications and mortality. Given that bladder cancer is increasing in prevalence particularly among the elderly, pre-operative risk stratification is crucial to inform decision making about surgical candidacy.

OBJECTIVES To develop the diagnostic criteria for benign and neoplastic conditions of the urinary tract using probe-based confocal laser endomicroscopy (pCLE), a new technology for dynamic, in vivo imaging with micron-scale resolution. The suggested diagnostic criteria will formulate a guide for pCLE image interpretation in urology. METHODS Patients scheduled for transurethral resection of bladder tumor (TURBT) or nephrectomy were recruited. After white-light cystoscopy (WLC), fluorescein was administered as contrast. Different areas of the urinary tract were imaged with pCLE via direct contact between the confocal probe and the area of interest. Confocal images were subsequently compared with standard hematoxylin and eosin analysis. RESULTS pCLE images were collected from 66 participants, including 2 patients who underwent nephrectomy. We identified key features associated with different anatomic landmarks of the urinary tract, including the kidney, ureter, bladder, prostate, and urethra. In vivo pCLE of the bladder demonstrated distinct differences between normal mucosa and neoplastic tissue. Using mosaicing, a post hoc image-processing algorithm, individual image frames were juxtaposed to form wideangle views to better evaluate tissue microarchitecture. CONCLUSIONS In contrast to standard pathologic analysis of fixed tissue with hematoxylin and eosin, pCLE provides real time microscopy of the urinary tract to enable dynamic interrogation of benign and neoplastic tissues in vivo. The diagnostic criteria developed in this study will facilitate adaptation of pCLE for use in conjunction with WLC to expedite diagnosis of urinary tract pathology, particularly bladder cancer.

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

Purpose Intraoperative optical biopsy technologies may aid identification of important anatomic landmarks and improve surgical outcomes of robotic-assisted radical prostatectomy (RARP).We sought to evaluate the feasibility of confocal laser endomicroscopy (CLE) during RARP. Materials and Methods Twenty-one patients with biopsy-proven prostate cancer scheduled for RARP were recruited. After intravenous administration of fluorescein, 15 patients underwent in vivo intraoperative CLE of prostatic and periprostatic structures using either a 2.6-mm or 0.85-mm imaging probe. Standard robotic instruments were used to grasp and maneuver the CLE probes for image acquisition. CLE imaging was performed ex vivo on fresh prostate specimens from 20 patients. Confocal video sequences acquired in vivo and ex vivo were reviewed and analyzed, with additional image processing using a mosaicing algorithm. Processed confocal images were compared with standard hematoxylin and eosin analysis of imaged regions. Results CLE was successfully integrated with robotic surgery, including co-registration of confocal video sequences with white light and probe handling with standard robotic instrumentation. Intraoperative CLE imaging of the neurovascular bundle prior to and following nerve-sparing dissection revealed characteristic features including dynamic vascular flow and intact axon fibers. Ex vivo confocal imaging of the prostatic parenchyma demonstrated the normal prostatic glands, stroma, and prostate carcinoma. Conclusions We report the initial feasibility of optical biopsy of prostatic and periprostatic tissue during RARP. Image guidance and tissue interrogation using CLE offers a new intraoperative imaging method that has the potential to improve the functional and oncologic outcomes of prostate cancer surgery.

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Background and Purpose: Emerging optical imaging technologies such as confocal laser endomicroscopy (CLE) hold promise in improving bladder cancer diagnosis. The purpose of this study was to determine the interobserver agreement of image interpretation using CLE for bladder cancer. Methods: Experienced CLE urologists (n = 2), novice CLE urologists (n = 6), pathologists (n = 4), and nonclinical researchers (n = 5) were recruited to participate in a 2-hour computer-based training consisting of a teaching and validation set of intraoperative white light cystoscopy (WLC) and CLE video sequences from patients undergoing transurethral resection of bladder tumor. Interobserver agreement was determined using the j statistic. Results: Of the 31 bladder regions analyzed, 19 were cancer and 12 were benign. For cancer diagnosis, experienced CLE urologists had substantial agreement for both CLE and WLC + CLE (90%, j 0.80) compared with moderate agreement for WLC alone (74%, j 0.46), while novice CLE urologists had moderate agreement for CLE (77%, j 0.55), WLC (78%, j 0.54), and WLC + CLE (80%, j 0.59). Pathologists had substantial agreement for CLE (81%, j 0.61), and nonclinical researchers had moderate agreement (77%, j 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, j 0.64), WLC (74%, j 0.67), and WLC + CLE (53%, j 0.33), as did novice CLE urologists for CLE (53%, j 0.39), WLC (66%, j 0.50), and WLC + CLE (61%, j 0.49). Pathologists (65%, j 0.55) and nonclinical researchers (61%, j 0.56) both had moderate agreement for CLE in cancer grading. Conclusions: CLE is an adoptable technology for cancer diagnosis in novice CLE observers after a short training with moderate interobserver agreement and diagnostic accuracy similar to WLC alone. Experienced CLE observers may be capable of achieving substantial levels of agreement for cancer diagnosis that is higher than with WLC alone.