Timothy Chang

Haptic Feedback Enhances Force Skill Learning

This paper explores the use of haptic feedback to teach an abstract motor skill that requires recalling a sequence of forces. Participants are guided along a trajectory and are asked to learn a sequence of one-dimensional forces via three paradigms: haptic training, visual training, or combined visuohaptic training. The extent of learning is measured by accuracy of force recall. We find that recall following visuohaptic training is significantly more accurate than recall following visual or haptic training alone, although haptic training alone is inferior to visual training alone. This suggests that in conjunction with visual feedback, haptic training may be an effective tool for teaching sensorimotor skills that have a force-sensitive component to them, such as surgery. We also present a dynamic programming paradigm to align and compare spatiotemporal haptic trajectories

Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimers disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death.

Endoscopic molecular imaging of human bladder cancer using a CD47 antibody

Fluorescently labeled CD47 antibody is an endoscopic molecular imaging agent to diagnose human bladder cancer. Lighting Up Bladder Cancer Lesions Molecular imaging of bladder cancer could greatly improve on current methods of diagnosis, which rely on white light–based imaging that looks for superficial tissue changes, such as color and texture. To this end, Pan et al. targeted the cancer-specific marker CD47 that is present on the surface of solid tumors, including in the bladder. The authors attached a brightly fluorescent tag, called a quantum dot, to a CD47 antibody. The fluorescent antibody was instilled into human bladders with muscle and nonmuscle invasive cancer that had been recently removed from patients. Overall, 119 bladder regions were analyzed using the fluorescent antibody and blue light cystoscopy. The authors reported a sensitivity of 82.9% and a specificity of 90.5%. They further correctly identified five of six carcinoma in situ lesions—a diagnostic challenge for white light imaging. Because this approach only requires topical administration of a fluorescent antibody and the use of already available clinical tools, it is hoped that this molecular imaging approach to diagnosing various bladder cancers will translate after further optimization. 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.

Interobserver agreement of confocal laser endomicroscopy for bladder cancer.

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 κ 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%, κ 0.80) compared with moderate agreement for WLC alone (74%, κ 0.46), while novice CLE urologists had moderate agreement for CLE (77%, κ 0.55), WLC (78%, κ 0.54), and WLC+CLE (80%, κ 0.59). Pathologists had substantial agreement for CLE (81%, κ 0.61), and nonclinical researchers had moderate agreement (77%, κ 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, κ 0.64), WLC (74%, κ 0.67), and WLC+CLE (53%, κ 0.33), as did novice CLE urologists for CLE (53%, κ 0.39), WLC (66%, κ 0.50), and WLC+CLE (61%, κ 0.49). Pathologists (65%, κ 0.55) and nonclinical researchers (61%, κ 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.

Probe-based confocal laser endomicroscopy of the urinary tract: the technique.

Probe-based confocal laser endomicroscopy (CLE) is an emerging optical imaging technology that enables real-time in vivo microscopy of mucosal surfaces during standard endoscopy. With applications currently in the respiratory and gastrointestinal tracts, CLE has also been explored in the urinary tract for bladder cancer diagnosis. Cellular morphology and tissue microarchitecture can be resolved with micron scale resolution in real time, in addition to dynamic imaging of the normal and pathological vasculature. The probe-based CLE system (Cellvizio, Mauna Kea Technologies, France) consists of a reusable fiberoptic imaging probe coupled to a 488 nm laser scanning unit. The imaging probe is inserted in the working channels of standard flexible and rigid endoscopes. An endoscope-based CLE system (Optiscan, Australia), in which the confocal endomicroscopy functionality is integrated onto the endoscope, is also used in the gastrointestinal tract. Given the larger scope diameter, however, application in the urinary tract is currently limited to ex vivo use. Confocal image acquisition is done through direct contact of the imaging probe with the target tissue and recorded as video sequences. As in the gastrointestinal tract, endomicroscopy of the urinary tract requires an exogenenous contrast agent-most commonly fluorescein, which can be administered intravenously or intravesically. Intravesical administration is a well-established method to introduce pharmacological agents locally with minimal systemic toxicity that is unique to the urinary tract. Fluorescein rapidly stains the extracellular matrix and has an established safety profile. Imaging probes of various diameters enable compatibility with different caliber endoscopes. To date, 1.4 and 2.6 mm probes have been evaluated with flexible and rigid cystoscopy. Recent availability of a < 1 mm imaging probe opens up the possibility of CLE in the upper urinary tract during ureteroscopy. Fluorescence cystoscopy (i.e. photodynamic diagnosis) and narrow band imaging are additional endoscope-based optical imaging modalities that can be combined with CLE to achieve multimodal imaging of the urinary tract. In the future, CLE may be coupled with molecular contrast agents such as fluorescently labeled peptides and antibodies for endoscopic imaging of disease processes with molecular specificity.

Optical Biopsy of Bladder Cancer Using Crowd-Sourced Assessment.

Crowdsourcing and optical biopsy are emerging technologies with broad applications in clinical medicine and research. Crowdsourcing, an interactive digital platform that uses multiple individual contributions to efficiently perform a complex task, has been successfully used in diverse disciplines ranging from performance assessment in surgery to optimization of tertiary protein conformations. 1,2 Optical biopsy technologies provide real-time tissue imaging with histology-like resolution and the potential to guide intraoperative decision making. 3-5 An example is confocal laser endomicroscopy (CLE), which can be used for the diagnosis and grading of bladder cancer. 6 To further assess the adoptability of optical biopsy as a diagnostic tool, we applied crowdsourcing to determine the barriers to learning how to diagnose cancer using CLE. We hypothesized that a nonmedically trained crowd could learn to rapidly and accurately distinguish between cancer and benign tissue. Methods | Amazon Mechanical Turk (Amazon.com) users were recruited as the crowd using a software platform developed by C-SATS. Each crowd worker first completed a validated training module 6 and answered a standard screening question, and then assessed a CLE video sequence randomly selected from a set of 12 sequences derived from a benign (n = 3) or cancer-ous (n = 9) urothelium (Figure 1). Videos were previously annotated by an expert user (J.C.L.), and diagnoses were confirmed by pathology under a Stanford University institutional review board–approved protocol. For a video to be categorized as showing a cancerous urothelium, correct classification by at least 70% of the crowd, which is the lowest statistical threshold for differentiation from random guessing, was required. Agreement with the expert user by at least 70% of crowd workers was also used to classify microscopic features with 2 categories (papillary structure, organization, morphology , cellular cohesiveness, and cellular borders). Microscopic vascular features with 3 categories were categorized based on a lower threshold of 35% agreement. Crowd workers were compensated 50¢ for each video assessed and blinded to patient history and diagnosis. Results | A total of 1283 ratings from 602 crowd workers were received in 9 hours, 27 minutes. A total of 1173 ratings were eligible for analysis based on correct screening response. The crowd accurately distinguished a cancerous urothelium from a benign urothelium in 11 of 12 video sequences (92%) (Figure 2). The single erroneous classification was of low-grade bladder cancer. In the assessment of microscopic characteristics , the crowds achieved the highest accuracy for cellular borders (10 of …

Image-Guided Transurethral Resection of Bladder Tumors – Current Practice and Future Outlooks

Transurethral resection of bladder tumor (TURBT) under white light cystoscopy (WLC) is the cornerstone for the diagnosis, removal and local staging of non-muscle invasive bladder cancer (NMIBC). Despite technological improvements over the decades, significant shortcomings remain with WLC for tumor detection, thereby impacting the surgical quality and contributing to tumor recurrence and progression. Enhanced cystoscopy modalities such as blue light cystoscopy (BLC) and narrow band imaging (NBI) aid resections by highlighting tumors that might be missed on WLC. Optical biopsy technologies such as confocal laser endomicroscopy (CLE) and optical coherence tomography (OCT) characterize tissue in real-time to ensure a more thorough resection. New resection techniques, particularly en bloc resection, are actively under investigation to improve the overall quality of resections and aid pathologic interpretation. Moreover, new image processing computer algorithms may improve perioperative planning and longitudinal follow-up. Clinical translation of molecular imaging agents is also on the horizon to improve optical diagnosis of bladder cancer. This review focuses on emerging technologies that can impact the quality of TURBT to improve the overall management of NMIBC.

V12-01 MULTIMODAL ENHANCED CYSTOSCOPY FOR IMPROVED BLADDER TUMOR RESECTIONS

LN group. The patient’s mean scar satisfaction score was higher in the LESS group (9.3 vs 8.3, p1⁄40.003). The mean days off work (20.7 vs 27.3 days, p1⁄40.07), the mean number of days to 100% activity (53.7 vs 70.6, p1⁄40.14) and the score given to the overall experience by the patient (8.8 vs 8.4, p1⁄40.3) did not differ significantly between the 2 groups CONCLUSIONS: LESS-N offers a superior cosmetic outcome compared to LN on the expense of operative time and surgical difficulty. However, the LN group also enjoyed excellent scar satisfaction. Many studies showed that the importance of cosmesis is more evident in younger patients and those with non-oncological conditions. We believe that the choice for LESS nephrectomy should be tailored to each specific patient according to his age, individual perception of scar importance, indication for nephrectomy and size of kidney to be removed rather than offering it unanimously to all our nephrectomy population

MP78-11 POSITIVE PREDICTIVE VALUE OF CT UROGRAPHY FOR UPPER TRACT UROTHELIAL CARCINOMA DIAGNOSIS USING DIAGNOSTIC URETEROSCOPY AS THE REFERENCE STANDARD

INTRODUCTION AND OBJECTIVES: We reported the lack of therapeutic effect of lymphadenectomy on lower ureteral cancer (LUC). We further examined this mechanism by analyzing the recurrence pattern and factors influencing the outcome of LUC. METHODS: From January 1988 to September 2016, we performed radical nephroureterectomy for 83 patients with non-metastatic (clinically N0 M0) LUC at two Japanese institutes. The lower ureter was designated as located below the crossing of the common iliac artery. Metastatic sites were identified with radiological imaging studies or resected specimens. Regional nodes of LUC were identified as ipsilateral pelvic nodes below the aortic bifurcation, according to the description in our previous study. RESULTS: The mean age of the 83 patients was 71.2 years (range: 38e90 years), and the mean follow-up period was 48 months (range: 2e225 months). Radical nephroureterectomy was performed for 41 patients with right LUC and for 42 patients with left LUC. No significant difference was found in the patients who underwent templatebased lymphadenectomy (34% in the right and 36% in the left LUC, p1⁄40.88). The 5-year recurrence-free and cancer-specific survival rates were respectively 71.9% and 80.1% in the right LUC, and 50.6% and 62.7% in the left LUC. The difference was statistically significant (p1⁄40.02 and 0.03, respectively; Figure 1). The incidence of lymph node recurrence was even higher in the patients with left LUC (24%) than in those with right LUC (2%), and 60% of the lymph node recurrences occurred at the extraregional nodes in the left LUC. The multivariate analysis revealed that the factors that influenced cancer-specific survival were left ureteral tumors (hazard ratio [HR], 3.38; p1⁄40.02) and pathological stage T3 or higher (HR, 28.9; p1⁄40.002). Template-based lymphadenectomy or adjuvant chemotherapy was not a significant factor. CONCLUSIONS: This multi-institutional study shows a higher risk of extraregional nodes recurrence after nephroureterectomy in patients with left LUC, which is likely to be associated with worse oncological outcome of left LUC than right LUC. Template-based lymphadenectomy alone appears inadequate to improve patient survival in left LUC.

In vivo biodistribution and toxicity of intravesical administration of quantum dots for optical molecular imaging of bladder cancer

Optical molecular imaging holds the potential to improve cancer diagnosis. Fluorescent nanoparticles such as quantum dots (QD) offer superior optical characteristics compared to organic dyes, but their in vivo application is limited by potential toxicity from systemic administration. Topical administration provides an attractive route for targeted nanoparticles with the possibility of minimizing exposure and reduced dose. Previously, we demonstrated successful ex vivo endoscopic imaging of human bladder cancer by topical (i.e. intravesical) administration of QD-conjugated anti-CD47. Herein we investigate in vivo biodistribution and toxicity of intravesically instilled free QD and anti-CD47-QD in mice. In vivo biodistribution of anti-CD47-QD was assessed with inductively coupled plasma mass spectrometry. Local and systemic toxicity was assessed using blood tests, organ weights, and histology. On average, there was no significant accumulation of QD outside of the bladder, although in some mice we detected extravesical biodistribution of QD suggesting a route for systemic exposure under some conditions. There were no indications of acute toxicity up to 7 days after instillation. Intravesical administration of targeted nanoparticles can reduce systemic exposure, but for clinical use, nanoparticles with established biosafety profiles should be used to decrease long-term toxicity in cases where systemic exposure occurs.