Virtual Reality Hemifield Measurements for Corrective Surgery Eligibility in Ptosis Patients: A Pilot Clinical Trial.

Purpose: We developed an accelerated virtual reality (VR) suprathreshold hemifield perimetry algorithm, the median cut hemifield test (MCHT). This study examines the ability of the MCHT to determine ptosis severity and its reversibility with an artificial improvement by eyelid taping on an HTC Vive Pro Eye VR headset and the Humphrey visual field analyzer (HVFA) to assess the capabilities of emerging technologies in evaluating ptosis. Methods: In a single visit, the MCHT was administered along with the HVFA 30-2 on ptotic untaped and taped eyelids in a randomized order. The primary end points were a superior field visibility comparison with severity of VF loss and VF improvement after taping for MCHT and HVFA. Secondary end points included evaluating patients' Likert-scaled survey responses on the comfort, speed, and overall experience with both testing modalities. Results: VR's MCHT superior field degrees visible correlated well for severe category margin to reflex distance (r = 0.78) compared with HVFA's (r = -0.21). The MCHT also demonstrated noninferiority (83.3% agreement; P = 1) against HVFA for detection of 30% or more superior visual field improvement after taping, warranting a corrective surgical intervention. In comparing hemi-VF in untaped eyes, both tests demonstrated relative obstruction to the field when comparing normal controls to severe ptosis (HVFA P < 0.05; MCHT P < 0.001), which proved sufficient to demonstrate percent improvement with taping. The secondary end point of patient satisfaction favored VR vision testing presentation mode in terms of comfort (P < 0.01), speed (P < 0.001), and overall experience (P < 0.01). Conclusions: This pilot trial supports the use of MCHT for the quantitative measurement of visual field loss owing to ptosis and the reversibility of ptosis that is tested when conducting a presurgical evaluation. We believe the adoption of MCHT testing in oculoplastic clinics could decrease patient burden and accelerate time to corrective treatment. Translational Relevance: In this study, we look at vision field outputs in patients with ptosis to evaluate its severity and improvement with eyelid taping on a low-profile VR-based technology and compare it with HVFA. Our results demonstrate that alternative, portable technologies such as VR can be used to grade the degree of ptosis and determine whether ptosis surgery could provide a significant superior visual field improvement of 30% or more, all while ensuring a more comfortable experience and faster testing time.

Circulating tumor cells from prostate cancer patients interact with E-selectin under physiologic blood flow.

Hematogenous metastasis accounts for the majority of cancer-related deaths, yet the mechanism remains unclear. Circulating tumor cells (CTCs) in blood may employ different pathways to cross blood endothelial barrier and establish a metastatic niche. Several studies provide evidence that prostate cancer (PCa) cell tethering and rolling on microvascular endothelium via E-selectin/E-selectin ligand interactions under shear flow theoretically promote extravasation and contribute to the development of metastases. However, it is unknown if CTCs from PCa patients interact with E-selectin expressed on endothelium, initiating a route for tumor metastases. Here we report that CTCs derived from PCa patients showed interactions with E-selectin and E-selectin expressing endothelial cells. To examine E-selectin-mediated interactions of PCa cell lines and CTCs derived from metastatic PCa patients, we used fluorescently-labeled anti-prostate specific membrane antigen (PSMA) monoclonal antibody J591-488 which is internalized following cell-surface binding. We employed a microscale flow device consisting of E-selectin-coated microtubes and human umbilical vein endothelial cells (HUVECs) on parallel-plate flow chamber simulating vascular endothelium. We observed that J591-488 did not significantly alter the rolling behavior in PCa cells at shear stresses below 3 dyn/cm(2). CTCs obtained from 31 PCa patient samples showed that CTCs tether and stably interact with E-selectin and E-selectin expressing HUVECs at physiological shear stress. Interestingly, samples collected during disease progression demonstrated significantly more CTC/E-selectin interactions than samples during times of therapeutic response (p=0.016). Analysis of the expression of sialyl Lewis X (sLe(x)) in patient samples showed that a small subset comprising 1.9-18.8% of CTCs possess high sLe(x) expression. Furthermore, E-selectin-mediated interactions between prostate CTCs and HUVECs were diminished in the presence of anti-E-selectin neutralizing antibody. CTC-Endothelial interactions provide a novel insight into potential adhesive mechanisms of prostate CTCs as a means to initiate metastasis.

Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device.

Cancer metastasis accounts for the majority of cancer-related deaths owing to poor response to anticancer therapies. Molecular understanding of metastasis-associated drug resistance remains elusive due to the scarcity of available tumor tissue. Isolation of circulating tumor cells (CTCs) from the peripheral blood of patients has emerged as a valid alternative source of tumor tissue that can be subjected to molecular characterization. However, issues with low purity and sensitivity have impeded adoption to clinical practice. Here we report a novel method to capture and molecularly characterize CTCs isolated from castrate-resistant prostate cancer patients (CRPC) receiving taxane chemotherapy. We have developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that combines an anti-prostate specific membrane antigen (PSMA) antibody with a 3D geometry that captures CTCs while minimizing nonspecific leukocyte adhesion. Enumeration of GEDI-captured CTCs (defined as intact, nucleated PSMA+/CD45- cells) revealed a median of 54 cells per ml identified in CRPC patients versus 3 in healthy donors. Direct comparison with the commercially available CellSearch® revealed a 2-400 fold higher sensitivity achieved with the GEDI device. Confocal microscopy of patient-derived GEDI-captured CTCs identified the TMPRSS2:ERG fusion protein, while sequencing identified specific androgen receptor point mutation (T868A) in blood samples spiked with only 50 PC C4-2 cells. On-chip treatment of patient-derived CTCs with docetaxel and paclitaxel allowed monitoring of drug-target engagement by means of microtubule bundling. CTCs isolated from docetaxel-resistant CRPC patients did not show any evidence of drug activity. These measurements constitute the first functional assays of drug-target engagement in living circulating tumor cells and therefore have the potential to enable longitudinal monitoring of target response and inform the development of new anticancer agents.