Eric Leung

Interstitial permeability and elasticity in human cervix cancer.

Malignant tumors are characterized by abnormalities of the vasculature and interstitium, which may impede the distribution of drugs and imaging agents. Here we describe a method for estimating tumor interstitial permeability and elasticity based on fitting a spatio-temporal fluid dynamic model to the time course of interstitial pressure (IFP) measurements. The model assumes that sudden insertion of the IFP measurement needle transiently perturbs the steady-state fluid balance, which recovers over time as a function of the vascular and interstitial hydraulic conductivities (L(p)S and K), the interstitial bulk modulus (E) and the extracellular, extravascular volume fraction (phi). Initial simulations showed that the time course of IFP recordings was mainly determined by K and E/phi. Mean values of K and E/phi in 60 newly diagnosed cervix cancers were 1.5 x 10(-7) (SE 2.2 x 10(-8)) cm(2)/mm Hg s and 2230 (SE 212) mm Hg, respectively. For comparison, K and E/phi were also measured in orthotopic ME-180 human cervix cancer xenografts and KHT-C fibrosarcomas in mice. K was higher in both of these tumors (7.0 x 10(-7) and 9.3 x 10(-7)) than in cervix cancer, and E/phi was lower (497 and 433). To our knowledge, these are the first measurements of interstitial permeability and elasticity in individual human cancers. Serial evaluation of these parameters may provide a means of clinically monitoring response to treatments that specifically target the tumor microenvironment.

Intra-operative 360° 3D transvaginal ultrasound guidance during high-dose-rate interstitial gynecologic brachytherapy needle placement

In high-dose-rate (HDR) interstitial gynecologic brachytherapy, needles are positioned into the tumor and surrounding area through a template to deliver radiotherapy. Optimal dose and avoidance of nearby organs requires precise needle placement; however, there is currently no standard method for intra-operative needle visualization or guidance. We have developed and validated a 360° three-dimensional (3D) transvaginal ultrasound (TVUS) system and created a sonolucent vaginal cylinder that is compatible with the current template to accommodate a conventional side-fire ultrasound probe. This probe is rotated inside the hollow sonolucent cylinder to generate a 3D image. We propose the use of this device for intra-operative verification of brachytherapy needle locations. In a feasibility study, the first ever 360° 3D TVUS image of a gynecologic brachytherapy patient was acquired and the image allowed key features, including bladder, rectum, vaginal wall, and bowel, to be visualized with needles clearly identifiable. Three patients were then imaged following needle insertion (28 needles total) and positions of the needles in the 3D TVUS image were compared to the clinical x-ray computed tomography (CT) image, yielding a mean trajectory difference of 1.67 ± 0.75°. The first and last visible points on each needle were selected in each modality and compared; the point pair with the larger distance was selected as the maximum difference in needle position with a mean maximum difference of 2.33 ± 0.78 mm. This study demonstrates that 360° 3D TVUS may be a feasible approach for intra-operative needle localization during HDR interstitial brachytherapy of gynecologic malignancies.

Circulating Human Papillomavirus DNA as a Biomarker of Response in Patients With Locally Advanced Cervical Cancer Treated With Definitive Chemoradiation

PurposeTo determine whether plasma human papillomavirus (HPV) DNA predates clinical recurrence and compare its accuracy with 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) in locally advanced cervical cancer.MethodsThis prospective multicenter study accrued 23 women with stage IB to IVA cervical cancer planned for definitive chemoradiation therapy (CRT). Plasma HPV DNA was measured serially by digital polymerase chain reaction, and FDG-PET was performed at 3 months post-CRT.ResultsOf the 19 women with HPV+ cervical cancer included in this analysis, 32% were stage IB, 58% IIB, and 10% IIIB/IVA. Median follow-up was 24 months (range, 18 to 30 months). All patients had detectable plasma HPV DNA before treatment. Six patients had detectable plasma HPV DNA at the end of CRT, and three of them developed metastases at 3 months. Of the 13 patients with undetectable plasma HPV DNA at end of CRT, to date, only one has developed recurrence. Six of those 13 patients had a positive 3-month FDG-PET w...

360-degree 3D transvaginal ultrasound system for high-dose-rate interstitial gynaecological brachytherapy needle guidance

Treatment for gynaecological cancers often includes brachytherapy; in particular, in high-dose-rate (HDR) interstitial brachytherapy, hollow needles are inserted into the tumour and surrounding area through a template in order to deliver the radiation dose. Currently, there is no standard modality for visualizing needles intra-operatively, despite the need for precise needle placement in order to deliver the optimal dose and avoid nearby organs, including the bladder and rectum. While three-dimensional (3D) transrectal ultrasound (TRUS) imaging has been proposed for 3D intra-operative needle guidance, anterior needles tend to be obscured by shadowing created by the template’s vaginal cylinder. We have developed a 360-degree 3D transvaginal ultrasound (TVUS) system that uses a conventional two-dimensional side-fire TRUS probe rotated inside a hollow vaginal cylinder made from a sonolucent plastic (TPX). The system was validated using grid and sphere phantoms in order to test the geometric accuracy of the distance and volumetric measurements in the reconstructed image. To test the potential for visualizing needles, an agar phantom mimicking the geometry of the female pelvis was used. Needles were inserted into the phantom and then imaged using the 3D TVUS system. The needle trajectories and tip positions in the 3D TVUS scan were compared to their expected values and the needle tracks visualized in magnetic resonance images. Based on this initial study, 360-degree 3D TVUS imaging through a sonolucent vaginal cylinder is a feasible technique for intra-operatively visualizing needles during HDR interstitial gynaecological brachytherapy.

Development of 3D ultrasound needle guidance for high-dose-rate interstitial brachytherapy of gynaecological cancers

High-dose-rate (HDR) interstitial brachytherapy is often included in standard-of-care for gynaecological cancers. Needles are currently inserted through a perineal template without any standard real-time imaging modality to assist needle guidance, causing physicians to rely on pre-operative imaging, clinical examination, and experience. While two-dimensional (2D) ultrasound (US) is sometimes used for real-time guidance, visualization of needle placement and depth is difficult and subject to variability and inaccuracy in 2D images. The close proximity to critical organs, in particular the rectum and bladder, can lead to serious complications. We have developed a three-dimensional (3D) transrectal US system and are investigating its use for intra-operative visualization of needle positions used in HDR gynaecological brachytherapy. As a proof-of-concept, four patients were imaged with post-insertion 3D US and x-ray CT. Using software developed in our laboratory, manual rigid registration of the two modalities was performed based on the perineal template’s vaginal cylinder. The needle tip and a second point along the needle path were identified for each needle visible in US. The difference between modalities in the needle trajectory and needle tip position was calculated for each identified needle. For the 60 needles placed, the mean trajectory difference was 3.23 ± 1.65° across the 53 visible needle paths and the mean difference in needle tip position was 3.89 ± 1.92 mm across the 48 visible needles tips. Based on the preliminary results, 3D transrectal US shows potential for the development of a 3D US-based needle guidance system for interstitial gynaecological brachytherapy.