Wai-Fung Cheong

Noninvasive Functional Imaging of Human Brain Using Light

Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

A randomized trial evaluating everolimus-eluting Absorb bioresorbable scaffolds vs. everolimus-eluting metallic stents in patients with coronary artery disease: ABSORB Japan

AIMS Theoretically, bioresorbable vascular scaffolds (BVSs) may provide superior long-term results compared with permanent metallic drug-eluting stents (DESs). However, whether BVSs are as safe and effective as metallic DESs prior to complete bioresorption is unknown. METHODS AND RESULTS ABSORB Japan was a single-blind, multicentre, active-controlled, randomized trial designed to support regulatory approval of the Absorb BVS in Japan. Eligible patients with one or two de novo lesions in different epicardial vessels were randomized at 38 Japanese sites in a 2:1 ratio to Absorb BVS vs. cobalt-chromium everolimus-eluting stents (CoCr-EESs). The primary endpoint was target lesion failure [TLF: a composite of cardiac death, myocardial infarction attributable to target vessel, or ischaemia-driven target lesion revascularization (ID-TLR)] at 12 months, powered for non-inferiority. The major secondary endpoint was angiographic in-segment late lumen loss (LLL) at 13 months. A total of 400 patients were randomized to BVSs (266 patients and 275 lesions) or CoCr-EESs (134 patients and 137 lesions). TLF through 12 months was 4.2% with BVSs and 3.8% with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.39% (3.95%); Pnon-inferiority < 0.0001]. Definite/probable stent/scaffold thrombosis at 12 months occurred in 1.5% of the patients with both devices (P = 1.0), and ID-TLR for restenosis was infrequent (1.1% with BVSs and 1.5% with CoCr-EESs, P = 1.0). With 96.0% angiographic follow-up, in-segment LLL at 13 months was 0.13 ± 0.30 mm with BVSs and 0.12 ± 0.32 mm with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.01 (0.07); Pnon-inferiority < 0.0001). CONCLUSION In the ABSORB Japan randomized trial, 12-month clinical and 13-month angiographic outcomes of BVSs were comparable to CoCr-EESs. CLINICAL REGISTRATION ClinicalTrials.gov, number NCT01844284.

Bioresorbable Vascular Scaffolds Versus Metallic Stents in Patients With Coronary Artery Disease: ABSORB China Trial

BACKGROUND The everolimus-eluting bioresorbable vascular scaffold (BVS) is designed to achieve results comparable to metallic drug-eluting stents at 1 year, with improved long-term outcomes. Whether the 1-year clinical and angiographic results of BVS are noninferior to current-generation drug-eluting stents has not been established. OBJECTIVES This study sought to evaluate the angiographic efficacy and clinical safety and effectiveness of BVS in a randomized trial designed to enable approval of the BVS in China. METHODS Eligible patients with 1 or 2 de novo native coronary artery lesions were randomized to BVS or cobalt-chromium everolimus-eluting stents (CoCr-EES) in a 1:1 ratio stratified by diabetes and the number of lesions treated. Angiographic and clinical follow-up were planned at 1 year in all patients. The primary endpoint was angiographic in-segment late loss (LL), powered for noninferiority with a margin of 0.15 mm. RESULTS A total of 480 patients were randomized (241 BVS vs. 239 CoCr-EES) at 24 sites. Acute clinical device success (98.0% vs. 99.6%; p = 0.22) and procedural success (97.0% and 98.3%; p = 0.37) were comparable in BVS- and CoCr-EES-treated patients, respectively. The primary endpoint of in-segment LL at 1 year was 0.19 ± 0.38 mm for BVS versus 0.13 ± 0.38 mm for CoCr-EES; the 1-sided 97.5% upper confidence limit of the difference was 0.14 mm, achieving noninferiority of BVS compared with CoCr-EES (pnoninferiority = 0.01). BVS and CoCr-EES also had similar 1-year rates of target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization; 3.4% vs. 4.2%, respectively; p = 0.62) and definite/probable scaffold/stent thrombosis (0.4% vs. 0.0%, respectively; p = 1.00). CONCLUSIONS In the present multicenter randomized trial, BVS was noninferior to CoCr-EES for the primary endpoint of in-segment LL at 1 year. (A Clinical Evaluation of Absorb Bioresorbable Vascular Scaffold [Absorb BVS] System in Chinese Population-ABSORB CHINA Randomized Controlled Trial [RCT]; NCT01923740).

Photoangioplasty: An emerging clinical cardiovascular role for photodynamic therapy.

Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.

Bedside Imaging of Intracranial Hemorrhage in the Neonate Using Light: Comparison with Ultrasound, Computed Tomography, and Magnetic Resonance Imaging

Medical optical imaging (MOI) uses light emitted into opaque tissues to determine the interior structure. Previous reports detailed a portable time-of-flight and absorbance system emitting pulses of near infrared light into tissues and measuring the emerging light. Using this system, optical images of phantoms, whole rats, and pathologic neonatal brain specimens have been tomographically reconstructed. We have now modified the existing instrumentation into a clinically relevant headband-based system to be used for optical imaging of structure in the neonatal brain at the bedside. Eight medical optical imaging studies in the neonatal intensive care unit were performed in a blinded clinical comparison of optical images with ultrasound, computed tomography, and magnetic resonance imaging. Optical images were interpreted as correct in six of eight cases, with one error attributed to the age of the clot, and one small clot not seen. In addition, one disagreement with ultrasound, not reported as an error, was found to be the result of a mislabeled ultrasound report rather than because of an inaccurate optical scan. Optical scan correlated well with computed tomography and magnetic resonance imaging findings in one patient. We conclude that light-based imaging using a portable time-of-flight system is feasible and represents an important new noninvasive diagnostic technique, with potential for continuous monitoring of critically ill neonates at risk for intraventricular hemorrhage or stroke. Further studies are now underway to further investigate the functional imaging capabilities of this new diagnostic tool.

Design of a visible-light spectroscopy clinical tissue oximeter

We develop a clinical visible-light spectroscopy (VLS) tissue oximeter. Unlike currently approved near-infrared spectroscopy (NIRS) or pulse oximetry (SpO2%), VLS relies on locally absorbed, shallow-penetrating visible light (475 to 625 nm) for the monitoring of microvascular hemoglobin oxygen saturation (StO2%), allowing incorporation into therapeutic catheters and probes. A range of probes is developed, including noncontact wands, invasive catheters, and penetrating needles with injection ports. Data are collected from: 1. probes, standards, and reference solutions to optimize each component; 2. ex vivo hemoglobin solutions analyzed for StO2% and pO2 during deoxygenation; and 3. human subject skin and mucosal tissue surfaces. Results show that differential VLS allows extraction of features and minimization of scattering effects, in vitro VLS oximetry reproduces the expected sigmoid hemoglobin binding curve, and in vivo VLS spectroscopy of human tissue allows for real-time monitoring (e.g., gastrointestinal mucosal saturation 69+/-4%, n=804; gastrointestinal tumor saturation 45+/-23%, n=14; and p<0.0001), with reproducible values and small standard deviations (SDs) in normal tissues. FDA approved VLS systems began shipping earlier this year. We conclude that VLS is suitable for the real-time collection of spectroscopic and oximetric data from human tissues, and that a VLS oximeter has application to the monitoring of localized subsurface hemoglobin oxygen saturation in the microvascular tissue spaces of human subjects.

STATIONARY HEADBAND FOR CLINICAL TIME-OF-FLIGHT OPTICAL IMAGING AT THE BEDSIDE

Conventional brain‐imaging modalities may be limited by high cost, difficulty of bedside use, noncontinuous operation, invasiveness or an inability to obtain measurements of tissue function, such as oxygenation during stroke. Our goal was to develop a bedside clinical device able to generate continuous, noninvasive, tomographic images of the brain using low‐power nonionizing optical radiation. We modified an existing stage‐based time‐of‐flight optical tomography system to allow imaging of patients under clinical conditions. First, a stationary headband consisting of thin, flexible optical fibers was constructed. The headband was then calibrated and tested, including an assessment of fiber lengths, the existing system software was modified to collect headband data and to perform simultaneous collection of data and image reconstruction, and the existing hardware was modified to scan optically using this headband. The headband was tested on resin models and allowed for the generation of tomographic images in vitro; the headband was tested on critically ill infants and allowed for optical tomographic images of the neonatal brain to be obtained in vivo.

Monitoring in vivo absorption of a drug-eluting bioabsorbable stent with intravascular ultrasound-derived parameters a feasibility study.

OBJECTIVES The aim of this study was to investigate the feasibility of using quantitative differential echogenicity to monitor the in vivo absorption process of a drug-eluting poly-l-lactic-acid (PLLA) bioabsorbable stent (BVS, Abbott Vascular, Santa Clara, California). BACKGROUND A new bioabsorbable, balloon-expanded coronary stent was recently evaluated in a first-in-man study. Little is known about the absorption process in vivo in diseased human coronary arteries. METHODS In the ABSORB (Clinical Evaluation of the BVS everolimus eluting stent system) study, 30 patients underwent treatment with the BVS coronary stent system and were examined with intracoronary ultrasound (ICUS) after implantation, at 6 months and at 2-year follow-up. Quantitative ICUS was used to measure dimensional changes, and automated ICUS-based tissue composition software (differential echogenicity) was used to quantify plaque compositional changes over time in the treated regions. RESULTS The BVS struts appeared as bright hyperechogenic structures and showed a continuous decrease of their echogenicity over time, most likely due to the polymer degradation process. In 12 patients in whom pre-implantation ICUS was available, at 2 years the percentage-hyperechogenic tissue was close to pre-implantation values, indicating that the absorption process was either completed or the remaining material was no longer differentially echogenic from surrounding tissues. CONCLUSIONS Quantitative differential echogenicity is a useful plaque compositional measurement tool. Furthermore, it seems to be valuable for monitoring the absorption process of bioabsorbable coronary stents made of semi-crystalline polymers.

Photodynamic therapy: applications in atherosclerotic vascular disease with motexafin lutetium.

Photodynamic therapy (PDT) has been approved as a tissue‐specific light‐activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque. Biotechnology has developed a new generation of selective photosensitizers and catheter‐based technological advances in light delivery have allowed the introduction of PDT into the vasculature. The largest experience to date is with motexafin lutetium (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The combination of the motexafin lutetium and endovascular illumination, or Antrin phototherapy, has been shown to reduce plaque in animal models. Antrin phototherapy generates cytotoxic singlet oxygen that has been shown to induce apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose‐ranging clinical trial in subjects with peripheral artery disease and is currently being examined in a phase 1 study in subjects with lesions of the native coronary arteries undergoing stent implantation. The preliminary results suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic. Cathet Cardiovasc Intervent 2002;57:387–394.

Photodynamic Therapy Trials with Lutetium Texaphyrin (Lu-Tex) in Patients with Locally Recurrent Breast Cancer

Photodynamic therapy (PDT) of locally recurrent breast cancer has been limited to treatment of small lesions because of non- selective necrosis of adjacent normal tissues in the treatment field. Lutetium Texaphyrin (PCI-0123, Lu-Tex) is a photosensitizer with improved tumor localization that is activated by 732 nm light, which can penetrate through larger tumors. We have evaluated Lu-Tex in a Phase I trial and in an ongoing Phase II trial in women with locally recurrent breast cancer with large tumors who have failed radiation therapy. Patients received Lu-Tex intravenously by rapid infusion 3 hours before illumination of cutaneous or subcutaneous lesions. In Phase I, Lu-Tex doses were escalated from 0.6 to 7.2 mg/kg in 7 cohorts. Sixteen patients with locally recurrent breast cancer lesions were treated. Dose limiting toxicities above 5.5 mg/kg were pain in the treatment field during therapy, and dysesthesias in light exposed areas. No necrosis of normal tissues in the treated field was noticed. Responses were observed in 60% of evaluable patients [n equals 15, 27% complete remission (CR), 33% partial remission (PR)], with 63% of lesions responding (n equals 73: 45% CR, 18% PR). In Phase II, 25 patients have been studied to date, receiving two treatments ranging from 1.0 to 3.0 mg/kg at a 21 day interval. Treatment fields up to 480 cm2 in size were treated successfully and activity has been observed. Patients have experienced pain at the treatment site but no tissue necrosis. These studies demonstrate the feasibility of Lu-Tex PDT to large chest wall areas in women who have failed radiation therapy for the treatment of locally recurrent breast cancer. Treatment conditions are currently being optimized in the ongoing Phase II trials.