The Scanning Fiber Endoscope: A Novel Surgical and High-Resolution Imaging Device for Intracranial Neurosurgery.

BACKGROUND: The scanning fiber endoscope (SFE) is a novel medical imaging device that has been used in various vascular beds as a form of angioscopy, as well as in tracts and duct systems for endoluminal imaging. Owing to its miniaturized form, high resolution, and flexibility, it has demonstrated success in imaging across a wide range of diagnostic applications. OBJECTIVE: To demonstrate, by performing a third ventriculostomy and visualizing the cranial nerves and brainstem anatomy, that, without modification, the SFE can be used through a transcranial approach in a therapeutic intraventricular neurosurgical application. METHODS: A 3.7 French SFE system was used without modification on a live porcine model to perform a third ventriculostomy and acquire high-resolution images of the animal's ventricular system, cranial nerves, and brainstem. A side-by-side comparison was made with one of the current standard-of-care rigid endoscopes as a context for size and image quality. RESULTS: High-resolution video-rate imaging was used to assist the successful, uncomplicated performance of a third ventriculostomy. High-resolution endoscopic images of the brainstem and cranial nerves were acquired. CONCLUSION: Although the SFE has been shown to be a superior device for imaging, here we demonstrate its first use as a potential therapeutic device in intracranial neurosurgery.

A double-blind randomised placebo-controlled trial of percutaneous coronary intervention for the relief of stable angina without antianginal medications: design and rationale of the ORBITA-2 trial.

Percutaneous coronary intervention (PCI) is frequently performed for stable angina. However, the first blinded trial, ORBITA, did not show a placebo-controlled increment in exercise time in patients with single-vessel disease, at 6 weeks, on maximal antianginal therapy. ORBITA-2 will assess the placebo-controlled efficacy of PCI on angina frequency in patients with single- or multivessel disease, at 12 weeks, on no antianginal therapy. ORBITA-2 is a double-blind placebo-controlled trial randomising participants with (i) angina at presentation, (ii) documented angina during the 2-week pre-randomisation symptom assessment phase, (iii) objective evidence of ischaemia, (iv) single- or multivessel disease, and (v) clinical eligibility for PCI. At enrolment, antianginals will be stopped, and angina questionnaires completed. Participants will record their symptoms on a smartphone application daily throughout the trial and will undergo exercise treadmill testing and stress echocardiography at pre-randomisation. They will then undergo coronary angiography with unblinded invasive physiology assessment. Eligible participants will then be sedated to a deep level of conscious sedation and randomised 1:1 between PCI and placebo. After the 12-week blinded follow-up period, they will return for questionnaires, exercise testing and stress echocardiography assessment. If angina becomes intolerable, antianginals will be introduced using a prespecified medication protocol. The primary outcome is an angina symptom score using an ordinal clinical outcome scale for angina. Secondary outcomes include exercise treadmill time, angina frequency, angina severity and quality of life. Trial registration: ClinicalTrials.gov: NCT03742050.

Daily angina documentation versus subsequent recall: development of a symptom smartphone app.

Aims: The traditional approach to documenting angina outcomes in clinical trials is to ask the patient to recall their symptoms at the end of a month. With the ubiquitous availability of smartphones and tablets, daily contemporaneous documentation might be possible. Methods and results: The ORBITA-2 symptom smartphone app was developed with a user-centred iterative design and testing cycle involving a focus group of previous ORBITA participants. The feasibility and acceptability were assessed in an internal pilot of participants in the ongoing ORBITA-2 trial. Seven days of app entries by ORBITA-2 participants were compared with subsequent participant recall at the end of the 7-day period. The design focus group tested a prototype app. They reported that the final version captured their symptoms and was easy to use. In the completion assessment group, 141 of 142 (99%) completed the app in full and 47 of 141 (33%) without reminders. In the recall assessment group, 29 of 29 (100%) participants said they could recall the previous day's symptoms, and 82% of them recalled correctly. For 2 days previously, 88% said they could recall and of those, 87% recalled correctly. The proportion saying they could recall their symptoms fell progressively thereafter: 89, 67, 61, 50%, and at 7 days, 55% (P < 0.001 for trend). The proportion of recalling correctly also fell progressively to 55% at 7 days (P = 0.04 for trend). Conclusion: Episode counts of angina are difficult to recall after a few days. For trials such as ORBITA-2 focusing on angina, daily symptom collection via a smartphone app will increase the validity of the results.

Evaluation of Novel Imaging Devices for Nanoparticle-Mediated Fluorescence-Guided Lung Tumor Therapy.

BACKGROUND: Nonsurgical and minimally invasive approaches for early-stage peripheral lung cancer are needed to avoid the known morbidity of surgical resection, particularly in high-risk patients. We previously demonstrated the utility of multifunctional porphyrin-phospholipid nanoparticles (porphysomes) for fluorescence imaging and phototherapy after preferential accumulation into tumors. The objective of this study was to demonstrate the feasibility of porphysome-mediated imaging and photothermal therapy using a newly developed fiberscope and thoracoscope. METHODS: To prepare this technology for clinical translation, we developed a porphysome-specific fiberscope (scanning fiber endoscope and porphysome-specific thoracoscope), both capable of detecting porphysome fluorescence, for image-guided transbronchial and transpleural photothermal therapy to treat endobronchial/peribronchial and subpleural tumors, respectively. These were tested in three animal models: human lung cancer xenografts (A549) in mice, orthotopic VX2 lung tumors in rabbits, and ex vivo pig lung into which A549 tumor tissue was transplanted. RESULTS: The scanning fiber endoscope, with a 1.2-mm diameter, is small enough to pass through the working channel of a conventional bronchoscope and could visualize porphysome-laden tumors located inside or close to the peripheral bronchial wall. The porphysome-specific thoracoscope system had high sensitivity for porphysome fluorescence and enabled image-guided thoracoscopic resection of porphysome-accumulating tumors close to the pleura. Porphysomes also enhanced the efficacy of scanning fiber endoscope-guided transbronchial photothermal therapy and porphysome-specific thoracoscope-guided transpleural photothermal therapy, resulting in selective and efficient tumor tissue ablation in the rabbit and pig models. CONCLUSIONS: These results support the potential for clinical translation of this novel platform to affect nonsurgical and minimally invasive treatment options for early-stage peripheral lung cancer.

High-Resolution Scanning Fiber Angioscopy as an Adjuvant to Fluoroscopy During Endovascular Interventions.

PURPOSE: To demonstrate the feasibility and potential utility of high-resolution angioscopy during common endovascular interventions. METHODS: A 3.7-F scanning fiber angioscope was used in 6 Yorkshire pigs to image branch vessel selection, subintimal dissection, wire snaring, and stent placement. The angioscope was introduced in a coaxial fashion within a standard 6-F guide catheter. A clear field of view was provided using continuous heparinized saline flush through the outer guide catheter. The flush flow rate was manually adjusted to provide clear imaging depending on the diameter of the vessel and local blood flow conditions. RESULTS: The scanning fiber angioscope was compatible with off-the-shelf catheters and devices commonly used in peripheral and aortic interventions. Video-rate, high-resolution images were obtained during all the interventions tested and provided information that was complementary to simultaneously acquired fluoroscopy. The scanning fiber angioscope was able to detect subintimal dissection and branch vessel stent coverage with higher resolution than fluoroscopy alone. CONCLUSION: Endoluminal imaging with the scanning fiber angioscope is feasible with current endovascular devices and provides additional relevant information that cannot be assessed fluoroscopically. The scanning fiber angioscope represents a novel optical platform on which new endovascular techniques may be developed that will minimize radiation and contrast doses for patients.

An Integrated Nanotechnology-Enabled Transbronchial Image-Guided Intervention Strategy for Peripheral Lung Cancer.

Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current nonsurgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460, and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon nonsurgical treatment of early-stage peripheral lung cancer. Cancer Res; 76(19); 5870-80. ©2016 AACR.

Repair of popliteal aneurysm and spontaneous arteriovenous fistula in a patient with Marfan syndrome.

Isolated extremity arterial aneurysms remain a rare entity, and the development of a spontaneous arteriovenous fistula from such an aneurysmal segment in a young patient should prompt a search for an underlying genetic predisposition. Endovascular repair of aneurysms or arteriovenous fistulas in the popliteal artery is appropriate in select populations; however, open repair allows for a more durable reconstruction of both the arterial and any involved venous segments in patients who can tolerate the procedure.

Wide-field multiplexed imaging of EGFR-targeted cancers using topical application of NIR SERS nanoprobes.

AIM: As the possibilities of molecular imaging in personalized medicine evolve rapidly, the optical advantages of extremely narrow and intense spectral bands makes surface-enhanced Raman scattering (SERS) an appealing candidate for multiplexed recognition of targeted biomarkers over other optical imaging modalities. MATERIALS & METHODS: In this proof-of-concept study, we report wide-field Raman detection of lung cancer using multimodal SERS nanoprobes specific to the EGF receptor family, both in vitro and in vivo. RESULTS: For the first time, we demonstrate wide-field multiplexed Raman imaging for cancer detection in vivo after topical application of a 'cocktail' of SERS nanoprobes. CONCLUSION: This advancement represents a key step towards sensitive wide-field Raman endoscopic imaging of multiple biomarkers for early and accurate diagnosis of EGF receptor-expressing tumors of different internal organs.

Rapid ratiometric biomarker detection with topically applied SERS nanoparticles.

Multiplexed surface-enhanced Raman scattering (SERS) nanoparticles (NPs) offer the potential for rapid molecular phenotyping of tissues, thereby enabling accurate disease detection as well as patient stratification to guide personalized therapies or to monitor treatment outcomes. The clinical success of molecular diagnostics based on SERS NPs would be facilitated by the ability to accurately identify tissue biomarkers under time-constrained staining and detection conditions with a portable device. In vitro, ex vivo and in vivo experiments were performed to optimize the technology and protocols for the rapid detection (0.1-s integration time) of multiple cell-surface biomarkers with a miniature fiber-optic spectral-detection probe following a brief (5 min) topical application of SERS NPs on tissues. Furthermore, we demonstrate that the simultaneous detection and ratiometric quantification of targeted and nontargeted NPs allows for an unambiguous assessment of molecular expression that is insensitive to nonspecific variations in NP concentrations.

Orthotopic lung cancer murine model by nonoperative transbronchial approach.

PURPOSE: The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. DESCRIPTION: Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5×10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. EVALUATION: When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. CONCLUSIONS: Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies.

High-resolution angioscopic imaging during endovascular neurosurgery.

BACKGROUND: Endoluminal optical imaging, or angioscopy, has not seen widespread application during neurointerventional procedures, largely as a result of the poor imaging resolution of existing angioscopes. Scanning fiber endoscopes (SFEs) are a novel endoscopic platform that allows high-resolution video imaging in an ultraminiature form factor that is compatible with currently used distal access endoluminal catheters. OBJECTIVE: To test the feasibility and potential utility of high-resolution angioscopy with an SFE during common endovascular neurosurgical procedures. METHODS: A 3.7-French SFE was used in a porcine model system to image endothelial disruption, ischemic stroke and mechanical thrombectomy, aneurysm coiling, and flow-diverting stent placement. RESULTS: High-resolution, video-rate imaging was shown to be possible during all of the common procedures tested and provided information that was complementary to standard fluoroscopic imaging. SFE angioscopy was able to assess novel factors such as aneurysm base coverage fraction and side branch patency, which have previously not been possible to determine with conventional angiography. CONCLUSION: Endovascular imaging with an SFE provides important information on factors that cannot be assessed fluoroscopically and is a novel platform on which future neurointerventional techniques may be based because it allows for periprocedural inspection of the integrity of the vascular system and the deployed devices. In addition, it may be of diagnostic use for inspecting the vascular wall and postprocedure device evaluation.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: potential for targeting experimental brain tumors.

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50nm or 120nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. FROM THE CLINICAL EDITOR: This study demonstrates the use of magnetic resonance image-guided transcranial focused ultrasound to open the BBB and enable spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS)-based molecular imaging for experimental tumor tracking.

Widefield quantitative multiplex surface enhanced Raman scattering imaging in vivo.

In recent years numerous studies have shown the potential advantages of molecular imaging in vitro and in vivo using contrast agents based on surface enhanced Raman scattering (SERS), however the low throughput of traditional point-scanned imaging methodologies have limited their use in biological imaging. In this work we demonstrate that direct widefield Raman imaging based on a tunable filter is capable of quantitative multiplex SERS imaging in vivo, and that this imaging is possible with acquisition times which are orders of magnitude lower than achievable with comparable point-scanned methodologies. The system, designed for small animal imaging, has a linear response from (0.01 to 100 pM), acquires typical in vivo images in <10 s, and with suitable SERS reporter molecules is capable of multiplex imaging without compensation for spectral overlap. To demonstrate the utility of widefield Raman imaging in biological applications, we show quantitative imaging of four simultaneous SERS reporter molecules in vivo with resulting probe quantification that is in excellent agreement with known quantities (R²>0.98).

Porphyrin-lipid stabilized gold nanoparticles for surface enhanced Raman scattering based imaging.

A porphyrin-phospholipid conjugate with quenched fluorescence was utilized to serve as both the Raman dye and a stabilizing, biocompatible surface coating agent on gold nanoparticles. Through simple synthesis and validation with spectroscopy and confocal microscopy, we show that this porphyrin-lipid stabilized AuNP is a novel SERS probe capable of cellular imaging. To date, this is the first use of porphyrin as a Raman reporter molecule for SERS based imaging.

Filter-based method for background removal in high-sensitivity wide-field-surface-enhanced Raman scattering imaging in vivo.

As molecular imaging moves towards lower detection limits, the elimination of endogenous background signals becomes imperative. We present a facile background-suppression technique that specifically segregates the signal from surface-enhanced Raman scattering (SERS)-active nanoparticles (NPs) from the tissue autofluorescence background in vivo. SERS NPs have extremely narrow spectral peaks that do not overlap significantly with endogenous Raman signals. This can be exploited, using specific narrow-band filters, to image picomolar (pM) concentrations of NPs against a broad tissue autofluorescence background in wide-field mode, with short integration times that compare favorably with point-by-point mapping typically used in SERS imaging. This advance will facilitate the potential applications of SERS NPs as contrast agents in wide-field multiplexed biomarker-targeted imaging in vivo.

Estimation of minimum doses for optimized quantum dot contrast-enhanced vascular imaging in vivo.

Quantum dot (QD) contrast-enhanced molecular imaging has potential for early cancer detection and image guided treatment, but there is a lack of quantitative image contrast data to determine optimum QD administered doses, affecting the feasibility, risk and cost of such procedures, especially in vivo. Vascular fluorescence contrast-enhanced imaging is performed on nude mice bearing dorsal skinfold window chambers, injected with 4 different QD solutions emitting in the visible and near infrared. Linear relationships are observed among the vascular contrast, injected contrast agent volume, and QD concentration in blood. Due primarily to differential light absorption by blood, the vasculature is optimally visualized when exciting in the 435-480 nm region in 81% of the cases (89 out of 110 regions of interest in 22 window chambers). The threshold dose, defined here as the quantity of injected nanoparticles required to yield a vascular target-to-autofluorescence ratio of 2, varies from 10.6 to 0.15 pmol g(-1) depending on the QD emission wavelength. The wavelength optimization maximum and broadband gain, defined as the ratio of threshold doses estimated for optimal and suboptimal (worst wavelength or broadband) spectral illumination, has average values of 4.5 and 1.9, respectively. This study demonstrates, for the first time, optimized QD imaging in vivo. It also proposes and validates a theoretical framework for QD dose estimation and quantifies the effects of blood absorption, QD emission wavelength, and vessel diameter relative to the threshold dose.

Diffusion-weighted MRI in cervical cancer.

The purpose was to investigate the potential value of apparent diffusion coefficient (ADC) measurement with MRI in the assessment of cervix cancer. Diffusion-weighted MRI was performed in 47 patients with cervical carcinoma undergoing chemoradiation therapy and 26 normal controls on a 1.5-T system with a b-value of 600 s/mm(2). FIGO stage, tumor volume, nodal status, interstitial fluid pressure (IFP) and oxygen measurements were recorded. Response was defined as no visible tumor 3-6 months following completion of therapy. The average median ADC (mADC) of cervical carcinomas (1.09+/-0.20 x 10(-3) mm(2)/s) was significantly lower than normal cervix (2.09+/-0.46 x 10(-3) mm(2)/s) (P<0.001). There was no correlation between mADC, nodal status, tumor volume, IFP or oxygen measurements. mADC was significantly lower in FIGO stages T1b/T2a (0.986 x 10(-3) mm(2)/s) compared to T2b (1.21 x 10(-3) mm(2)/s) and T3/T4 (1.10 x 10(-3) mm(2)/s) (P<0.001). In patients with squamous carcinomas the 90th percentile of ADC values was lower in responders than non-responders (P<0.05). Median ADC in cervix carcinoma is significantly lower compared to normal cervix. ADC may have predictive value in squamous tumors, but further long-term study will determine the ultimate clinical utility.