Daniel M. de Bruin

A New Generation of Optical Diagnostics for Bladder Cancer: Technology, Diagnostic Accuracy, and Future Applications

CONTEXT New developments in optical diagnostics have a potential for less invasive and improved detection of bladder cancer. OBJECTIVE To provide an overview of the technology and diagnostic yield of recently developed optical diagnostics for bladder cancer and to outline their potential future applications. EVIDENCE ACQUISITION A PubMed literature search was performed, and papers on Raman spectroscopy (RS), optical coherence tomography (OCT), photodynamic diagnosis (PDD) and narrow-band imaging (NBI) regarding bladder cancer were reviewed. Technology, clinical evidence, and future applications of the techniques are discussed. EVIDENCE SYNTHESIS With RS, the molecular components of tissue can be measured objectively in qualitative and quantitative ways. The first studies demonstrating human in vivo applicability are still awaited. OCT produces high-resolution, cross-sectional images of tissue, comparable with histopathology, and provides information about depth of tumour growth. The first in vivo studies of OCT demonstrated promising diagnostic accuracy. RS and OCT are not suitable for scanning the entire bladder. PDD is a technique using fluorescence to indicate pathologic tissue. Several studies have shown that PDD increases the detection rate of bladder tumours and improves resection, resulting in fewer early recurrences. The relatively low specificity of PDD remains a problem. NBI enhances contrast of mucosal surface and microvascular structures. The NBI technique has clear advantages over PDD, and the two studies published to date have shown promising preliminary results. PDD and NBI do not contribute to histopathologic diagnosis. CONCLUSIONS RS and OCT aim at providing a real-time, minimally invasive, objective prediction of histopathologic diagnosis, while PDD and NBI aim at improving visualisation of bladder tumours. For RS, OCT, and NBI, more research has to be conducted before these techniques can be implemented in the management of bladder cancer. All techniques might be of value in specific clinical scenarios.

In-vivo three-dimensional imaging of neovascular age related macular degeneration using optical frequency domain imaging at 1050 nm

PURPOSE To assess the application of optical frequency domain imaging (OFDI) at 1050 nm for the detection of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) and its response to treatment. Three patients presenting with blurred vision and exudative AMD were imaged before and after anti-VEGF treatment with ranibizumab. METHODS The patients were imaged with OFDI, a swept-source-based, high-speed optical coherence tomography (OCT) system developed at the Wellman Center for Photomedicine. A center wavelength of 1050 nm was used that has been demonstrated to provide better imaging of the deeper structures of the retina below the RPE, such as the choroidal vasculature. Three-dimensional data sets were acquired in 2 to 4 seconds. RESULTS En face images were compiled from cross-sectional OFDI data and correlated with color fundus photography (CF) and fluorescein angiograms (FAs). Cross-sectional images were coregistered with CF and FA to obtain depth-resolved information about CNV, CNV volume, retinal thickness, subretinal fluid volume and height of neurosensory detachment before and after treatment with ranibizumab. A band of reduced reflectivity below the RPE was identified in all three subjects that corresponded to areas of confirmed and suspected occult CNV on FA. After treatment, this band was reduced in volume in all patients. CONCLUSIONS High-speed 3-D OFDI at 1050 nm is a promising technology for imaging the retina and choroid in neovascular AMD. The developed system at 1050 nm provides good contrast for occult (type 1) CNV and may have advantages compared with time domain and current state of the art spectral domain OCT systems (SD-OCT) at 850 nm.

Volumetric In-Vivo Visualization of Upper Urinary Tract Tumors Using Optical Coherence Tomography: A Pilot Study

PURPOSE Knowledge of tumor stage and grade is paramount for treatment decision making in cases of upper urinary tract urothelial carcinoma but this condition cannot be accurately assessed by current techniques. Optical coherence tomography can hypothetically provide the urologist with real-time intraoperative information on tumor grade and stage. In this pilot study we report what are to our knowledge the first results of optical coherence tomography for grading and staging upper urinary tract urothelial carcinoma. MATERIALS AND METHODS Eight consecutive patients underwent ureterorenoscopy for suspicion or followup of upper urinary tract urothelial carcinoma. Optical coherence tomography data sets were intraoperatively obtained from the ureter and renal pelvis. All patients eventually underwent nephroureterectomy. Optical coherence tomography staging was done by visual inspection of lesions found on optical coherence tomography images. Optical coherence tomography grading was done by quantifying optical coherence tomography signal attenuation in mm(-1) on lesions and comparing results with the histopathological diagnosis. The Wilcoxon rank sum test was used for statistical analysis. RESULTS For 7 in vivo optical coherence tomography diagnoses staging was in accordance with histology. In patient 8 tumor thickness transcended optical coherence tomography imaging depth range and, therefore, invasiveness findings were inconclusive. For grading the median attenuation coefficient for grade 2 and 3 lesions was 1.97 (IQR 1.57-2.30) and 3.53 mm(-1) (IQR 2.74-3.94), respectively (p<0.001). Healthy urothelium was too thin to reliably determine the attenuation coefficient. CONCLUSIONS Optical coherence tomography is a promising, minimally invasive tool for real-time intraoperative optical diagnosis of tumors in the upper urinary tract. Our results warrant future research in a larger sample size to determine the accuracy of grading and staging by optical coherence tomography, and its possible implementation in the diagnostic algorithm for upper urinary tract urothelial carcinoma.

Differentiation between normal renal tissue and renal tumours using functional optical coherence tomography: a phase I in vivo human study.

Whats known on the subject? and What does the study add?

Irreversible electroporation: state of the art

The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate.

Detection of buried Barrett's glands after radiofrequency ablation with volumetric laser endomicroscopy.

BACKGROUND AND AIMS The prevalence and clinical relevance of buried Barretts glands (BB) after radiofrequency ablation (RFA) in Barretts esophagus (BE) are debated. Recent optical coherence tomography studies demonstrated a high prevalence of BBs. Direct histological correlation, however, has been lacking. Volumetric laser endomicroscopy (VLE) is a second-generation optical coherence tomography system capable of scanning a large surface of the esophageal wall layers with low-power microscopy resolution. The aim was to evaluate whether post-RFA subsquamous glandular structures (SGSs), detected with VLE, actually correspond to BBs by pursuing direct histological correlation with VLE images. METHODS In vivo VLE was performed to detect SGSs in patients with endoscopic regression of BE post-RFA. A second in vivo VLE scan was performed to confirm correct delineation of the SGSs. After endoscopic resection, the specimens were imaged ex vivo with VLE. Extensive histological sectioning of SGS areas was performed, and all histology slides were evaluated by an expert BE pathologist. RESULTS Seventeen patients underwent successful in vivo VLE (histological diagnosis before endoscopic treatment: early adenocarcinoma in 8 patients and high-grade dysplasia in 9). In 4 of 17 patients, no SGSs were identified during VLE, and a random resection was performed. In the remaining 13 patients (76%), VLE detected SGS areas, which were all confirmed on a second in vivo VLE scan and subsequently resected. Most SGSs identified by VLE corresponded to normal histological structures (eg, dilated glands and blood vessels). However, 1 area containing BBs was found on histology. No specific VLE features to distinguish between BBs and normal SGSs were identified. CONCLUSIONS VLE is able to detect subsquamous esophageal structures. One area showed BBs beneath endoscopically normal-appearing neosquamous epithelium; however, most post-RFA SGSs identified by VLE correspond to normal histological structures. ( CLINICAL TRIAL REGISTRATION NUMBER NTR4056.).

Advanced diagnostics in renal mass using optical coherence tomography: a preliminary report

OBJECTIVE To avoid unnecessary surgical treatment of small renal masses (≤ 4 cm), a more accurate diagnostic method would be desirable since radiological differentiation between malignant and benign is difficult and nondiagnostic biopsies account from 9% to 37%. Optical coherence tomography (OCT) measures backscattered light versus depth, with an attenuation coefficient (μ(t)) that may vary among different histological types. We hypothesize that quantitative measurements of μ(t) using OCT can differentiate between normal renal parenchyma and renal cell carcinoma (RCC). MATERIALS AND METHODS Both normal and tumor renal tissues (RCC) were harvested after partial or radical nephrectomy. Analysis of μ(t) was based on difference of (1) μ(t) between normal and tumor tissue across all patients and (2) μ(t) between normal and tumor tissue within individual patients. RESULTS Tissue samples of 18 patients were measured, of which 4 were excluded (urothelial carcinoma, oncocytoma, and benign lesion without normal tissue available). Of the remaining 14 patients, 8 contributed with both normal and RCC tissue and 6 with only normal or RCC tissue. Independent observation showed a significant difference between the median μ(t) of normal renal tissue (4.95 mm⁻¹) and the median μ(t) of RCC (8.86 mm⁻¹). No statistically significant difference was found when comparing the difference in μ(t) between normal renal parenchyma and RCC within individual patients. CONCLUSION There is a significant difference in μ(t) between normal and RCC tissue across all patients. These results overpower the lack of significant difference within individuals, encouraging further research and suggesting a possible role for OCT in the diagnostic work-up of renal masses.

Optical Coherence Tomography in vulvar intraepithelial neoplasia

Abstract. Vulvar squamous cell carcinoma (VSCC) is a gynecological cancer with an incidence of two to three per 100,000 women. VSCC arises from vulvar intraepithelial neoplasia (VIN), which is diagnosed through painful punch biopsy. In this study, optical coherence tomography (OCT) is used to differentiate between normal and VIN tissue. We hypothesize that (a) epidermal layer thickness measured in OCT images is different in normal tissue and VIN, and (b) quantitative analysis of the attenuation coefficient (μoct) extracted from OCT data differentiates VIN from normal vulvar tissue. Twenty lesions from 16 patients are imaged with OCT. Directly after data acquisition, a biopsy is performed. Epidermal thickness is measured and values of μoct are extracted from 200 OCT scans of normal and VIN tissue. For both methods, statistical analysis is performed using Paired Mann–Whitney-test. Correlation between the two methods is tested using a Spearman-correlation test. Both epidermal layer thickness as well as the μoct are different between normal vulvar tissue and VIN lesions (p<0.0001). Moreover, no correlation is found between the epidermal layer thickness and μoct. This study demonstrates that both the epidermal thickness and the attenuation coefficient of vulvar epithelial tissue containing VIN are different from that of normal vulvar tissue.

Thermal Energy during Irreversible Electroporation and the Influence of Different Ablation Parameters

PURPOSE Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE. MATERIALS AND METHODS IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated. RESULTS A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C). CONCLUSIONS Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.

Irreversible electroporation: Just another form of thermal therapy?

Irreversible electroporation (IRE) is (virtually) always called non‐thermal despite many reports showing that significant Joule heating occurs. Our first aim is to validate with mathematical simulations that IRE as currently practiced has a non‐negligible thermal response. Our second aim is to present a method that allows simple temperature estimation to aid IRE treatment planning.