Publications by authors named "Arjen Amelink"

49 Publications

Investigation of methods to extract confocal function parameters for the depth resolved determination of attenuation coefficients using OCT in intralipid samples, titanium oxide phantoms, and in vivo human retinas.

Biomed Opt Express 2021 Nov 7;12(11):6814-6830. Epub 2021 Oct 7.

LaserLaB, Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, The Netherlands.

The attenuation coefficient provides a quantitative parameter for tissue characterization and can be calculated from optical coherence tomography (OCT) data, but accurate determination requires compensation for the confocal function. We present extensive measurement series for extraction of the focal plane and the apparent Rayleigh length from the ratios of OCT images acquired with different focus depths and compare these results with two alternative approaches. By acquiring OCT images for a range of different focus depths the optimal focus plane difference is determined for intralipid and titanium oxide (TiO) phantoms with different scatterer concentrations, which allows for calculation of the attenuation coefficient corrected for the confocal function. The attenuation coefficient is determined for homogeneous intralipid and TiO samples over a wide range of concentrations. We further demonstrate very good reproducibility of the determined attenuation coefficient of layers with identical scatter concentrations in a multi-layered phantom. Finally, this method is applied to in vivo retinal data.
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http://dx.doi.org/10.1364/BOE.440574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606142PMC
November 2021

Digital Resilience Biomarkers for Personalized Health Maintenance and Disease Prevention.

Front Digit Health 2020 22;2:614670. Epub 2021 Jan 22.

Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), Zeist, Netherlands.

Health maintenance and disease prevention strategies become increasingly prioritized with increasing health and economic burden of chronic, lifestyle-related diseases. A key element in these strategies is the empowerment of individuals to control their health. Self-measurement plays an essential role in achieving such empowerment. Digital measurements have the advantage of being measured non-invasively, passively, continuously, and in a real-world context. An important question is whether such measurement can sensitively measure subtle disbalances in the progression toward disease, as well as the subtle effects of, for example, nutritional improvement. The concept of resilience biomarkers, defined as the dynamic evaluation of the biological response to an external challenge, has been identified as a viable strategy to measure these subtle effects. In this review, we explore the potential of integrating this concept with digital physiological measurements to come to digital resilience biomarkers. Additionally, we discuss the potential of wearable, non-invasive, and continuous measurement of molecular biomarkers. These types of innovative measurements may, in the future, also serve as a digital resilience biomarker to provide even more insight into the personal biological dynamics of an individual. Altogether, digital resilience biomarkers are envisioned to allow for the measurement of subtle effects of health maintenance and disease prevention strategies in a real-world context and thereby give personalized feedback to improve health.
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http://dx.doi.org/10.3389/fdgth.2020.614670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521930PMC
January 2021

Early Upper Aerodigestive Tract Cancer Detection Using Electron Microscopy to Reveal Chromatin Packing Alterations in Buccal Mucosa Cells.

Microsc Microanal 2021 08;27(4):878-888

Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, Postbus 2040, 3000CARotterdam, the Netherlands.

A profound characteristic of field cancerization is alterations in chromatin packing. This study aimed to quantify these alterations using electron microscopy image analysis of buccal mucosa cells of laryngeal, esophageal, and lung cancer patients. Analysis was done on normal-appearing mucosa, believed to be within the cancerization field, and not tumor itself. Large-scale electron microscopy (nanotomy) images were acquired of cancer patients and controls. Within the nuclei, the chromatin packing of euchromatin and heterochromatin was characterized. Furthermore, the chromatin organization was quantified through chromatin packing density scaling. A significant difference was found between the cancer and control groups in the chromatin packing density scaling parameter for length scales below the optical diffraction limit (200 nm) in both the euchromatin (p = 0.002) and the heterochromatin (p = 0.006). The chromatin packing scaling analysis also indicated that the chromatin organization of cancer patients deviated significantly from the control group. They might allow for novel strategies for cancer risk stratification and diagnosis with high sensitivity. This could aid clinicians in personalizing screening strategies for high-risk patients and follow-up strategies for treated cancer patients.
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http://dx.doi.org/10.1017/S1431927621000507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8939050PMC
August 2021

In vivo subdiffuse scanning laser oximetry of the human retina.

J Biomed Opt 2019 09;24(9):1-14

Vrije Universiteit Amsterdam, LaserLaB, Department of Physics and Astronomy, Amsterdam, The Netherlands.

Scanning laser ophthalmoscopes (SLOs) have the potential to perform high speed, high contrast, functional imaging of the human retina for diagnosis and follow-up of retinal diseases. Commercial SLOs typically use a monochromatic laser source or a superluminescent diode for imaging. Multispectral SLOs using an array of laser sources for spectral imaging have been demonstrated in research settings, with applications mainly aiming at retinal oxygenation measurements. Previous SLO-based oximetry techniques are predominantly based on wavelengths that depend on laser source availability. We describe an SLO system based on a supercontinuum (SC) source and a double-clad fiber using the single-mode core for illumination and the larger inner cladding for quasi-confocal detection to increase throughput and signal-to-noise ratio. A balanced detection scheme was implemented to suppress the relative intensity noise of the SC source. The SLO produced dual wavelength, high-quality images at 10  frames  /  s with a maximum 20 deg imaging field-of-view with any desired combination of wavelengths in the visible spectrum. We demonstrate SLO-based dual-wavelength oximetry in vessels down to 50  μm in diameter. Reproducibility was demonstrated by performing three different imaging sessions of the same volunteer, 8 min apart. Finally, by performing a wavelength sweep between 485 and 608 nm, we determined, for our SLO geometry, an approximately linear relationship between the effective path length of photons through the blood vessels and the vessel diameter.
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http://dx.doi.org/10.1117/1.JBO.24.9.096009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997660PMC
September 2019

Optical pre-screening for laryngeal cancer using reflectance spectroscopy of the buccal mucosa.

Biomed Opt Express 2018 Oct 6;9(10):4665-4678. Epub 2018 Sep 6.

Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.

A new approach in early cancer detection focuses on detecting field cancerization (FC) instead of the tumor itself. The aim of the current study is to investigate whether reflectance spectroscopy can detect FC in the buccal mucosa of patients with laryngeal cancer. The optical properties of the buccal mucosa of patients were measured with multidiameter single-fiber reflectance spectroscopy. The blood oxygen saturation and blood volume fraction were significantly lower in the buccal mucosa of laryngeal cancer patients than in non-oncologic controls. The data of these two parameters were combined to form a single 'biomarker α', which optimally discriminates these two groups. Alpha was lower in the laryngeal cancer group (0.28) than the control group (0.30, p = 0.007). Alpha could identify oncologic patients with a sensitivity of 78% and a specificity of 74%. These results might be the first step toward optical pre-screening for laryngeal cancer.
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http://dx.doi.org/10.1364/BOE.9.004665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179391PMC
October 2018

Optimal wavelengths for subdiffuse scanning laser oximetry of the human retina.

J Biomed Opt 2018 08;23(8):1-15

Vrije Universiteit Amsterdam, LaserLaB, Department of Physics and Astronomy, Amsterdam, The Netherlands.

Retinal blood vessel oxygenation is considered to be an important marker for numerous eye diseases. Oxygenation is typically assessed by imaging the retinal vessels at different wavelengths using multispectral imaging techniques, where the choice of wavelengths will affect the achievable measurement accuracy. Here, we present a detailed analysis of the error propagation of measurement noise in retinal oximetry, to identify optimal wavelengths that will yield the lowest uncertainty in saturation estimation for a given measurement noise level. In our analysis, we also investigate the effect of hemoglobin packing in discrete blood vessels (pigment packaging), which may result in a nonnegligible bias in saturation estimation if unaccounted for under specific geometrical conditions, such as subdiffuse sampling of smaller blood vessels located deeper within the retina. Our analyses show that using 470, 506, and 592 nm, a fairly accurate estimation of the whole oxygen saturation regime [0 1] can be realized, even in the presence of the pigment packing effect. To validate the analysis, we developed a scanning laser ophthalmoscope to produce high contrast images with a maximum pixel rate of 60 kHz and a maximum 30-deg imaging field of view. Confocal reflectance measurements were then conducted on a tissue-mimicking scattering phantom with optical properties similar to retinal tissue including narrow channels filled with absorbing dyes to mimic blood vessels. By imaging at three optimal wavelengths, the saturation of the dye combination was calculated. The experimental values show good agreement with our theoretical derivations.
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http://dx.doi.org/10.1117/1.JBO.23.8.086003DOI Listing
August 2018

Optical detection of field cancerization in the buccal mucosa of patients with esophageal cancer.

Clin Transl Gastroenterol 2018 04 30;9(4):152. Epub 2018 Apr 30.

Erasmus MC Cancer Institute, 's-Gravendijkwal 230, Rotterdam, 3015 CE, The Netherlands.

Introduction: Esophageal cancer is an increasingly common type of neoplasm with a very poor prognosis. This prognosis could improve with more early tumor detection. We have previously shown that we can use an optical spectroscopy to detect field cancerization in the buccal mucosa of patients with laryngeal cancer. The aim of this prospective study was to investigate whether we could detect field cancerization of buccal mucosa of patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).

Methods: Optical measurements were performed in vivo using a novel optical technique: multidiameter single-fiber reflectance (MDSFR) spectroscopy. MDSFR spectra were acquired by a handheld probe incorporating three fiber diameters. Multiple absorption and scattering parameters that are related to the physiological and ultrastructural properties of the buccal mucosa were derived from these spectra. A linear discriminant analysis of the parameters was performed to create a combined biomarker σ to discriminate oncologic from non-oncologic patients.

Results: Twelve ESCC, 12 EAC, and 24 control patients were included in the study. The median value of our biomarker σ was significantly higher in patients with ESCC (2.07 [1.93-2.10]) than control patients (1.86 [1.73-1.95], p = 0.022). After cross-validation σ was able to identify ESCC patients with a sensitivity of 66.7% and a specificity of 70.8%. There were no significant differences between the EAC group and the control group.

Conclusion: Field cancerization in the buccal mucosa can be detected using optical spectroscopy in ESCC patients. This may be the first step towards non-invasive ESCC cancer screening.
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http://dx.doi.org/10.1038/s41424-018-0023-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928160PMC
April 2018

Toward optical guidance during endoscopic ultrasound-guided fine needle aspirations of pancreatic masses using single fiber reflectance spectroscopy: a feasibility study.

J Biomed Opt 2017 02;22(2):24001

Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands.

Endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) of pancreatic masses suffer from sample errors and low-negative predictive values. Fiber-optic spectroscopy in the visible to near-infrared wavelength spectrum can noninvasively extract physiological parameters from tissue and has the potential to guide the sampling process and reduce sample errors. We assessed the feasibility of single fiber (SF) reflectance spectroscopy measurements during EUS-FNA of pancreatic masses and its ability to distinguish benign from malignant pancreatic tissue. A single optical fiber was placed inside a 19-gauge biopsy needle during EUS-FNA and at least three reflectance measurements were taken prior to FNA. Spectroscopy measurements did not cause any related adverse events and prolonged procedure time with ? 5 ?? min . An accurate correlation between spectroscopy measurements and cytology could be made in nine patients (three benign and six malignant). The oxygen saturation and bilirubin concentration were significantly higher in benign tissue compared with malignant tissue (55% versus 21%, p = 0.038 ; 166 ?? ? mol / L versus 17 ?? ? mol / L , p = 0.039 , respectively). To conclude, incorporation of SF spectroscopy during EUS-FNA was feasible, safe, and relatively quick to perform. The optical properties of benign and malignant pancreatic tissue are different, implying that SF spectroscopy can potentially guide the FNA sampling.
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http://dx.doi.org/10.1117/1.JBO.22.2.024001DOI Listing
February 2017

Sources of variability in the quantification of tissue optical properties by multidiameter single-fiber reflectance and fluorescence spectroscopy.

J Biomed Opt 2015 May;20(5):57002

Erasmus Medical Center, Center for Optical Diagnostics and Therapy, Department of Dermatology, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.

Recently, a multidiameter single-fiber reflectance and fluorescence spectroscopy device has been developed that enabled us to extract the autofluorescence of tissue that is corrected for the optical properties. Such a system has been incorporated in the population-based Rotterdam Study to investigate the autofluorescence of the skin. Since the device will be used by different operators over many years, it is essential that the results are comparable between users. It is, however, unclear how different methods of handling the probe might influence the outcome. Variability of blood oxygen saturation, blood volume fraction and vessel diameter, average gamma, reduced scattering coefficient at 800 nm, and integrated intrinsic fluorescence measured in three volunteers were assessed within and between eight untrained users. A variability of less than one standard deviation from the group mean was defined as an acceptable limit. Three mature volunteers were also included to assess the intrauser variability of mature skin. The variation in the measured parameters suggests that variation is dominated by tissue heterogeneity. Most users measured within one standard deviation of the group mean. Notably, corrected intrinsic fluorescence showed low intra- and interuser variability. These results strongly suggest that variability is mostly caused by tissue heterogeneity and is not user induced.
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http://dx.doi.org/10.1117/1.JBO.20.5.057002DOI Listing
May 2015

Differentiation between nerve and adipose tissue using wide-band (350-1,830 nm) in vivo diffuse reflectance spectroscopy.

Lasers Surg Med 2014 Sep 4;46(7):538-45. Epub 2014 Jun 4.

Department of Surgery, Maastricht University Medical Center & NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands; van't Hoff Program on Medical Photonics, Netherlands Organization for Applied Scientific Research TNO, Eindhoven, The Netherlands.

Background: Intraoperative nerve localization is of great importance in surgery. In certain procedures, where nerves show visual resemblance to surrounding adipose tissue, this can be particularly challenging for the human eye. An example of such a delicate procedure is thyroid and parathyroid surgery, where iatrogenic injury of the recurrent laryngeal nerve can result in transient or permanent vocal problems (0.5-2.0% reported incidence). A camera system, enabling nerve-specific image enhancement, would be useful in preventing such complications. This might be realized with hyperspectral camera technology using silicon (Si) or indium gallium arsenide (InGaAs) sensor chips.

Methods: As a first step towards such a camera, we evaluated the performance of diffuse reflectance spectroscopy by analysing spectra collected during 18 thyroid and parathyroid resections. We assessed the contrast information present in two different spectral ranges, for respectively Si and InGaAs sensors. Two hundred fifty three in vivo, wide-band diffuse reflectance spectra (350-1,830 nm range, 1 nm resolution) were acquired on 52 tissue spots, including nerve (n = 22), muscle (n = 12), and adipose tissue (n = 18). We extracted 36 features from these spectroscopic data: 18 gradients and 18 amplitude differences at predefined points in the tissue spectra. Best distinctive feature combinations were established using binary logistic regression. Classification performance was evaluated in a cross-validation (CV) approach by leave-one-out (LOO). To generalize nerve recognition applicability, we performed a train-test (TT) validation using the thyroid and parathyroid surgery data for training purposes and carpal tunnel release surgery data (10 nerve spots and 5 adipose spots) for classification purposes.

Results: For combinations of two distinctive spectral features, LOO revealed an accuracy of respectively 78% for Si-sensors and 95% for InGaAs-sensors. TT revealed accuracies of respectively 67% and 100%.

Conclusions: Using diffuse reflectance spectroscopy we have identified that InGaAs sensors are better suited for automated discrimination between nerves and surrounding adipose tissue than Si sensors.
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http://dx.doi.org/10.1002/lsm.22264DOI Listing
September 2014

Influence of sildenafil on blood oxygen saturation of the obstructed bladder.

BMC Urol 2014 May 29;14:44. Epub 2014 May 29.

Department of Urology and Pediatric Urology, Erasmus Medical Center Rotterdam, Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Blood oxygen saturation (BOS) is decreased in a low-compliant, overactive obstructed bladder. The objective of this study is to determine the effect of Sildenafil (SC) on bladder function and BOS) in an in vivo animal model of bladder outlet obstruction.

Methods: Thirty-two guinea pigs; sham operated (n = 8), sham operated + SC (n = 8), urethrally obstructed (n = 8) and urethrally obstructed + SC (n = 8) were studied during an 8 week period. BOS of the bladder wall was measured by differential path-length spectroscopy (DPS) before obstruction, at day 0, and at week 8. The bladder function was evaluated by urodynamic studies every week.

Results: Before surgery and after sham operation all study parameters were comparable. After sham operation, bladder function and BOS did not change. In the obstructed group the urodynamic parameters were deteriorated and BOS was decreased. In the group obstruction + SC, bladder compliance remained normal and overactivity occurred only sporadic. BOS remained unchanged compared to the sham group and was significantly higher compared to the obstruction group.

Conclusions: In an obstructed bladder the loss of bladder function is accompanied by a significant decrease in BOS. Treatment of obstructed bladders with SC yields a situation of high saturation, high bladder compliance and almost no overactivity. Maintaining the microcirculation of the bladder wall might result in better bladder performance without significant loss of bladder function. Measurement of BOS and interventions focussing on tissue microcirculation may have a place in the evaluation / treatment of various bladder dysfunctions.
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http://dx.doi.org/10.1186/1471-2490-14-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060762PMC
May 2014

Intrinsic photosensitizer fluorescence measured using multi-diameter single-fiber spectroscopy in vivo.

J Biomed Opt 2014 Jan;19(1):15010

Center for Optical Diagnostics and Therapy, Department of Otolaryngology-Head and Neck Surgery, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Quantification of fluorescence in vivo is complicated by the influence of tissue optical properties on the collected fluorescence signal. When tissue optical properties in the measurement volume are quantified, one can obtain the intrinsic fluorescence, which equals the product of fluorophore absorption coefficient and quantum yield. We applied this method to in vivo single-fiber fluorescence spectroscopy measurements on mouse tongue, skin, liver, and oral squamous cell carcinoma, where we detected intrinsic fluorescence spectra of the photosensitizers chlorin e6 and Bremachlorin at t=[3,4.5,6,24,48]  h incubation time. We observed a tissue-dependent maximum of 35% variation in the total correction factor over the visible wavelength range. Significant differences in spectral shape over time between sensitizers were observed. Although the wavelength position of the fluorescence intensity maximum for ce6 shifted to the red, Bremachlorin showed a blue shift. Furthermore, the Bremachlorin peak appeared to be broader than the ce6 fluorescence peak. Intrinsic fluorescence intensity, which can be related to photosensitizer concentration, was decreasing for all time points but showed significantly more Bremachlorin present compared to ce6 at long incubation times. Results from this study can be used to define an optimal treatment protocol for Bremachlorin-based photodynamic therapy.
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http://dx.doi.org/10.1117/1.JBO.19.1.015010DOI Listing
January 2014

Microscopic analysis of the localization of two chlorin-based photosensitizers in OSC19 tumors in the mouse oral cavity.

Lasers Surg Med 2014 Mar 16;46(3):224-34. Epub 2014 Jan 16.

Department of Radiation Oncology, Center for Optical Diagnostics and Therapy, Postgraduate School Molecular Medicine, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

Background And Objective: The effect of photodynamic therapy (PDT) is dependent on the localization of photosensitizer in the treatment volume at the time of illumination. Investigation of photosensitizer pharmacokinetics in and around the treatment volume aids in determining the optimal drug light interval for PDT.

Materials And Methods: In this paper we have investigated the distribution of the photosensitizers chlorin e6 and Bremachlorin in the oral squamous cell carcinoma cell-line OSC19-Luc-Gfp in a tongue tumor, tumor boundary, invasive tumor boundary, and normal tongue tissue by the use of confocal microscopy of frozen sections. Tongues were harvested at t = [3, 4.5, 6, 24, 48] hours after injection.

Results: Both photosensitizers showed a decreasing fluorescence with increasing incubation time, and at all time points higher fluorescence was measured in tumor boundary than in tumor itself. For short incubation times, a higher fluorescence intensity was observed in the invasive tumor border and normal tissue compared to tumor tissue. Bremachlorin showed a small increase in tumor to normal ratio at 24 and 48 hours incubation time. Ce6 was undetectable at 48 hours. We did not find a correlation between photosensitizer localization and the presence of vasculature.

Conclusion: The modest tumor/tumor boundary to normal selectivity of between 1.2 and 2.5 exhibited by Bremachlorin 24 and 48 hours after administration may allow selective targeting of tongue tumors. Further studies investigating the relationship between Bremachlorin concentration and therapeutic efficacy PDT with long incubation times are warranted.
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http://dx.doi.org/10.1002/lsm.22220DOI Listing
March 2014

Localization of liposomal mTHPC formulations within normal epithelium, dysplastic tissue, and carcinoma of oral epithelium in the 4NQO-carcinogenesis rat model.

Lasers Surg Med 2013 Dec 30;45(10):668-78. Epub 2013 Oct 30.

Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, The Netherlands.

Background And Objective: Foslip and Fospeg are liposomal formulations of the photosensitizer mTHPC (Foscan), which is used for photodynamic therapy (PDT) of malignancies. Literature suggests that liposomal mTHPC formulations have better properties and increased tumor uptake compared to Foscan. To investigate this, we used the 4NQO-induced carcinogen model to compare the localization of the different mTHPC formulations within normal, precancerous, and cancerous tissue. In contrast to xenograft models, the 4NQO model closely mimics the carcinogenesis of human oral dysplasia.

Materials And Methods: Fifty-four rats drank water with the carcinogen 4NQO. When oral examination revealed tumor, the rats received 0.15 mg/kg mTHPC (Foscan, Foslip, or Fospeg). At 2, 4, 8, 24, 48, or 96 hours after injection the rats were sacrificed. Oral tissue was sectioned for HE slides and for fluorescence confocal microscopy. The HE slides were scored on the severity of dysplasia by the epithelial atypia index (EAI). The calibrated fluorescence intensity per formulation or time point was correlated to EAI.

Results: Fospeg showed higher mTHPC fluorescence in normal and tumor tissue compared to both Foscan and Foslip. Significant differences in fluorescence between tumor and normal tissue were found for all formulations. However, at 4, 8, and 24 hours only Fospeg showed a significant difference. The Pearson's correlation between EAI and mTHPC fluorescence proved weak for all formulations.

Conclusion: In our induced carcinogenesis model, Fospeg exhibited a tendency for higher fluorescence in normal and tumor tissue compared to Foslip and Foscan. In contrast to Foscan and Foslip, Fospeg showed significantly higher fluorescence in tumor versus normal tissue at earlier time points, suggesting a possible clinical benefit compared to Foscan. Low correlation between grade of dysplasia and mTHPC fluorescence was found.
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http://dx.doi.org/10.1002/lsm.22197DOI Listing
December 2013

Method for rapid multidiameter single-fiber reflectance and fluorescence spectroscopy through a fiber bundle.

J Biomed Opt 2013 Oct;18(10):107005

We have recently demonstrated a means for quantifying the absorption and scattering properties of biological tissue through multidiameter single-fiber reflectance (MDSFR) spectroscopy. These measurements can be used to correct single-fiber fluorescence (SFF) spectra for the influence of optical properties, enabling quantification of intrinsic fluorescence. In our previous work, we have used a series of pinholes to show that selective illumination and light collection using a coherent fiber bundle can simulate a single solid-core optical fiber with variable diameter for the purposes of MDSFR spectroscopy. Here, we describe the construction and validation of a clinical MDSFR/SFF spectroscopy system that avoids the limitations encountered with pinholes and free-space optics. During one measurement, the new system acquires reflectance spectra at the effective diameters of 200, 600, and 1000 μm, and a fluorescence spectrum at an effective diameter of 1000 μm. From these spectra, we measure the absolute absorption coefficient, μ(a), reduced scattering coefficient, μ'(s'), phase function parameter, γ, and intrinsic fluorescence, Qμ(a,x)(f), across the measured spectrum. We validate the system using Intralipid- and polystyrene sphere-based scattering phantoms, with and without the addition of the absorber Evans Blue. Finally, we demonstrate the combined MDSFR/SFF of phantoms with varying concentrations of Intralipid and fluorescein, wherein the scattering properties are measured by MDSFR and used to correct the SFF spectrum for accurate quantification of Qμ(a,x)(f).
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http://dx.doi.org/10.1117/1.JBO.18.10.107005DOI Listing
October 2013

Single fiber reflectance spectroscopy on cervical premalignancies: the potential for reduction of the number of unnecessary biopsies.

J Biomed Opt 2013 Jan;18(1):17002

Shahid Beheshti University, Department of Radiation Medicine Engineering, Evin, Tehran, Iran.

We have assessed the value of single fiber reflectance (SFR) spectroscopy in prediction of cervical squamous intraepithelial lesions (SIL). SFR was used to measure reflected light from 32 patients undergoing standard colposcopy. Seven parameters extracted from the spectra in addition to two biographic parameters were compared in biopsy-confirmed SIL versus nonSIL. The significant parameters in the model were determined using stepwise logistic regression. The classification performance was evaluated by a leave-one-out cross-validation method and reported by receiver operating characteristic (ROC) curves. Light absorption properties and biographic characteristics of the patient contributed significantly to the accuracy of the model. Combining important parameters, the best retrospective sensitivity, specificity and area under the ROC curve for SIL sites versus nonSIL were 89%, 80% and 0.89%, respectively. SFR spectroscopy shows promise as a noninvasive, real-time method to guide the clinician in reducing the number of unnecessary biopsies. Discrimination of SIL from other abnormalities compares favorably with that obtained by fluorescence alone and by fluorescence combined with reflectance spectroscopy while the simplicity and low cost of the presented system are dominant.
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http://dx.doi.org/10.1117/1.JBO.18.1.017002DOI Listing
January 2013

In vivo quantification of photosensitizer concentration using fluorescence differential path-length spectroscopy: influence of photosensitizer formulation and tissue location.

J Biomed Opt 2012 Jun;17(6):067001

University Medical Center Groningen, Department of Oral and Maxillofacial Surgery, Division of Oncology, The Netherlands.

In vivo measurement of photosensitizer concentrations may optimize clinical photodynamic therapy (PDT). Fluorescence differential path-length spectroscopy (FDPS) is a non-invasive optical technique that has been shown to accurately quantify the concentration of Foscan® in rat liver. As a next step towards clinical translation, the effect of two liposomal formulations of mTHPC, Fospeg® and Foslip®, on FDPS response was investigated. Furthermore, FDPS was evaluated in target organs for head-and-neck PDT. Fifty-four healthy rats were intravenously injected with one of the three formulations of mTHPC at 0.15 mg kg(-1). FDPS was performed on liver, tongue, and lip. The mTHPC concentrations estimated using FDPS were correlated with the results of the subsequent harvested and chemically extracted organs. An excellent goodness of fit (R(2)) between FDPS and extraction was found for all formulations in the liver (R(2)=0.79). A much lower R(2) between FDPS and extraction was found in lip (R(2)=0.46) and tongue (R(2)=0.10). The lower performance in lip and in particular tongue was mainly attributed to the more layered anatomical structure, which influences scattering properties and photosensitizer distribution.
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http://dx.doi.org/10.1117/1.JBO.17.6.067001DOI Listing
June 2012

Extraction of intrinsic fluorescence from single fiber fluorescence measurements on a turbid medium.

Opt Lett 2012 Mar;37(5):948-50

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.

This study utilizes Monte Carlo simulations of single fiber fluorescence to develop an empirical model that corrects for the influence of scattering and absorption on fluorescence intensity (F(SF)). The model expresses F(SF) in terms of the reduced scattering coefficient (μs') and absorption coefficient (μ(a)), each determined independently at excitation and emission wavelengths (λ(x) and λ(m)), and the fiber diameter (d(f)). This model returns accurate descriptions (mean residual <6%) of F(SF) across a biologically relevant range of μs' and μ(a) values and is insensitive to the form of the scattering phase function.
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http://dx.doi.org/10.1364/OL.37.000948DOI Listing
March 2012

The future of medical diagnostics: review paper.

Head Neck Oncol 2011 Aug 23;3:38. Epub 2011 Aug 23.

Head and Neck Optical Diagnostics Society Council, International Society of Minimally Invasive Diagnostics, University College London, London, UK.

While histopathology of excised tissue remains the gold standard for diagnosis, several new, non-invasive diagnostic techniques are being developed. They rely on physical and biochemical changes that precede and mirror malignant change within tissue. The basic principle involves simple optical techniques of tissue interrogation. Their accuracy, expressed as sensitivity and specificity, are reported in a number of studies suggests that they have a potential for cost effective, real-time, in situ diagnosis.We review the Third Scientific Meeting of the Head and Neck Optical Diagnostics Society held in Congress Innsbruck, Innsbruck, Austria on the 11th May 2011. For the first time the HNODS Annual Scientific Meeting was held in association with the International Photodynamic Association (IPA) and the European Platform for Photodynamic Medicine (EPPM). The aim was to enhance the interdisciplinary aspects of optical diagnostics and other photodynamic applications. The meeting included 2 sections: oral communication sessions running in parallel to the IPA programme and poster presentation sessions combined with the IPA and EPPM posters sessions.
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http://dx.doi.org/10.1186/1758-3284-3-38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180646PMC
August 2011

Clinical feasibility of monitoring m-THPC mediated photodynamic therapy by means of fluorescence differential path-length spectroscopy.

J Biophotonics 2011 Oct 22;4(10):740-51. Epub 2011 Aug 22.

The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Department of Head and Neck Oncology and Surgery, 121 Plesmanlaan, 1066CX Amsterdam, The Netherlands.

The objective quantitative monitoring of light, oxygen, and photosensitizer is challenging in clinical photodynamic therapy settings. We have previously developed fluorescence differential path-length spectroscopy (FDPS), a technique that utilizes reflectance spectroscopy to monitor microvascular oxygen saturation, blood volume fraction, and vessel diameter, and fluorescence spectroscopy to monitor photosensitizer concentration. In this paper the clinical feasibility of the technique is tested on eight healthy volunteers and on three patients undergoing PDT of oral cavity cancers. Model-based analysis of the measured spectra provide quantitative tissue parameters that are corrected for background tissue absorption, autofluorescence, and the transmission of the optical system; this method allows comparison of intra- and inter-subject parameters. The FDPS correctly estimated the absence of m-THPC in volunteers and detected photobleaching in the areas receiving treatment light in patients undergoing PDT treatment. This study demonstrates the feasibility of monitoring clinical photodynamic therapy treatments using optical spectroscopy.
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http://dx.doi.org/10.1002/jbio.201100051DOI Listing
October 2011

In vivo measurement of bladder wall oxygen saturation using optical spectroscopy.

J Biophotonics 2011 Oct 15;4(10):715-20. Epub 2011 Aug 15.

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

Current diagnosis, follow-up and treatment of patients suffering from bladder dysfunction are mainly symptom-targeted. A recently recognized cause of continuing bladder function loss is a deteriorated bladder microvasculature. Incorporating this aspect into the clinical diagnostic toolbox may improve treatment results. Recent developments in the field of optical spectroscopy now allow for non-invasive measurement of microvascular blood oxygen saturation in living tissue. We have recently reported pre-clinical data that show that this marker can be successfully measured in an animal bladder. In the animal model the marker differentiated bladders with loss of function from those with normal function. In the present paper, we report on the first in vivo measurement of this marker in the human bladder, as proof of principle, in the muscle of bladders with a normal function.
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http://dx.doi.org/10.1002/jbio.201100043DOI Listing
October 2011

Monitoring blood volume and saturation using superficial fibre optic reflectance spectroscopy during PDT of actinic keratosis.

J Biophotonics 2011 Oct 15;4(10):721-30. Epub 2011 Aug 15.

Department of Dermatology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Optically monitoring the vascular physiology during photodynamic therapy (PDT) may help understand patient-specific treatment outcome. However, diffuse optical techniques have failed to observe changes herein, probably by optically sampling too deep. Therefore, we investigated using differential path-length spectroscopy (DPS) to obtain superficial measurements of vascular physiology in actinic keratosis (AK) skin. The AK-specific DPS interrogation depth was chosen up to 400 microns in depth, based on the thickness of AK histology samples. During light fractionated aminolevulinic acid-PDT, reflectance spectra were analyzed to yield quantitative estimates of blood volume and saturation. Blood volume showed significant lesion-specific changes during PDT without a general trend for all lesions and saturation remained high during PDT. This study shows that DPS allows optically monitoring the superficial blood volume and saturation during skin PDT. The patient-specific variability supports the need for dosimetric measurements. In DPS, the lesion-specific optimal interrogation depth can be varied based on lesion thickness.
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http://dx.doi.org/10.1002/jbio.201100053DOI Listing
October 2011

Method to quantitatively estimate wavelength-dependent scattering properties from multidiameter single fiber reflectance spectra measured in a turbid medium.

Opt Lett 2011 Aug;36(15):2997-9

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

This study utilizes experimentally validated Monte Carlo simulations to identify a mathematical formulation of the reflectance intensity collected by a single fiber probe expressed in terms of the reduced scattering coefficient (μs'), fiber diameter d(fiber), and a property of the first two moments of the scattering phase function (γ). This model is then utilized to accurately obtain wavelength-dependent estimates of μs'(λ) and γ(λ) from multiple single fiber spectral measurements of a turbid medium obtained with different diameters. This method returns accurate descriptions (mean residual <3%) of both μs' and γ across the biologically relevant range.
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http://dx.doi.org/10.1364/OL.36.002997DOI Listing
August 2011

Method to quantitate absorption coefficients from single fiber reflectance spectra without knowledge of the scattering properties.

Opt Lett 2011 Aug;36(15):2791-3

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.

This study presents a methodology to accurately extract the absorption coefficient from single fiber reflectance spectra measured in turbid media without a priori knowledge of either the reduced scattering coefficient or the phase function. This novel approach accounts for the interrelated effects these properties have on the photon path length, yielding estimates of an absorption coefficient on average within <7.5% of true values over a wide range of biologically relevant optical properties.
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http://dx.doi.org/10.1364/OL.36.002791DOI Listing
August 2011

Changes in bladder wall blood oxygen saturation in the overactive obstructed bladder.

J Urol 2011 Sep 23;186(3):1128-33. Epub 2011 Jul 23.

Department of Urology and Pediatric Urology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, The Netherlands.

Purpose: Several studies suggest that hypoxia of the bladder wall contributes to bladder dysfunction but the exact relation between bladder function and blood oxygen saturation, a surrogate marker for hypoxia, is not known. We determined bladder wall blood oxygen saturation in vivo in an animal model of bladder outlet obstruction to establish the exact relation between blood oxygen saturation and bladder function.

Materials And Methods: In 8 sham operated and 8 urethrally obstructed guinea pigs we measured blood oxygen saturation of the bladder wall by differential path length spectroscopy before surgery and 8 weeks postoperatively. Urodynamic investigations performed during the whole 8-week period provided data on bladder function.

Results: Before surgery and 8 weeks after sham surgery blood oxygen saturation in the bladder wall was between 88% and 95% during filling. It decreased during voiding and returned to greater than 90% within 30 seconds. Eight weeks after obstruction saturation was significantly lower than in the sham operated group during filling and voiding. The decrease was positively related to bladder pressure during filling and voiding, and was more pronounced when overactivity was present. Local bladder contractions occurred without a measurable increase in bladder pressure but were associated with a decrease in saturation.

Conclusions: A normal bladder maintains a high oxygen saturation level during filling. Bladder obstruction compromises this ability, especially when it involves overactivity. Local bladder contractions without a measurable increase in bladder pressure were associated with a decrease in blood saturation.
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http://dx.doi.org/10.1016/j.juro.2011.04.111DOI Listing
September 2011

Fluorescence localization and kinetics of mTHPC and liposomal formulations of mTHPC in the window-chamber tumor model.

Lasers Surg Med 2011 Aug;43(6):528-36

Department of Oral and Maxillofacial Surgery, Division of Oncology, University Medical Center Groningen, The Netherlands.

Background And Objective: Foslip® and Fospeg® are liposomal formulations of the photosensitizer mTHPC, intended for use in Photodynamic Therapy (PDT) of malignancies. Foslip consists of mTHPC encapsulated in conventional liposomes, Fospeg consists of mTHPC encapsulated in pegylated liposomes. Possible differences in tumor fluorescence and vasculature kinetics between Foslip, Fospeg, and Foscan® were studied using the rat window-chamber model.

Material And Methods: In 18 rats a dorsal skin fold window chamber was installed and a mammary carcinoma was transplanted in the subcutaneous tissue. The dosage used for intravenous injection was 0.15 mg/kg mTHPC for each formulation. At seven time-points after injection (5 minutes to 96 hours) fluorescence images were made with a CCD. The achieved mTHPC fluorescence images were corrected for tissue optical properties and autofluorescence by the ratio fluorescence imaging technique of Kascakova et al. Fluorescence intensities of three different regions of interest (ROI) were assessed; tumor tissue, vasculature, and surrounding connective tissue.

Results: The three mTHPC formulations showed marked differences in their fluorescence kinetic profile. After injection, vascular mTHPC fluorescence increased for Foslip and Fospeg but decreased for Foscan. Maximum tumor fluorescence is reached at 8 hours for Fospeg and at 24 hours for Foscan and Foslip with overall higher fluorescence for both liposomal formulations. Foscan showed no significant difference in fluorescence intensity between surrounding tissue and tumor tissue (selectivity). However, Fospeg showed a trend toward tumor selectivity at early time points, while Foslip reached a significant difference (P < 0.05) at these time points.

Conclusions: Our results showed marked differences in fluorescence intensities of Fospeg, Foslip, and Foscan, which suggest overall higher bioavailability for the liposomal formulations. Pegylated liposomes seemed most promising for future application; as Fospeg showed highest tumor fluorescence at the earlier time points.
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http://dx.doi.org/10.1002/lsm.21082DOI Listing
August 2011

Non-contact spectroscopic determination of large blood volume fractions in turbid media.

Biomed Opt Express 2011 Jan 24;2(2):396-407. Epub 2011 Jan 24.

We report on a non-contact method to quantitatively determine blood volume fractions in turbid media by reflectance spectroscopy in the VIS/NIR spectral wavelength range. This method will be used for spectral analysis of tissue with large absorption coefficients and assist in age determination of bruises and bloodstains. First, a phantom set was constructed to determine the effective photon path length as a function of μ(a) and μ(s)' on phantoms with an albedo range: 0.02-0.99. Based on these measurements, an empirical model of the path length was established for phantoms with an albedo > 0.1. Next, this model was validated on whole blood mimicking phantoms, to determine the blood volume fractions ρ = 0.12-0.84 within the phantoms (r = 0.993; error < 10%). Finally, the model was proved applicable on cotton fabric phantoms.
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http://dx.doi.org/10.1364/BOE.2.000396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038454PMC
January 2011

In vivo quantification of photosensitizer fluorescence in the skin-fold observation chamber using dual-wavelength excitation and NIR imaging.

Lasers Med Sci 2011 Nov 29;26(6):789-801. Epub 2011 Jan 29.

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Center, Room Ee-1675, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

A major challenge in biomedical optics is the accurate quantification of in vivo fluorescence images. Fluorescence imaging is often used to determine the pharmacokinetics of photosensitizers used for photodynamic therapy. Often, however, this type of imaging does not take into account differences in and changes to tissue volume and optical properties of the tissue under interrogation. To address this problem, a ratiometric quantification method was developed and applied to monitor photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC) pharmacokinetics in the rat skin-fold observation chamber. The method employs a combination of dual-wavelength excitation and dual-wavelength detection. Excitation and detection wavelengths were selected in the NIR region. One excitation wavelength was chosen to be at the Q band of mTHPC, whereas the second excitation wavelength was close to its absorption minimum. Two fluorescence emission bands were used; one at the secondary fluorescence maximum of mTHPC centered on 720 nm, and one in a region of tissue autofluorescence. The first excitation wavelength was used to excite the mTHPC and autofluorescence and the second to excite only autofluorescence, so that this could be subtracted. Subsequently, the autofluorescence-corrected mTHPC image was divided by the autofluorescence signal to correct for variations in tissue optical properties. This correction algorithm in principle results in a linear relation between the corrected fluorescence and photosensitizer concentration. The limitations of the presented method and comparison with previously published and validated techniques are discussed.
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http://dx.doi.org/10.1007/s10103-011-0888-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183248PMC
November 2011

Characterization of mediastinal lymph node physiology in vivo by optical spectroscopy during endoscopic ultrasound-guided fine needle aspiration.

J Thorac Oncol 2010 Jul;5(7):981-7

Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, University Hospital, Rotterdam, The Netherlands.

Introduction: Esophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a minimally invasive staging procedure for mediastinal lymph nodes in patients diagnosed with lung cancer. But, a substantial false negative rate necessitates that patients returning a negative EUS-FNA result must undergo a subsequent surgical staging procedure. This study incorporates a fiberoptic reflectance spectroscopy device into the EUS-FNA procedure to asses the vascular physiology within the sampled lymph node. The aims of this pilot study were to determine the feasibility of incorporating a reflectance spectroscopy device into the EUS-FNA clinical procedure and to gather preliminary information about the vascular physiology within the center of normal and metastatic lymph nodes.

Methods: This study included 10 patients with proven or suspected lung cancer and an indication for EUS-FNA. The procedure was performed on seven normal (unenlarged, positron emission tomography negative) nodes and seven suspicious (enlarged, positron emission tomography positive), with the malignant status of all nodes cytologically confirmed. Reflectance spectra were acquired using a single optical fiber that fits through the end of the EUS-FNA biopsy needle, with an outer fiber diameter of 0.38 mm.

Results: The procedure was successfully performed and did not introduce complications. Model-based analysis of single fiber reflectance spectra provided quantitative information about the vascular physiology within the sampled lymph node. We observed that metastatic lymph nodes were characterized by lower microvascular oxygen saturation (50% versus 84%, p < 0.01) and lower blood volume fraction (5.6% versus 13.5%, p < 0.01) than normal nodes.

Conclusions: Single fiber reflectance spectroscopy has the potential to detect abnormal lymph node physiology.
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http://dx.doi.org/10.1097/jto.0b013e3181ddbc0eDOI Listing
July 2010

Differential pathlength spectroscopy for the quantitation of optical properties of gold nanoparticles.

ACS Nano 2010 Jul;4(7):4081-9

Biomedical Photonic Imaging Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.

An accurate estimation of optical absorption coefficient (microabs) and scattering coefficient (microsca) is important in characterizing nanoparticles for identifying or optimizing applications such as photothermal therapy and photoacoustic imaging. In this exciting period where several fascinating methods have been unveiled for the synthesis of various nanoparticles, the field is still lacking in the availability of efficient characterization methods. We introduce an accurate and simple methodology to optically characterize nanoparticles which could fill the gap. This is based on differential pathlength spectroscopy (DPS), a dual optical fiber approach, originally developed to detect cancer endoscopically by measuring the optical properties of tissue in small interrogation volumes. We expand its use to nanoparticles in a method that allows us to resolve the effects of microabs and microsca in the extinction coefficient of low concentration samples. We outline the measurement protocol using the DPS system and describe the analysis of the data taking additional inputs from electron microscopy and discrete dipole approximation (DDA) simulations. The DPS signal from the sample is first translated into the backscattering coefficient using a calibration constant. Further, the backscattering coefficient is converted via the simulated scattering phase function into the scattering coefficient. With this knowledge and extinction coefficient measured using a conventional photospectrometer, the absorption coefficient is calculated. We prove the validity of the method using spherical and rod-shaped gold nanoparticles, comparing the results with outputs from DDA simulations. We also briefly touch upon the dilemma of the choice of the appropriate dielectric function for gold at the nanoscale.
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http://dx.doi.org/10.1021/nn1009165DOI Listing
July 2010
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