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  • 1.
    Candefjord, Stefan
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Combining a resonance and a Raman sensor: towards a new method for localizing prostate tumors in vivo2007Report (Other academic)
    Abstract [en]

    Prostate cancer is the most common malignancy diagnosed in western men today. Measuring the amount of prostate-specific antigen in blood is the most widespread tool for diagnosing prostate cancer early on. However, clinical investigations show that many people with high levels of PSA can be healthy and vice versa. Ultrasound-guided biopsies is the clinical method used to prove prostate cancer. Unfortunately, many tumors are overlooked by this procedure. It has been estimated that about 30% of the biopsy examinations fail to find a present tumor. The resonance technique, which can differentiate hard and soft materials, has in vitro been shown to be able to distinguish prostate cancer and healthy epithelial prostate tissue. Raman spectroscopy is also a good candidate for detecting prostate cancer. Our novel idea of combining the resonance and Raman techniques into a portable probe, appropriate for in vivo examinations of the prostate, will be discussed in this report. The two techniques are presented and explained, and the feasibility of combining them is discussed. Planned experiments and investigations are outlined.

  • 2.
    Candefjord, Stefan
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Combining the tactile resonance method and Raman spectroscopy for tissue characterization towards prostate cancer detection2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer (PCa) is the most common male cancer in Europe and the US, and only lung and colorectal cancer have a higher mortality among European men. In Sweden, PCa is the most common cause of cancer-related death for men.The overall aim of this thesis was to explore the need for new and complementary methods for PCa detection and to take the rst step towards a novel approach: combining the tactile resonance method (TRM) and Raman spectroscopy (RS). First, the main methods for PCa detection were reviewed. Second, to establish a robust protocol for RS experiments in vitro, the eects of snap-freezing and laser illumination on porcine prostate tissue were studied using RS and multivariate statistics. Third, measurements on porcine and human tissue were performed to compare the TRM and RS data via multivariate techniques, and to assess the accuracy of classifying healthy and cancerous tissue using a support vector machine algorithm.It was concluded through the literature review that the gold standard for PCa detection and diagnosis, the prostate specic antigen test and systematic biopsy, have low sensitivity and specicity. Indolent and aggressive tumors cannot be reliably dierentiated, and many men are therefore treated either unnecessarily or too late. Clinical benets of the state-of-the-art in PCa imaging - advanced ultrasound and MR techniques - have still not been convincingly shown. There is a need for complementary and cost-eective detection methods. TRM and RS are promising techniques, but hitherto their potential for PCa detection have only been investigated in vitro.In the RS study no evidence of tissue degradation due to 830 nm laser illumination at an irradiance of ∼3 · 1010 W m-2 were found. Snap-freezing and subsequent storage at -80° C gave rise to subtle but signicant changes in Raman spectra, most likely related to alterations in the protein structure. The major changes due to PCa do not seem to be related to the protein structure, hence snap-freezing may be applied in our experiments.The combined measurements on porcine and human prostate tissue showed that RS provided additional discriminatory power to TRM. The classication accuracy for healthy porcine prostate tissue, and for healthy and cancerous human prostate tissue, was > 73%. This shows the power of the support vector machine applied to the combined data.In summary, this work indicates that an instrument combining TRM and RS is a promising complementary method for PCa detection. Snap-freezing of samples may be used in future RS studies of PCa. A combined instrument could be used for tumor-border demarcation during surgery, and potentially for guiding prostate biopsies towards lesions suspicious for cancer. All of this should provide a more secure diagnosis and consequently more effcient treatment of the patient.

  • 3.
    Candefjord, Stefan
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Towards new sensors for prostate cancer detection: combining Raman spectroscopy and resonance sensor technology2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer (PCa) is the most common male cancer in Europe and the US, and only lung and colorectal cancer have a higher mortality among European men. In Sweden, PCa is the most common cause of cancer-related death for men.The overall aim of this licentiate work was to explore the need for new and complementary methods for PCa detection and to take the first step towards a novel approach: combining Raman spectroscopy and resonance sensor technology. Firstly, the main methods for PCa detection were reviewed. Secondly, to establish a robust protocol for Raman experiments in vitro, the effects of snap-freezing and laser illumination on porcine prostate tissue were studied using Raman spectroscopy and multivariate statistics. Thirdly, measurements on pork belly tissue using both a resonance sensor and a Raman fiberoptic probe were evaluated regarding correlation of the data.It was concluded that the gold standard for PCa detection and diagnosis, the prostate specific antigen test and systematic biopsy, have low sensitivity and specificity. Indolent and aggressive tumors cannot be reliably differentiated, and many men are therefore treated either unnecessarily or too late. Clinical benefits of the state-of-the-art in PCa imaging - advanced ultrasound and MR techniques - have still not been convincingly shown. There is a need for complementary and cost-effective detection methods. Raman spectroscopy and resonance sensor technology are promising alternative techniques, but hitherto their potential for PCa detection have only been investigated in vitro.No evidence of tissue degradation due to 830 nm laser illumination at an irradiance of 3 1010 W/m2 were found. Snap-freezing and subsequent storage at -80◦C gave rise to subtle but significant changes in Raman spectra, most likely related to alterations in the protein structure. The major changes in cancerous prostate tissue do not seem to be related to the protein structure, hence snap-freezing may be applied.The combined measurements on pork belly tissue showed that Raman spectroscopy provided additional discriminatory power to the resonance sensor. The Raman data explained 67% of the variability of the stiffness parameter. The differentiation of tissue types using the resonance sensor was relatively poor, likely due to its large sample volume compared to the Raman sensor. A smaller resonance sensor tip may improve the results.In summary, this work indicates that an instrument combining Raman spectroscopy and resonance sensor technology is a promising complementary method for PCa detection. Snap-freezing of samples may be used in future Raman studies of PCa. A combined instrument could potentially be used to guide prostate biopsies towards lesions suspicious for cancer, and for tumor-border demarcation during surgery. All of this should provide a more secure diagnosis and consequently more efficient treatment of the patient.

  • 4.
    Candefjord, Stefan
    et al.
    Chalmers University of Technology.
    Murayama, Yoshinobu
    College of Engineering, Nihon University.
    Nyberg, Morgan
    Hallberg, Josef
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Ramser, Kerstin
    Ljungberg, Börje
    Umeå University, Department of Surgical and Perioperative Science, Urology and Andrology.
    Bergh, Anders
    Department of Medical Biosciences Pathology, Umeå University.
    Lindahl, Olof
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Combining scanning haptic microscopy and fibre optic Raman spectroscopy for tissue characterisation2012In: Journal of Medical Engineering & Technology, ISSN 0309-1902, E-ISSN 1464-522X, Vol. 36, no 6, p. 319-327Article in journal (Refereed)
    Abstract [en]

    The tactile resonance method (TRM) and Raman spectroscopy (RS) are promising for tissue characterisation in vivo. Our goal is to combine these techniques into one instrument, to use TRM for swift scanning, and RS for increasing the diagnostic power. The aim of this study was to determine the classification accuracy, using support vector machines, for measurements on porcine tissue and also produce preliminary data on human prostate tissue. This was done by developing a new experimental setup combining micro-scale TRM — scanning haptic microscopy (SHM) — for assessing stiffness on a micro-scale, with fibre optic RS measurements for assessing biochemical content. We compared the accuracy for using SHM alone versus SHM combined with RS, for different degrees of tissue homogeneity. The cross-validation classification accuracy for healthy porcine tissue types using SHM alone was 65–81%, and when RS was added it was increased to 81–87%. The accuracy for healthy and cancerous human tissue was 67–70% when only SHM was used, and increased to 72–77% for the combined measurements. This shows that the potential for swift and accurate classification of healthy and cancerous prostate tissue is high. This is promising for developing a tool for probing the surgical margins during prostate cancer surgery.

  • 5.
    Candefjord, Stefan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Nyberg, Morgan
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Jalkanen, Ville
    Umeå University. Department of Applied Physics and Electronics.
    Ramser, Kerstin
    Lindahl, Olof
    Combining fibre optic Raman spectroscopy and tactile resonance measurement for tissue characterization2010In: Measurement science and technology, ISSN 0957-0233, E-ISSN 1361-6501, Vol. 21, no 12Article in journal (Refereed)
    Abstract [en]

    Tissue characterization is fundamental for identification of pathological conditions. Raman spectroscopy (RS) and tactile resonance measurement (TRM) are two promising techniques that measure biochemical content and stiffness, respectively. They have potential to complement the golden standard-–histological analysis. By combining RS and TRM, complementary information about tissue content can be obtained and specific drawbacks can be avoided. The aim of this study was to develop a multivariate approach to compare RS and TRM information. The approach was evaluated on measurements at the same points on porcine abdominal tissue. The measurement points were divided into five groups by multivariate analysis of the RS data. A regression analysis was performed and receiver operating characteristic (ROC) curves were used to compare the RS and TRM data. TRM identified one group efficiently (area under ROC curve 0.99). The RS data showed that the proportion of saturated fat was high in this group. The regression analysis showed that stiffness was mainly determined by the amount of fat and its composition. We concluded that RS provided additional, important information for tissue identification that was not provided by TRM alone. The results are promising for development of a method combining RS and TRM for intraoperative tissue characterization.

  • 6. Candefjord, Stefan
    et al.
    Nyberg, Morgan
    Jalkanen, Ville
    Umeå University. Department of Applied Physics and Electronics.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Evaluating the use of a Raman fiberoptic probe in conjunction with a resonance sensor for measuring porcine tissue in vitro2009In: World Congress on Medical Physics and Biomedical Engineering: September 7 - 12, 2009, Munich, Germany / [ed] Olaf Dössel; Wolfgang C. Schlegel, Berlin: Springer Science+Business Media B.V., 2009, Vol. 7, p. 414-417Conference paper (Refereed)
    Abstract [en]

    Prostate cancer is the most common form of cancer and the third leading cause of cancer-related death in European men. There is a need for new methods that can accurately localize and diagnose prostate cancer. In this study a new approach is presented: a combination of resonance sensor technology and Raman spectroscopy. Both methods have shown promising results for prostate cancer detection in vitro. The aim of this study was to evaluate the combined information from measurements with a Raman fiberoptic probe and a resonance sensor system. Pork belly tissue was used as a model system. A three-dimensional translation table was equipped with an in-house developed software, allowing measurements to be performed at the same point using two separate instruments. The Raman data was analyzed using principal component analysis and hierarchical clustering analysis. The spectra were divided into 5 distinct groups. The mean stiffness of each group was calculated from the resonance sensor measurements. One of the groups differed significantly (p < 0.05) from the others. A regression analysis, with the stiffness parameter as response variable and the principal component scores of the Raman data as the predictor variables, explained 67% of the total variability. The use of a smaller resonance sensor tip would probably increase the degree of correlation. In conclusion, Raman spectroscopy provides additional discriminatory power to the resonance sensor

  • 7. Candefjord, Stefan
    et al.
    Nyberg, Morgan
    Jalkanen, Ville
    Umeå universitet.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Kombinationsinstrument för detektering av prostatacancer: korrelation mellan resonanssensor och fiberoptisk Ramanprobe2009Conference paper (Other academic)
  • 8.
    Candefjord, Stefan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Ramser, Kerstin
    Lindahl, Olof
    Effects of snap-freezing and laser illumination of tissue on near-infrared Raman spectra of porcine prostate tissue2008Conference paper (Other academic)
  • 9. Candefjord, Stefan
    et al.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Effects of snap-freezing and near-infrared laser illumination on porcine prostate tissue as measured by Raman spectroscopy2009In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 134, no 9, p. 1815-1821Article in journal (Refereed)
    Abstract [en]

    Most Raman spectroscopic studies on tissue are performed in vitro. To assure that the results are applicable to in vivo examinations, preparation protocols and measurement procedures of tissue for in vitro studies should preserve tissue characteristics close to the native state. This study had two aims. The first was to elucidate if photoinduced effects arise during 5 minutes' continuous illumination of tissue with an 830 nm laser at an irradiance of 3 × 1010 W/m2. The second was to investigate the effects of snap-freezing of porcine prostate tissue in liquid nitrogen and subsequent storage at -80 °C, by means of multivariate analysis. 830 nm laser illumination of the specified irradiance did not affect the Raman spectra. A decrease of the spectral background was observed, likely due to photobleaching of tissue fluorophores. Snap-freezing and subsequent storage at -80 °C gave rise to subtle but significant alterations in Raman spectra, most likely related to changes in the protein conformations

  • 10.
    Candefjord, Stefan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Ramser, Kerstin
    Lindahl, Olof
    En ny metod för att lokalisera och diagnostisera prostatacancer2007In: Medicinteknikdagarna, 2007, p. 33-34Conference paper (Other academic)
  • 11.
    Candefjord, Stefan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Kombinationsinstrument för detektering av prostatacancer: mätningar på snitt av grisprostata med resonanssensor och fiberoptisk Ramanprobe2010Conference paper (Refereed)
  • 12. Candefjord, Stefan
    et al.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Technologies for localization and diagnosis of prostate cancer2009In: Journal of Medical Engineering & Technology, ISSN 0309-1902, E-ISSN 1464-522X, Vol. 33, no 8, p. 585-603Article in journal (Refereed)
    Abstract [en]

    The gold standard for detecting prostate cancer (PCa), systematic biopsy, lacks sensitivity as well as grading accuracy. PSA screening leads to over-treatment of many men, and it is unclear whether screening reduces PCa mortality. This review provides an understanding of the difficulties of localizing and diagnosing PCa. It summarizes recent developments of ultrasound (including elastography) and MRI, and discusses some alternative experimental techniques, such as resonance sensor technology and vibrational spectroscopy. A comparison between the different methods is presented. It is concluded that new ultrasound techniques are promising for targeted biopsy procedures, in order to detect more clinically significant cancers while reducing the number of cores. MRI advances are very promising, but MRI remains expensive and MR-guided biopsy is complex. Resonance sensor technology and vibrational spectroscopy have shown promising results in vitro. There is a need for large prospective multicentre trials that unambiguously prove the clinical benefits of these new techniques.

  • 13.
    Candefjord, Stefan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Towards new sensors for cancer detection in vivo, a handheld detector combining a bre-optic Raman probe and a resonance sensor2007Conference paper (Refereed)
  • 14.
    Nyberg, Morgan
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Candefjord, Stefan
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Jalkanen, Ville
    Umeå University. Department of Applied Physics and Electronics.
    Ramser, Kerstin
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Lindahl, Olof
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    A combined tactile and Raman probe for tissue characterization: design considerations2012In: Measurement science and technology, ISSN 0957-0233, E-ISSN 1361-6501, Vol. 23, no 6Article in journal (Refereed)
    Abstract [en]

    Histopathology is the golden standard for cancer diagnosis and involves the characterization of tissue components. It is labour intensive and time consuming. We have earlier proposed a combined fibre-optic near-infrared Raman spectroscopy (NIR-RS) and tactile resonance method (TRM) probe for detecting positive surgical margins as a complement to interoperative histopathology. The aims of this study were to investigate the effects of attaching an RS probe inside a cylindrical TRM sensor and to investigate how laser-induced heating of the fibre-optic NIR-RS affected the temperature of the RS probe tip and an encasing TRM sensor. In addition, the possibility to perform fibre-optic NIR-RS in a well-lit environment was investigated. A small amount of rubber latex was preferable for attaching the thin RS probe inside the TRM sensor. The temperature rise of the TRM sensor due to a fibre-optic NIR-RS at 270 mW during 20 s was less than 2 °C. Fibre-optic NIR-RS was feasible in a dimmed bright environment using a small light shield and automatic subtraction of a pre-recorded contaminant spectrum. The results are promising for a combined probe for tissue characterization.

  • 15.
    Ramser, Kerstin
    et al.
    Luleå University of Technology, Department of Computer Science, Electrical and Space Engineering, Signals and Systems.
    Malinina, Evgenya
    Luleå University of Technology.
    Candefjord, Stefan
    Chalmers University of Technology.
    Resonance microRaman investigations of the rat medial preoptic nucleus- effects of a low iron diet on the neuroglobin content2012In: Applied Spectroscopy, ISSN 0003-7028, E-ISSN 1943-3530, Vol. 66, no 12, p. 1454-1460Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the medial preoptic nucleus (MPN) of the anterior hypothalamus by resonance Raman spectroscopy (514.5 nm) to determine if it is possible to enhance the Raman scattering of hemoproteins in fresh brain tissue slices. The resonance effect was compared with near-infrared Raman spectra. Two groups of male Sprague Dawley rats were studied, one control group on a normal diet and one group on a low-iron diet to evoke iron deficiency. Each group consisted of four rats, 38-41 days old. The diets lasted for 11, 12, and 15 days. The MPN regions of brain tissue slices were analyzed by monitoring raw and pre-processed mean data, by cluster analysis, and by deriving difference spectra from pre-processed mean spectra. Cluster analysis of the resonance Raman spectra could identify different hemoprotein groups, namely, hemoglobin (Hb) and neuroglobin (Ngb). Spectra from randomly distributed spots revealed high Hb content, whereas Ngb was evenly distributed in the MPN. The different spectra showed a decrease of the Ngb and lipid content for the animals on the low-iron diet. The Ngb decrease was approximately 20%. The data show that resonance Raman spectroscopy is well suited to study hemoproteins in fresh brain tissue.

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