Photodynamic therapy (PDT) is a two-step therapeutic technique in which the topical or systemic delivery of photosensitizing drugs is followed by irradiation with visible light. Activated photosensitizers transfer energy to molecular oxygen, generating reactive oxygen species (ROS). The subsequent oxidation of lipids, amino acids and proteins induces cell necrosis and apoptosis. In addition, ROS indirectly stimulate the transcription and release of inflammatory mediators. The photosensitizers are selective, in that they penetrate and accumulate in tumour cells or in the endothelium of newly formed vessels while generally avoiding the surrounding healthy tissue. The mechanisms of penetration through the cell membrane and the pattern of subcellular localization strongly influence the type of cellular effect. The photobiology and photoimmunology of the haematoporphyrin (Hp) derivative and its purified, lyophilized and concentrated form porfimer sodium have been investigated over the past 30 years. However, interest in PDT in dermatology was not raised until the 1990s with the availability of a simple and effective technique, the topical application of aminolaevulinic acid (ALA) and its methyl ester (methyl aminolaevulinate, MAL) followed by irradiation with broadband red light. At the same time, several new 'second-generation' synthetic sensitizers (e.g. benzoporphyrin derivatives, phthalocyanines, chlorins and porphycenes) became available. These compounds are chemically pure, highly efficient, selective and safe, while offering the advantage that the generalized skin photosensitivity they produce lasts for only a short time. They are currently under clinical evaluation but have not yet been approved for clinical use. This paper provides an overview of the chemistry of the photosensitizers, the photobiology and photoimmunology of the photodynamic reaction as well as the photophysical characteristics of the light sources available for PDT.

Photodynamic therapy: update 2006 Part 1: Photochemistry and photobiology

Photodynamic therapy (PDT), a non-invasive therapeutic modality, has received increasing attention owing to its high selectivity and limited side effects Although significant clinical research progress has been made in PDT, the breadth and depth of its clinical application have not been fully realized due to the limitations such as inadequate light penetration depth, non-targeting photosensitizers (PSs), and tumor hypoxia Consequently, numerous investigations put their emphasis on innovative strategies to overcome the aforementioned limitations and enhance the therapeutic effect of PDT Herein, up-to-date advances in these innovative methods for PDT are summarized by introducing the design of PS systems, their working mechanisms and application examples In addition, current challenges of these innovative strategies for clinical application, and future perspectives on further improvement of PDT are also discussed

Recent advances in innovative strategies for enhanced cancer photodynamic therapy.

Photodynamic therapy (PDT) uses a photosensitizer, light energy, and molecular oxygen to cause cell damage. Cells exposed to the photosensitizer are susceptible to destruction upon light absorption because excitation of the photosensitizing agents leads to the production of reactive oxygen species and, subsequently, direct cytotoxicity. Using the intrinsic cellular heme biosynthetic pathway, topical PDT selectively targets abnormal cells, while preserving normal surrounding tissues. This selective cytotoxic effect is the basis for the use of PDT in antitumor treatment. Clinically, PDT is a widely used therapeutic regimen for oncologic skin conditions such as actinic keratosis, squamous cell carcinoma in situ, and basal cell carcinoma. PDT has been shown, under certain circumstances, to stimulate the immune system and produce antibacterial, and/or regenerative effects while protecting cell viability. Thus, it may be useful for treating benign skin conditions. An increasing number of studies support the idea that PDT may be effective for treating acne vulgaris and several other inflammatory/infective skin diseases, including psoriasis, rosacea, viral warts, and aging-related changes. This review provides an overview of the clinical investigations of PDT and discusses each of the essential aspects of the sequence: its mechanism of action, common photosensitizers, light sources, and clinical applications in dermatology. Of the numerous clinical trials of PDT in dermatology, this review focuses on those studies that have reported remarkable therapeutic benefits following topical PDT for benign skin conditions such as acne vulgaris, viral warts, and photorejuvenation without causing severe side effects.

https://www.mdpi.com/1422-0067/16/10/23259/pdf

Topical PDT in the Treatment of Benign Skin Diseases: Principles and New Applications

The growing incidence of cutaneous malignancies each year necessitates the development of new and more effective methods for both the diagnosis and the treatment of cancerous lesions, while assuring better cosmetic results and improving patient satisfaction. With that in mind, the use of topical photodynamic therapy (PDT) has been explored in the treatment as well as the diagnosis of various cutaneous malignancies. Using the intrinsic cellular haem biosynthetic pathway and principles of photoillumination, topical PDT carries the goal of selectively targeting abnormal cells, while preserving the normal surrounding structures. This paper will discuss the various applications and data on the use of topical PDT in dermatology.

Topical photodynamic therapy in clinical dermatology

Raman spectroscopy (RS) is a powerful technique that permits the non-destructive chemical analysis of cells and tissues without the need for expensive and complex sample preparation. To date, samples have been routinely mounted onto calcium fluoride (CaF2) as this material possesses the desired mechanical and optical properties for analysis, but CaF2 is both expensive and brittle and this prevents the technique from being routinely adopted. Furthermore, Raman scattering is a weak phenomenon and CaF2 provides no means of increasing signal. For RS to be widely adopted, particularly in the clinical field, it is crucial that spectroscopists identify an alternative, low-cost substrate capable of providing high spectral signal to noise ratios with good spatial resolution. Results show that these desired properties are attainable when using mirrored stainless steel as a Raman substrate. When compared with CaF2, data show that stainless steel has a low background signal and provides an average signal increase of 1.43 times during tissue analysis and 1.64 times when analyzing cells. This result is attributed to a double-pass of the laser beam through the sample where the photons from the source laser and the forward scattered Raman signal are backreflected and retroreflected from the mirrored steel surface and focused towards collection optics. The spatial resolution on stainless steel is at least comparable to that on CaF2 and it is not compromised by the reflection of the laser. Steel is a fraction of the cost of CaF2 and the reflection and focusing of photons improve signal to noise ratios permitting more rapid mapping. The low cost of steel coupled with its Raman signal increasing properties and robust durability indicates that steel is an ideal substrate for biological and clinical RS as it possesses key advantages over routinely used CaF2. © 2016 The Authors. Journal of Raman Spectroscopy Published by John Wiley & Sons Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jrs.4980

Mirrored stainless steel substrate provides improved signal for Raman spectroscopy of tissue and cells

Photodynamic therapy is a method for local destruction of tissue or organisms by generating toxic oxygen and other reactive species using light absorbed by an administered or an endogenously generated photosensitiser. It is a highly promising treatment for patients with cancer. More recently it has found increasing use as a method of therapy for non-cancerous illnesses. It depends on the exploitation of natural and vital reactions widespread in nature that have driven and preserved life on this planet. Following administration of a photosensitiser or its precursor there is an accumulation or retention in areas of cancer and disease relative to adjacent normal tissue. The photosensitiser is inactive until irradiated by light, following which cellular destruction occurs. The clear attraction of this method is the possibility of some targeting of the disease by drug and by the area irradiated. This explanation although oversimplified has been the reason for the scientific and clinical interest in photodynamic therapy. An understanding of evolutionary photobiology is enormously helpful to understand disease response and clinical outcomes.

https://journals.sagepub.com/doi/pdf/10.3184/003685002783238825

Clinical aspects of photodynamic therapy.

Introduction Non-endoscopic detection of Barrett’s oesophagus (BO) and associated neoplasia would allow population screening and could potentially replace endoscopic surveillance. A swallowed cytology brush has been developed (‘Cytosponge’) for oesophageal cell collection. A recent study (BEST2) assessing the Cytosponge used immunostaining with Trefoil Factor 3 (TFF3) as a means of BO detection. Accurate identification of neoplasia could enable risk stratification to determine who requires endoscopy. Infrared spectroscopy (IR) of biological samples analyses sample biochemistry: subtle spectral differences can be used to classify samples into pathological subtypes. This study aimed to evaluate IR as a diagnostic tool for automated detection of neoplasia in oesophageal cytology. Method Brush cytology was collected from patients undergoing endoscopy for BO, with contemporaneous biopsy from the same region. Cells were fixed in formalin, centrifuged and plated onto calcium fluoride slides. IR spectra were measured across the entire sample area. Data pre-processing steps selected spectra from individual cells and removed confounding effects from water vapour and non-cellular debris. Contemporaneous endoscopy and biopsy results provided a reference for developing a predictive model. Prinicipal component analysis (PCA), linear discriminant analysis (LDA), and leave-one-out cross-validation (LOOCV) were used to develop and test classification models. Results Samples were measured from 20 patients (7 BO, 13 dysplasia or adenocarcinoma). LOOCV testing showed a sensitivity for detecting neoplastic change (dysplasia or adenocarcinoma) of 79.9%, with specificity 75.8%. Conclusion These results show feasibility of using IR to detect neoplasia in Barrett’s screening. Further work is required to expand our preliminary results and refine pre-processing steps to improve sensitivity, and develop trials using the Cytosponge. Disclosure of interest None Declared. References Ross-Innes, et al . Evaluation of a minimally invasive cell sampling device, coupled with assessment of Trefoil Factor 3 expression for diagnosiing Barrett’s esophagus: a multi-centre case-controlled study. PLoS Med. 2015;12(1):e1001780 Kadri, et al . Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study. BMJ 2010; 341 :c4372 Townsend, et al . Infrared microspectroscopy for cyto-pathological classification of esophageal cells. Analyst 2015 doi: 10.1039/C4AN01884B

https://gut.bmj.com/content/gutjnl/64/Suppl_1/A485.1.full.pdf

PTH-174 Non-endoscopic screening for barrett’s oesophagus: identifying neoplasia with infrared spectroscopy

Introduction Raman spectroscopy has been shown to accurately classify tissue pathology in a variety of conditions and organ systems. Much of this work has been performed using Raman microspectrometers on ex vivo tissue sections with long acquisition times, and measurements can take many hours. To enable translation of this technology to a clinical setting, either as an adjunct for pathologists or an in vivo probe for point of care testing, measurement times must be reduced. By using Renishaw’s Streamline™ technologywhich combines a line focusing technique and pixel binning, it is possible to collect Raman spectral measurements much faster without compromising signal to noise. This study aims to assess the ability of this technique to accurately classify tissue pathology, using an oesophageal model. Method Tissue was collected from the oesophagus in patients undergoing endoscopy of open surgery on the oesophagus. Specimens were collected from patients with Barrett’s oesophagus (BO), dysplasia and adenocarcinoma, and snap frozen in liquid nitrogen. 8 µm tissue sections were prepared onto calcium fluoride slides, with contiguous sections stained with haematoxylin and eosin (H&E) for histological comparison. Raman spectra were collected across homogeneous regions of tissue pathology, using Streamline™ acquisitions of 60 s per pixel, at 1.1 µm spatial resolution. Classification models were constructed to discriminate pathology subtypes. Results Advanced multivariate statistic analysis tools were used to develop pathology classification models, which were then tested using leave-one-out cross-validation. The sensitivity and specificity of this pathology classification model using Raman Spectroscopy to discriminate dysplasia/adenocarcinoma from Barrett’s oesophagus produced sensitivity and specificities >75% and >75%, respectively. Conclusion By combining multivariate statistical analysis with Streamline TM Raman acquisition of spectral data, we have demonstrated good sensitivities and specificities. This study illustrates the potential of non-invasive rapid Raman spectral mapping measurements and development of a robust and validated oesophageal classification model that are able to classify tissue pathology both providing a clinical tool for pathologists and clinicians. Disclosure of interest None Declared. Reference Shetty G, et al . Raman spectroscopy: elucidation of biochemical changes in carcinogenesis of oesophagus. Br J Cancer. 2006;94(10):1460–4

https://gut.bmj.com/content/gutjnl/64/Suppl_1/A485.2.full.pdf

PTH-175 Raman mapping for pathology classification: the need for speed

Introduction Colorectal cancer is the second most common cause of cancer death in the UK. 1 Colonic adenomas are often removed during colonoscopy as part of the Bowel Cancer Screening Programme to identify early cancers and improve patient survival rates. 2 Sigmoid adenomas may show features of benign epithelial misplacement in the submucosal stalk which in some cases may resemble an early infiltrating adenocarcinoma or polyp cancer 3 causing substantial diagnostic conundrum for pathologists. The aim of this study was to investigate and demonstrate the use of novel high resolution infrared spectroscopy to differentiate colonic epithelial misplacement (EM) from polyp cancer. Method 28 cases in total for the EM and cancer pathology groups were identified from 2011–2014. Tissue samples were formalin fixed and paraffin embedded, routinely processed and thin sections mounted onto calcium fluoride slides. Rapid mapping using a novel high resolution infrared spectrometer with a spatial resolution of 1.1 microns was performed on the tissue sections and the absorption spectra measured for each case. Accepted methods of multivariate spectral analysis were undertaken to elucidate the differences between the two pathologies across the dataset and classify the tissue based on the spectra. Results High resolution infrared spectral imaging was successfully performed on the colonic tissue. Analysis of 28 cases in two pathology groups generated over 500,000 spectra representative of the molecular biology of EM and cancer cases. Spectral differences between the two groups were analysed using principal component and linear discriminant analysis and a classification model built. Leave one sample out cross validation (LOSOCV) resulted in a sensitivity of 74.6% and a specificity of 82.3% for the technique to successfully discriminate EM from cancer. Conclusion Analysis of spectral data generated from novel high resolution infrared spectral imaging of colonic tissue has been proven to be successful in differentiating EM from cancer cases. The diagnostic difficultly of differentiating these cases is well documented, especially as one disease state approaches that of the other. However, novel high resolution spectroscopy may offer a new tool to aid the accurate diagnosis of early cancers. This technique has the potential to be used as an automated adjunct to traditional pathological diagnostics, may increase diagnostic speed in difficult cases and improve the efficiency of the patient management pathway. Disclosure of interest None Declared. References www.cancerresearchuk.org Mandel JS, Church TR, Bond JH, et al . N Engl J Med. 2000;343:1603–1607 Muto T, Bussey HRJ, Morson BC. J Clin Pathol. 1973; 26 :25–31

https://gut.bmj.com/content/gutjnl/64/Suppl_1/A553.1.full.pdf

PTH-327 Epithelial misplacement versus polyp cancer: shedding new light on the diagnostic conundrum

Citation: Upchurch E, Isabelle M, Lloyd GR, Kendall C, Stone N, et al. (2018) The Role of Raman Spectroscopy in Differentiating Grades of Dysplasia in Barrett’s Oesophagus: Is It Currently Good Enough?. Int J Exp Spectroscopic Tech 3:013 Copyright: © 2018 Upchurch E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. *Corresponding author: Emma Upchurch, Biophotonics Research Unit, Department of Upper GI Surgery, Gloucestershire Royal Hospital, Great Western Road, Gloucester, GL1 3NN, UK, E-mail: em_upchurch@hotmail.com Received: November 19, 2017: Accepted: February 15, 2018: Published: February 17, 2018 VIBGYOR ISSN: 2631-505X

/pdf/the-role-of-raman-spectroscopy-in-differentiating-grades-of-2ltyff1az8.pdf

The Role of Raman Spectroscopy in Differentiating Grades of Dysplasia in Barrett's Oesophagus: Is It Currently Good Enough?

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