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      Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy

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          Abstract

          There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3 rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

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          Most cited references29

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          Capecitabine and oxaliplatin for advanced esophagogastric cancer.

          We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].). Copyright 2008 Massachusetts Medical Society.
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            Surrogate markers of small fiber damage in human diabetic neuropathy.

            Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.
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              Chemotherapy-induced neuropathy.

              Neurotoxic side effects of cancer therapy are second in frequency to hematological toxicity. Unlike hematological side effects that can be treated with hematopoietic growth factors, neuropathies cannot be treated and protective treatment strategies have not been effective. For the neurologist, the diagnosis of a toxic neuropathy is primarily based on the case history, the clinical and electrophysiological findings, and knowledge of the pattern of neuropathy associated with specific agents. In most cases, toxic neuropathies are length-dependent, sensory, or sensorimotor neuropathies often associated with pain. The platinum compounds are unique in producing a sensory ganglionopathy. Neurotoxicity is usually dependent on cumulative dose. Severity of neuropathy increases with duration of treatment and progression stops once drug treatment is completed. The platinum compounds are an exception where sensory loss may progress for several months after cessation of treatment ("coasting"). As more effective multiple drug combinations are used, patients will be treated with several neurotoxic drugs. Synergistic neurotoxicity has not been extensively investigated. Pre-existent neuropathy may influence the development of a toxic neuropathy. Underlying inherited or inflammatory neuropathies may predispose patients to developing very severe toxic neuropathies. Other factors such as focal radiotherapy or intrathecal administration may enhance neurotoxicity. The neurologist managing the cancer patient who develops neuropathy must answer a series of important questions as follows: (1) Are the symptoms due to peripheral neuropathy? (2) Is the neuropathy due to the underlying disease or the treatment? (3) Should treatment be modified or stopped because of the neuropathy? (4) What is the best supportive care in terms of pain management or physical therapy for each patient? Prevention of toxic neuropathies is most important. In patients with neuropathy, restorative approaches have not been well established. Symptomatic and other management are necessary to maintain and improve quality of life.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 October 2015
                2015
                : 10
                : 10
                : e0139394
                Affiliations
                [1 ]Institute of Human Development, Centre for Endocrinology & Diabetes, Faculty of Medical and Human Sciences, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
                [2 ]Department of Clinical Neurophysiology, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
                [3 ]Weill Cornell Medical College Qatar, Division of Research, Qatar Foundation, Education City, Doha, Qatar
                [4 ]The Christie NHS Foundation Trust, Manchester, United Kingdom
                Hirosaki University Graduate School of Medicine, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RAM WM. Performed the experiments: MF SA INP HF GP AM MT IM WM. Analyzed the data: MF RAM. Contributed reagents/materials/analysis tools: RAM WM. Wrote the paper: MF RAM WM.

                Article
                PONE-D-15-26381
                10.1371/journal.pone.0139394
                4592260
                26430773
                c93eaf92-c206-4590-a120-d6def20afdb1
                Copyright @ 2015

                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

                History
                : 16 June 2015
                : 11 September 2015
                Page count
                Figures: 1, Tables: 3, Pages: 9
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                Data are available on Figshare (DOI= http://dx.doi.org/10.6084/m9.figshare.1449256).

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