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Altshuler RD, Minasian LM, Schweppe CA, Kadan-Lottick NS. Chemotherapy-induced peripheral neuropathy research: a National Institutes of Health (NIH) grant portfolio analysis (2014-2023). JNCI Cancer Spectr 2025; 9:pkaf039. [PMID: 40257752 DOI: 10.1093/jncics/pkaf039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 03/10/2025] [Accepted: 04/08/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating acute and long-term toxicity in cancer patients. We sought to describe the landscape of CIPN research funded by the National Institutes of Health (NIH) and identify gaps and opportunities. METHODS Using the NIH Query View Report system, we identified 180 competitive grants between 2014-2023 containing text pertaining to CIPN in the Abstract or Specific Aims. These were categorized as preclinical, clinical, or both and described by preclinical model, clinical population, CIPN assessments, and/or clinical trial design. We identified 5 additional NCI-funded trials through the NCORP network pertaining to CIPN. RESULTS Of 185 studies, 125 were preclinical, 56 clinical, and 4 both preclinical/clinical. Among preclinical studies, most studies used rodent CIPN models, of which 17% were tumor-bearing. Most preclinical studies investigated paclitaxel; none studied newer immune therapies. The 60 clinical studies were 53% observational and 47% interventional, focusing most frequently on breast cancer, unspecified cancers, and colorectal cancer diagnoses. Overall, 8% included patients <18 years, whereas a higher proportion included those 18-39 (85%), 40-64 (90%), and ≥65 (92%). Among 28 interventional trials, studies investigated behavioral interventions (39%), pharmacological agents (32%), and devices (29%). CONCLUSIONS The number of CIPN grants awarded by NIH since 2014 represents a substantial investment, but critical gaps and opportunities remain. Preclinically, novel strategies to mimic human CIPN may improve translatability. Important gaps in CIPN-associated cancer diagnoses and therapy exposures, including novel agents, would benefit from future research. Also, clinical studies are needed in young patients with potential long-term CIPN.
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Affiliation(s)
- Rachel D Altshuler
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - Lori M Minasian
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - Catherine A Schweppe
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - Nina S Kadan-Lottick
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
- Department of Oncology Cancer Prevention and Control Program, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, United States
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Jung Wu C, Ho YF, Bai LY, Wu CF, Chen TT, Wang YJ. Distinct Trajectories of Chemotherapy-Induced Peripheral Neuropathy in Lymphoma Survivors Treated With R-CHOP. Oncol Nurs Forum 2025; 52:191-204. [PMID: 40293933 PMCID: PMC12056829 DOI: 10.1188/25.onf.191-204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/10/2024] [Indexed: 04/30/2025]
Abstract
OBJECTIVES To explore the trajectories of chemotherapy-induced peripheral neuropathy (CIPN) in lymphoma survivors and assess subdomains of CIPN in this population. SAMPLE & SETTING 80 newly diagnosed lymphoma survivors treated with R-CHOP were enrolled. METHODS & VARIABLES CIPN was assessed before chemotherapy (T1), after the first chemotherapy cycle (T2), after the fourth chemotherapy cycle (T3), after the completion of chemotherapy (T4), and 10 weeks post-treatment (T5). CIPN was measured using the Total Neuropathy Score clinical version and the MD Anderson Symptom Inventory. RESULTS Patients were categorized into high and low CIPN groups based on CIPN changes over time. The high CIPN group was older and experienced significantly more severe sensory peripheral neuropathy from T1 to T5, with the most severe symptoms observed at T4, followed by T3 and T5. IMPLICATIONS FOR NURSING Healthcare providers should closely monitor older patients, those with pretreatment peripheral neuropathy symptoms, and those exhibiting pronounced sensory neuropathy during treatment to provide timely and effective symptom management, reducing the impact of CIPN.
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Thomsen MB, Singh A, Thebeau CN, Gao VD, Schulze NF, Avraham O, Yang SX, Koneru S, Geier SS, Landon SM, Pelea A, Cavalli V, Geisler S. Macrophage depletion restores the DRG microenvironment and prevents axon degeneration in bortezomib-induced neuropathy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634362. [PMID: 39896673 PMCID: PMC11785175 DOI: 10.1101/2025.01.22.634362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Peripheral neuropathy is a common and debilitating side effect of the chemotherapeutic bortezomib (BTZ). To explore the mechanisms underlying BTZ-induced neuropathy (BIPN), we developed a mouse model that replicates the route of administration and approximates the prolonged BTZ exposure experienced by patients. We find that male mice treated with BTZ experience more severe sensorimotor dysfunction and axon loss compared to females and observed similar results when analyzing human data. Using single cell RNA-sequencing, we reveal that BTZ significantly alters the dorsal root ganglia (DRG) microenvironment in mice, producing pronounced sex-specific changes in satellite glial cells (SGCs) in males and females and dysregulation of the extracellular matrix (ECM), particularly in males. These changes are accompanied by expansion of macrophages, which is more pronounced in males. We identify four macrophage subtypes in the DRG, including a pro-fibrotic population that is exclusively associated with BIPN. Depletion of macrophages via anti-CSF1R treatment in male mice prevents BTZ-induced SGC activation and aberrant collagen deposition in DRGs, potently preserves peripheral axons, and improves functional outcomes. These findings highlight SGCs, neuroinflammation and dysregulation of the ECM as drivers of sex-specific differences in BIPN and suggest that targeting neuroinflammation is a promising therapeutic strategy to treat this disease.
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Affiliation(s)
| | - Abhishek Singh
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Christina N. Thebeau
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Vivian D. Gao
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Nicholas F. Schulze
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Oshri Avraham
- Department of Neuroscience, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Sarah X. Yang
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Shriya Koneru
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Sami S. Geier
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Shannon M. Landon
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Aidan Pelea
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Valeria Cavalli
- Department of Neuroscience, Washington University School of Medicine in St. Louis; St. Louis, USA
- Hope Center for Neurological Diseases, Washington University School of Medicine in St. Louis; St. Louis, USA
- Center of Regenerative Medicine, Washington University School of Medicine in St. Louis; St. Louis, USA
| | - Stefanie Geisler
- Department of Neurology, Washington University School of Medicine in St. Louis; St. Louis, USA
- Hope Center for Neurological Diseases, Washington University School of Medicine in St. Louis; St. Louis, USA
- Siteman Cancer Center; St. Louis, USA
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Yang Y, Zhao B, Lan H, Sun J, Wei G. Bortezomib-induced peripheral neuropathy: Clinical features, molecular basis, and therapeutic approach. Crit Rev Oncol Hematol 2024; 197:104353. [PMID: 38615869 DOI: 10.1016/j.critrevonc.2024.104353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/01/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
Bortezomib is the first-line standard and most effective chemotherapeutic for multiple myeloma; however, bortezomib-induced peripheral neuropathy (BIPN) severely affects the chemotherapy regimen and has long-term impact on patients under maintenance therapy. The pathogenesis of BIPN is poorly understood, and basic research and development of BIPN management drugs are in early stages. Besides chemotherapy dose reduction and regimen modification, no recommended prevention and treatment approaches are available for BIPN apart from the International Myeloma Working Group guidelines for peripheral neuropathy in myeloma. An in-depth exploration of the pathogenesis of BIPN, development of additional therapeutic approaches, and identification of risk factors are needed. Optimizing effective and standardized BIPN treatment plans and providing more decision-making evidence for clinical diagnosis and treatment of BIPN are necessary. This article reviews the recent advances in BIPN research; provides an overview of clinical features, underlying molecular mechanisms, and therapeutic approaches; and highlights areas for future studies.
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Affiliation(s)
- Yang Yang
- Department of Oncology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China; Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Bing Zhao
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Lan
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinbing Sun
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China.
| | - Guoli Wei
- Department of Oncology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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Huo H, Zhou S, Xue Y, Mu X, Du N, Cao Z. Implementation of personalized multidisciplinary neuropathy management program for chemotherapy-induced peripheral neuropathy symptoms in breast cancer patients. Int J Neurosci 2024:1-8. [PMID: 38652002 DOI: 10.1080/00207454.2024.2347556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/20/2024] [Indexed: 04/25/2024]
Abstract
OBJECTIVE To construct a personalized multidisciplinary neurotoxicity management program for chemotherapy-induced peripheral neuropathy (CIPN) symptoms in breast cancer patients and evaluate its application effects. METHODS A retrospective analysis was conducted on clinical data of 133 breast cancer chemotherapy patients admitted to our hospital from January 2022 to January 2024. Based on the nursing protocols received, patients were divided into a control group (n = 66) and an intervention group (n = 67). The control group received conventional nursing interventions, while the intervention group received personalized nursing interventions in addition to the control group interventions. The nursing programs were carried out during chemotherapy. A comparison was made between the two groups before chemotherapy and 3 months after chemotherapy in terms of the degree of neuropathy, cancer-related fatigue, negative emotional status, and symptom management knowledge, attitudes, and practices (KAP). RESULTS The intervention group showed significantly lower neuropathy severity (FACT/GOG-Ntx), cancer-related fatigue (CFS), and negative emotions (PHQ-9, GAD-7) scores after chemotherapy compared to the control group (p < 0.05). Additionally, the intervention group exhibited higher scores for symptom management knowledge, beliefs, and behaviors (p < 0.05). CONCLUSION Personalized multidisciplinary neurotoxicity management program significantly improved neuropathy severity, reduced cancer-related fatigue and negative emotions, and enhanced symptom management knowledge, attitudes, and practices among breast cancer patients undergoing chemotherapy.
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Affiliation(s)
- Hongbo Huo
- Department of Breast Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shaoguang Zhou
- Department of Breast Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanyan Xue
- Department of Breast Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xinxin Mu
- Department of Breast Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Na Du
- Department of Breast Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhongru Cao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Araldi D, Khomula EV, Bonet IJM, Bogen O, Green PG, Levine JD. Role of pattern recognition receptors in chemotherapy-induced neuropathic pain. Brain 2024; 147:1025-1042. [PMID: 37787114 PMCID: PMC10907096 DOI: 10.1093/brain/awad339] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/25/2023] [Accepted: 09/12/2023] [Indexed: 10/04/2023] Open
Abstract
Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN.
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Affiliation(s)
- Dionéia Araldi
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Eugen V Khomula
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Ivan J M Bonet
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Oliver Bogen
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Paul G Green
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Jon D Levine
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
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Berry D, Ene J, Nathani A, Singh M, Li Y, Zeng C. Effects of Physical Cues on Stem Cell-Derived Extracellular Vesicles toward Neuropathy Applications. Biomedicines 2024; 12:489. [PMID: 38540102 PMCID: PMC10968089 DOI: 10.3390/biomedicines12030489] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/12/2024] [Accepted: 02/17/2024] [Indexed: 11/28/2024] Open
Abstract
The peripheral nervous system undergoes sufficient stress when affected by diabetic conditions, chemotherapeutic drugs, and personal injury. Consequently, peripheral neuropathy arises as the most common complication, leading to debilitating symptoms that significantly alter the quality and way of life. The resulting chronic pain requires a treatment approach that does not simply mask the accompanying symptoms but provides the necessary external environment and neurotrophic factors that will effectively facilitate nerve regeneration. Under normal conditions, the peripheral nervous system self-regenerates very slowly. The rate of progression is further hindered by the development of fibrosis and scar tissue formation, which does not allow sufficient neurite outgrowth to the target site. By incorporating scaffolding supplemented with secretome derived from human mesenchymal stem cells, it is hypothesized that neurotrophic factors and cellular signaling can facilitate the optimal microenvironment for nerve reinnervation. However, conventional methods of secretory vesicle production are low yield, thus requiring improved methods to enhance paracrine secretions. This report highlights the state-of-the-art methods of neuropathy treatment as well as methods to optimize the clinical application of stem cells and derived secretory vesicles for nerve regeneration.
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Affiliation(s)
- Danyale Berry
- Department of Industrial and Manufacturing Engineering, FAMU-FSU College of Engineering, Florida Agricultural and Mechanical University, Tallahassee, FL 32310, USA;
- High Performance Materials Institute, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 23210, USA
| | - Justice Ene
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32310, USA;
| | - Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA; (A.N.); (M.S.)
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL 32307, USA; (A.N.); (M.S.)
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32310, USA;
| | - Changchun Zeng
- Department of Industrial and Manufacturing Engineering, FAMU-FSU College of Engineering, Florida Agricultural and Mechanical University, Tallahassee, FL 32310, USA;
- High Performance Materials Institute, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 23210, USA
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Akhilesh, Uniyal A, Mehta A, Tiwari V. Combination chemotherapy in rodents: a model for chemotherapy-induced neuropathic pain and pharmacological screening. Metab Brain Dis 2024; 39:43-65. [PMID: 37991674 DOI: 10.1007/s11011-023-01315-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/09/2023] [Indexed: 11/23/2023]
Abstract
Chemotherapy-induced neuropathic pain (CINP) remains a therapeutic challenge, with no US-FDA approved drugs or effective treatments available. Despite significant progress in unravelling the pathophysiology of CINP, the clinical translation of this knowledge into tangible outcome remains elusive. Here, we employed behavioural and pharmacological approaches to establish and validate a novel combination-based chemotherapeutic model of peripheral neuropathy. Male Sprague Dawley rats were subjected to chemotherapy administration followed by assessment of pain behaviour at different time-points post-chemotherapy. Paclitaxel-treated animals displayed an enhanced thermal and mechanical hypersensitivity from day four onwards which continued till day thirty-five post last paclitaxel injection. Notably, rats subjected to combination chemotherapy, displayed prolonged hypersensitivity that emerged on day four and persisted until day fifty-six. RT-PCR analysis revealed significant upregulation in DRG and spinal mRNA expressions of TRP channels (TRPA1, TRPV1, & TRPM8), pro-inflammatory cytokines (TNF-α & IL-1β) and neuropeptides, Substance P and CGRP in both the pain models. Interestingly, the combination chemotherapy model demonstrated a significant increase in DRG and spinal NR2B expressions compared to rats solely treated with paclitaxel. Pharmacological investigations revealed that gabapentin treatment substantially mitigates pain hypersensitivity in both the combined chemotherapy and paclitaxel-administered groups, with the simultaneous reversal of cellular and molecular changes observed in the lumbar DRG and spinal cord of rats. The findings from this study suggests that combination chemotherapy model exhibits heightened and prolonged hypersensitivity in comparison to the conventional paclitaxel-induced neuropathic pain model. This model not only recapitulates clinical biomarkers of neuropathy but also presents a potential alternative platform for screening analgesic drugs targeted at CINP.
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Affiliation(s)
- Akhilesh
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India
| | - Ankit Uniyal
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India
| | - Anuj Mehta
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India
| | - Vinod Tiwari
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India.
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de Miranda Drummond PL, Dos Santos RMM, Silveira LP, Malta JS, Moreira Reis AM, Costa NL, de Paula E Silva RO, Fagundes EM, de Pádua CAM. Chemotherapy-Induced Peripheral Neuropathy Impacts Quality of Life and Activities of Daily Living of Brazilian Multiple Myeloma Patients. Curr Drug Saf 2024; 19:356-367. [PMID: 37592770 DOI: 10.2174/1574886318666230817162424] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 07/04/2023] [Accepted: 07/13/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapyinduced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health- Related Quality of Life (HRQoL) and activities of daily living (ADL). OBJECTIVE We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL. METHODS This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables. RESULTS In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL. CONCLUSION MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities.
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Affiliation(s)
- Paula Lana de Miranda Drummond
- Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Ezequiel Dias Foundation, Regulatory Affairs, Belo Horizonte, Brazil
| | | | - Lívia Pena Silveira
- Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jéssica Soares Malta
- Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Naiane Lima Costa
- Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Sohn SY, San TT, Kim J, Kim HJ. Bortezomib Is Toxic but Induces Neurogenesis and Inhibits TUBB3 Degradation in Rat Neural Stem Cells. Biomol Ther (Seoul) 2024; 32:65-76. [PMID: 38072501 PMCID: PMC10762278 DOI: 10.4062/biomolther.2023.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/17/2023] [Accepted: 10/25/2023] [Indexed: 12/28/2023] Open
Abstract
Bortezomib (BTZ) is a proteasome inhibitor used to treat multiple myeloma (MM). However, the induction of peripheral neuropathy is one of the major concerns in using BTZ to treat MM. In the current study, we have explored the effects of BTZ (0.01-5 nM) on rat neural stem cells (NSCs). BTZ (5 nM) induced cell death; however, the percentage of neurons was increased in the presence of mitogens. BTZ reduced the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein ratio in proliferating NSCs and differentiated cells. Inhibition of βIII-tubulin (TUBB3) degradation was observed, but not inhibition of glial fibrillary acidic protein degradation, and a potential PEST sequence was solely found in TUBB3. In the presence of growth factors, BTZ increased cAMP response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (Bdnf) transcription, BDNF expression, and Tubb3 transcription in NSCs. However, in the neuroblastoma cell line, SH-SY5Y, BTZ (1-20 nM) only increased cell death without increasing CREB phosphorylation, Bdnf transcription, or TUBB3 induction. These results suggest that although BTZ induces cell death, it activates neurogenic signals and induces neurogenesis in NSCs.
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Affiliation(s)
- Seung Yeon Sohn
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Thin Thin San
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Junhyung Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyun-Jung Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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Balayssac D, Durif J, Lambert C, Dalbos C, Chapuy E, Etienne M, Demiot C, Busserolles J, Martin V, Sapin V. Exploring Serum Biomarkers for Neuropathic Pain in Rat Models of Chemotherapy-Induced Peripheral Neuropathy: A Comparative Pilot Study with Oxaliplatin, Paclitaxel, Bortezomib, and Vincristine. TOXICS 2023; 11:1004. [PMID: 38133405 PMCID: PMC10747971 DOI: 10.3390/toxics11121004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023]
Abstract
Blood biomarkers, including neurofilament light chain (NfL), have garnered attention as potential indicators for chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting adverse effect of neurotoxic anticancer drugs. However, no blood biomarker has been established for routine application or translational research. This pilot study aimed to evaluate a limited panel of blood biomarkers in rat models of CIPN and their correlations with neuropathic pain. CIPN models were induced through repeated injections of oxaliplatin, paclitaxel, bortezomib, and vincristine. Electronic von Frey testing was used to assess tactile allodynia. Post anticancer injections, serum concentrations of 31 proteins were measured. Allodynia thresholds decreased in anticancer-treated animals compared to controls. No consistent modifications were observed in the biomarkers across CIPN models. The most noteworthy biomarkers with increased concentrations in at least two CIPN models were NfL (paclitaxel, vincristine), MCP-1, and RANTES (oxaliplatin, vincristine). Vincristine-treated animals exhibited strong correlations between LIX, MCP-1, NfL, and VEGF concentrations and tactile allodynia thresholds. No single biomarker can be recommended as a unique indicator of CIPN-related pain. Because of the study limitations (single dose of each anticancer drug, young animals, and single time measurement of biomarkers), further investigations are necessary to define the kinetics, specificities, and sensitivities of MCP-1, RANTES, and NfL.
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Affiliation(s)
- David Balayssac
- Direction de la Recherche Clinique et de l’Innovation, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (C.D.); (E.C.); (J.B.)
| | - Julie Durif
- Laboratoire de Biochimie et de Génétique Moléculaire, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France;
| | - Céline Lambert
- Unité de Biostatistiques, Direction de la Recherche Clinique et de l’Innovation, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France;
| | - Cristelle Dalbos
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (C.D.); (E.C.); (J.B.)
| | - Eric Chapuy
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (C.D.); (E.C.); (J.B.)
| | - Monique Etienne
- Metabolic Adaptations to Exercise under Physiological and Pathological Conditions (AME2P), Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (M.E.)
| | - Claire Demiot
- UR 20218—Neuropathies et Innovations Thérapeutiques (NeurIT), Faculties of Medicine and Pharmacy, University of Limoges, F-87025 Limoges, France;
| | - Jérôme Busserolles
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (C.D.); (E.C.); (J.B.)
| | - Vincent Martin
- Metabolic Adaptations to Exercise under Physiological and Pathological Conditions (AME2P), Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; (M.E.)
- Institut Universitaire de France (IUF), F-75000 Paris, France
| | - Vincent Sapin
- Laboratoire de Biochimie et de Génétique Moléculaire, CNRS, INSERM, iGReD, CHU Clermont-Ferrand, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France;
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Kuang Y, Ding Q, Huang J, Yang S, Yao A, Yang X, Xiao M, Pei Q, Yang G. Pharmacokinetics, safety, and efficacy of GM1 ganglioside in healthy subjects and patients with multiple myeloma: Two dose-escalation studies. Eur J Pharm Sci 2023; 190:106565. [PMID: 37586437 DOI: 10.1016/j.ejps.2023.106565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/06/2023] [Accepted: 08/13/2023] [Indexed: 08/18/2023]
Abstract
PURPOSE This study aimed to assess the pharmacokinetics, safety, and efficacy of GM1 in healthy Chinese subjects and patients with multiple myeloma. METHODS The data used in this study was derived from two dose-escalation trials: GM1-101, involving 70 healthy subjects, and GM1-201, which included 160 multiple myeloma patients. Population pharmacokinetics (PopPK) analysis was conducted on a subset of 90 participants using a nonlinear mixed-effects approach, and potential covariates were explored quantitatively. Observations of any abnormalities in vital signs, physical examinations, laboratory tests, and electrocardiograms during the study period, along with any spontaneously reported and directly observed adverse events, were documented for safety evaluation. Furthermore, neurotoxicity scales were used to assess the efficacy of GM1 as a prophylaxis for chemotherapy-induced peripheral neuropathy and to perform exposure-response analyses in conjunction with pharmacokinetic parameters. RESULTS A one-compartment model with first-order elimination best characterized the pharmacokinetics of GM1. The clearance and volume of distribution, as estimated by the final model, were 0.0942 L/h and 3.27 L for GM1-A, and 0.0714 L/h and 2.82 L for GM1-B, respectively. Covariates such as sex, body weight, and albumin significantly influenced pharmacokinetic parameters, yet the variation in steady-state exposure between subjects and reference subjects was less than 45% within their 90% confidence interval. Adverse reactions related to GM1 occurred in 20 (28.6%) and 57 (35.6%) subjects in the GM1-101 and GM1-201 cohorts, respectively. The changes in TNSc and FACT-Ntx scores from baseline at the end of periods 4 and 6 were lower in each GM1 dose group compared to the blank control group. The 400 mg dose group of GM1 displayed greater effectiveness than other dose groups. However, exposure-response analysis revealed no significant modification in efficacy with increasing GM1 exposure. CONCLUSIONS This study provides the first population pharmacokinetic analysis of GM1. GM1 exhibits a favorable safety profile among healthy subjects and patients with multiple myeloma. GM1 proved effective in mitigating chemotherapy-induced peripheral neuropathy, but this study observed no significant correlation between its efficacy and exposure. TRIAL REGISTRATION NUMBERS ChiCTR2000041283 and ChiCTR2000041283.
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Affiliation(s)
- Yun Kuang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - Qin Ding
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - Jie Huang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - Shuang Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - An Yao
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - Xiaoyan Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China
| | - Min Xiao
- Drug Evaluation and Adverse Drug Reaction Monitoring Center of Hunan, Changsha, China
| | - Qi Pei
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China.
| | - Guoping Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China; Department of Pharmacy, The Third Xiangya Hospital, Central South University, 172 Tongzipo Road, Changsha 410013, China; National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology, Changsha, China.
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Zeng L, Huang H, Qirong C, Ruan C, Liu Y, An W, Guo Q, Zhou J. Multiple myeloma patients undergoing chemotherapy: Which symptom clusters impact quality of life? J Clin Nurs 2023; 32:7247-7259. [PMID: 37303229 DOI: 10.1111/jocn.16791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 04/12/2023] [Accepted: 05/30/2023] [Indexed: 06/13/2023]
Abstract
AIMS AND OBJECTIVES To identify symptom clusters and examine their association with health-related quality of life. BACKGROUND Multiple myeloma patients undergoing chemotherapy suffer from disease symptoms and adverse effects during the course of the disease. However, single symptom management has little effect, and symptom management for these patients remains challenging. Symptom clusters open a new perspective and provide important clues for symptom management. DESIGN A cross-sectional study. METHOD Participants were invited to complete the Chinese version of the Memorial Symptom Assessment Scale and Quality of Life Questionnaire-core 30. Appropriate indicators were used for descriptive statistics. Principal component analysis was used to identify symptom clusters. Associations between symptom clusters and quality of life were examined with Pearson correlation coefficients, Pearson correlation matrix and multiple linear regression. This study was reported following the STROBE checklist. RESULTS A total of 177 participants were recruited from seven hospitals in this study. We identified self-image disorder, psychological, gastrointestinal, neurological, somatic and pain symptom clusters in multiple myeloma patients with chemotherapy. Approximately 97.65% of patients suffer from multiple symptom clusters. The pain, psychological and gastrointestinal symptom clusters have negatively influence on health-related quality of life. The strongest association was found with the pain symptom cluster. CONCLUSION Most of multiple myeloma patients suffer from multiple symptom clusters. When improving the multiple myeloma patients' health-related quality of life, the clinical staff should prioritise relieving the pain symptom cluster. RELEVANCE TO CLINICAL PRACTICE When multiple myeloma patients undergoing chemotherapy suffer from multiple symptom clusters, nurses should prioritise relieving the pain symptom cluster to improve their health-related quality of life. When drawing up and providing interventions, nurses should focus on the correlation among symptoms rather than single symptom. By relieving one symptom in a given cluster, other symptoms within the same symptom cluster may also be relieved.
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Affiliation(s)
- Lihong Zeng
- Xiangya School of Nursing, Central South University, Changsha, China
| | - Hui Huang
- The Third Xiangya Hospital, Central South University, Changsha, China
| | - Chen Qirong
- Xiangya School of Nursing, Central South University, Changsha, China
| | - Chunhong Ruan
- The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yaqi Liu
- The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wenhong An
- School of Health and Wellness, Panzhihua University, Sichuan, China
| | - Qinqin Guo
- Xiangya School of Nursing, Central South University, Changsha, China
| | - Jiandang Zhou
- The Third Xiangya Hospital, Central South University, Changsha, China
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McEvoy L, Cliff J, Carr DF, Jorgensen A, Lord R, Pirmohamed M. CYP3A genetic variation and taxane-induced peripheral neuropathy: a systematic review, meta-analysis, and candidate gene study. Front Pharmacol 2023; 14:1178421. [PMID: 37469869 PMCID: PMC10352989 DOI: 10.3389/fphar.2023.1178421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/21/2023] [Indexed: 07/21/2023] Open
Abstract
Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Methods: A systematic review identified 12 pharmacogenetic studies investigating genetic variation in CYP3A4*22 and CYP3A5*3 and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for CYP3A4*22 and CYP3A5*3. Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible. Results: In the systematic review, no significant association was found between CYP3A5*3 and TIPN in seven studies, with one study reporting a protective association. For CYP3A4*22, one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel (p < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP (CYP3A5*3 and CYP3A4*22) and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status. Summary: We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size.
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Affiliation(s)
- Laurence McEvoy
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Joanne Cliff
- Clatterbridge Cancer Centre, Liverpool, United Kingdom
| | - Daniel F Carr
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Andrea Jorgensen
- Health Data Science, University of Liverpool, Liverpool, United Kingdom
| | - Rosemary Lord
- Clatterbridge Cancer Centre, Liverpool, United Kingdom
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
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Wang T, Lu Q, Tang L. Assessment tools for patient-reported outcomes in multiple myeloma. Support Care Cancer 2023; 31:431. [PMID: 37389673 DOI: 10.1007/s00520-023-07902-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/23/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Patients with multiple myeloma experience severe symptom burden. Patient participation in self-reporting is essential as medical staff's assessment of patient symptom severity is often lower than patient self-reporting. This article reviews patient-reported outcome (PRO) assessment tools and their application in the field of multiple myeloma. RESULTS The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is the universal patient-reported outcome assessment tool most frequently used to evaluate the life quality in people with multiple myeloma. Among the specific patient-reported outcome assessment tools, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Multiple Myeloma Module (EORTC QLQ-MY20), the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM), and the M.D. Anderson Symptom Inventory-Multiple Myeloma Module (MDASI-MM) are the most widely used, with some scholars using the EORTC QLQ-MY20 as a calibration correlate for scale development. Most current assessment instruments were developed using classical measurement theory methods; future researchers could combine classic theory tests and item response theory to create scientific assessment instruments. In addition, researchers select the appropriate assessment tool based on the purpose of the study. They can translate high-quality assessment tools into different languages and consider applying them more often to assessing multiple myeloma patients. Finally, most existing PROs focus on measuring life quality and symptoms in people with multiple myeloma, with less research on outcomes such as adherence and satisfaction, thus failing to comprehensively evaluate the patient treatment and disease management. CONCLUSIONS Research has shown that the field of PROs in multiple myeloma is in an exploratory phase. There is still a need to enrich the content of PROs and develop more high-quality PRO scales for multiple myeloma based on the strengths and weaknesses of existing tools. With the successful advancement of information technology, PROs for people with multiple myeloma could be integrated with electronic information systems, allowing patients to report their health status in real time and doctors to track their condition and adjust their treatment, thereby improving patient outcomes.
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Affiliation(s)
- Ting Wang
- Department of Haematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China
| | - Qin Lu
- Department of Haematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China
| | - LeiWen Tang
- Department of Nursing, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China.
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Mao J, Chao K, Jiang FL, Ye XP, Yang T, Li P, Zhu X, Hu PJ, Zhou BJ, Huang M, Gao X, Wang XD. Comparison and development of machine learning for thalidomide-induced peripheral neuropathy prediction of refractory Crohn’s disease in Chinese population. World J Gastroenterol 2023; 29:3855-3870. [PMID: 37426324 PMCID: PMC10324537 DOI: 10.3748/wjg.v29.i24.3855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/07/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease (CD). However, thalidomide-induced peripheral neuropathy (TiPN), which has a large individual variation, is a major cause of treatment failure. TiPN is rarely predictable and recognized, especially in CD. It is necessary to develop a risk model to predict TiPN occurrence.
AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.
METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model. The National Cancer Institute Common Toxicity Criteria Sensory Scale (version 4.0) was used to assess TiPN. With 18 clinical features and 150 genetic variables, five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), specificity, sensitivity (recall rate), precision, accuracy, and F1 score.
RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248 [P = 0.0004, odds ratio (OR): 8.983, 95% confidence interval (CI): 2.497-30.90], dose (mg/d, P = 0.002), brain-derived neurotrophic factor (BDNF) rs2030324 (P = 0.001, OR: 3.164, 95%CI: 1.561-6.434), BDNF rs6265 (P = 0.001, OR: 3.150, 95%CI: 1.546-6.073) and BDNF rs11030104 (P = 0.001, OR: 3.091, 95%CI: 1.525-5.960). In the training set, gradient boosting decision tree (GBDT), extremely random trees (ET), random forest, logistic regression and extreme gradient boosting (XGBoost) obtained AUROC values > 0.90 and AUPRC > 0.87. Among these models, XGBoost and GBDT obtained the first two highest AUROC (0.90 and 1), AUPRC (0.98 and 1), accuracy (0.96 and 0.98), precision (0.90 and 0.95), F1 score (0.95 and 0.98), specificity (0.94 and 0.97), and sensitivity (1). In the validation set, XGBoost algorithm exhibited the best predictive performance with the highest specificity (0.857), accuracy (0.818), AUPRC (0.86) and AUROC (0.89). ET and GBDT obtained the highest sensitivity (1) and F1 score (0.8). Overall, compared with other state-of-the-art classifiers such as ET, GBDT and RF, XGBoost algorithm not only showed a more stable performance, but also yielded higher ROC-AUC and PRC-AUC scores, demonstrating its high accuracy in prediction of TiPN occurrence.
CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables. With the ability to identify high-risk patients using single nucleotide polymorphisms, it offers a feasible option for improving thalidomide efficacy in CD patients.
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Affiliation(s)
- Jing Mao
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Fu-Lin Jiang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xiao-Ping Ye
- Department of Pharmacy, Guangdong Women and Children Hospital, Guangzhou 510000, Guangdong Province, China
| | - Ting Yang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Pan Li
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xia Zhu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Pin-Jin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Bai-Jun Zhou
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
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Wang SH, Huang SH, Hsieh MC, Lu IC, Chou PR, Tai MH, Wu SH. Hyperbaric Oxygen Therapy Alleviates Paclitaxel-Induced Peripheral Neuropathy Involving Suppressing TLR4-MyD88-NF-κB Signaling Pathway. Int J Mol Sci 2023; 24:ijms24065379. [PMID: 36982452 PMCID: PMC10049379 DOI: 10.3390/ijms24065379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/06/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
Paclitaxel (PAC) results in long-term chemotherapy-induced peripheral neuropathy (CIPN). The coexpression of transient receptor potential vanilloid 1 (TRPV1) and Toll-like receptor 4 (TLR4) in the nervous system plays an essential role in mediating CIPN. In this study, we used a TLR4 agonist (lipopolysaccharide, LPS) and a TLR4 antagonist (TAK-242) in the CIPN rat model to investigate the role of TLR4-MyD88 signaling in the antinociceptive effects of hyper-baric oxygen therapy (HBOT). All rats, except a control group, received PAC to induce CIPN. Aside from the PAC group, four residual groups were treated with either LPS or TAK-242, and two of them received an additional one-week HBOT (PAC/LPS/HBOT and PAC/TAK-242/HBOT group). Mechanical allodynia and thermal hyperalgesia were then assessed. The expressions of TRPV1, TLR4 and its downstream signaling molecule, MyD88, were investigated. The mechanical and thermal tests revealed that HBOT and TAK-242 alleviated behavioral signs of CIPN. Immunofluorescence in the spinal cord dorsal horn and dorsal root ganglion revealed that TLR4 overexpression in PAC- and PAC/LPS-treated rats was significantly downregulated after HBOT and TAK-242. Additionally, Western blots showed a significant reduction in TLR4, TRPV1, MyD88 and NF-κB. Therefore, we suggest that HBOT may alleviate CIPN by modulating the TLR4-MyD88-NF-κB pathway.
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Affiliation(s)
- Shih-Hung Wang
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Shu-Hung Huang
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung 812, Taiwan
| | - Meng-Chien Hsieh
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
| | - I-Cheng Lu
- Department of Anesthesiology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung 812, Taiwan
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ping-Ruey Chou
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Sheng-Hua Wu
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Anesthesiology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
- Correspondence:
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Côté J, Kotb R, Bergstrom DJ, LeBlanc R, Mian HS, Othman I, Louzada ML. First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:340-354. [PMID: 36925389 DOI: 10.1016/j.clml.2023.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/14/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.
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Affiliation(s)
- Julie Côté
- Centre hospitalier universitaire de Québec, Quebec, QC, Canada.
| | - Rami Kotb
- CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | | | - Richard LeBlanc
- Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Hira S Mian
- Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
| | - Ibraheem Othman
- Allan Blair Cancer Centre, University of Saskatchewan, Regina, SK, Canada
| | - Martha L Louzada
- London Health Sciences Centre, Western University, London, ON, Canada
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Snijders RAH, Brom L, Theunissen M, van den Beuken-van Everdingen MHJ. Update on Prevalence of Pain in Patients with Cancer 2022: A Systematic Literature Review and Meta-Analysis. Cancers (Basel) 2023; 15:591. [PMID: 36765547 PMCID: PMC9913127 DOI: 10.3390/cancers15030591] [Citation(s) in RCA: 137] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Experiencing pain and insufficient relief can be devastating and negatively affect a patient's quality of life. Developments in oncology such as new treatments and adjusted pain management guidelines may have influenced the prevalence of cancer pain and severity in patients. This review aims to provide an overview of the prevalence and severity of pain in cancer patients in the 2014-2021 literature period. A systematic literature search was performed using the databases PubMed, Embase, CINAHL, and Cochrane. Titles and abstracts were screened, and full texts were evaluated and assessed on methodological quality. A meta-analysis was performed on the pooled prevalence and severity rates. A meta-regression analysis was used to explore differences between treatment groups. We identified 10,637 studies, of which 444 studies were included. The overall prevalence of pain was 44.5%. Moderate to severe pain was experienced by 30.6% of the patients, a lower proportion compared to previous research. Pain experienced by cancer survivors was significantly lower compared to most treatment groups. Our results imply that both the prevalence of pain and pain severity declined in the past decade. Increased attention to the assessment and management of pain might have fostered the decline in the prevalence and severity of pain.
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Affiliation(s)
- Rolf A. H. Snijders
- Netherlands Comprehensive Cancer Organisation (IKNL), Department of Research & Development, 3511 DT Utrecht, The Netherlands
- Netherlands Association for Palliative Care (PZNL), 3511 DT Utrecht, The Netherlands
| | - Linda Brom
- Netherlands Comprehensive Cancer Organisation (IKNL), Department of Research & Development, 3511 DT Utrecht, The Netherlands
- Netherlands Association for Palliative Care (PZNL), 3511 DT Utrecht, The Netherlands
| | - Maurice Theunissen
- Centre of Expertise for Palliative Care, Maastricht University Medical Centre+ (MUMC+), 6229 HX Maastricht, The Netherlands
- Department of Anaesthesiology and Pain Management, Maastricht University Medical Centre+ (MUMC+), 6229 HX Maastricht, The Netherlands
| | - Marieke H. J. van den Beuken-van Everdingen
- Centre of Expertise for Palliative Care, Maastricht University Medical Centre+ (MUMC+), 6229 HX Maastricht, The Netherlands
- Department of Anaesthesiology and Pain Management, Maastricht University Medical Centre+ (MUMC+), 6229 HX Maastricht, The Netherlands
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20
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Major A, Jakubowiak A, Derman B. Longitudinal Real-World Neuropathy and Patient-Reported Outcomes With Bortezomib and Lenalidomide in Newly Diagnosed Multiple Myeloma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e1000-e1008. [PMID: 35922273 DOI: 10.1016/j.clml.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/01/2022] [Accepted: 07/06/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Peripheral neuropathy is a common treatment-emergent side effect during the treatment of newly diagnosed multiple myeloma. Although bortezomib is most commonly implicated, real-world data suggest that lenalidomide and dexamethasone (VRd) and autologous stem cell transplantation (ASCT) may also contribute to neuropathy and health-related quality of life (HRQoL). METHODS The Multiple Myeloma Research Foundation (MMRF) CoMMpass Registry was queried for all patients who received frontline VRd or bortezomib, cyclophosphamide and dexamethasone (VCd). Incidence of neuropathy and patient-reported HRQoL outcomes over the first 12 months after diagnosis were compared between patients receiving VRd or VCd with or without early ASCT before 6 months. RESULTS There were 368 and 191 patients treated with VRd and VCd, respectively. VRd with early ASCT was associated with worse grade 1 neuropathy compared to VRd without early ASCT, as well as compared to VCd with early ASCT. There were no differences in neuropathy between VRd and VCd without early ASCT, and no differences in grade ≥2 neuropathy. There were significant improvements in HRQoL between baseline and 12 months in both VRd and VCd cohorts, regardless of early ASCT. Development of neuropathy was not associated with decrements in progression-free survival or overall survival. CONCLUSIONS In this longitudinal database analysis, there were no differences in grade ≥2 neuropathy between VRd and VCd frontline induction, and overall HRQoL significantly improved across all cohorts. However, differences in grade 1 neuropathy between VRd and VCd induction suggest that lenalidomide and high-dose melphalan may augment the risk of neuropathy in newly diagnosed multiple myeloma.
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Affiliation(s)
- Ajay Major
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL.
| | - Andrzej Jakubowiak
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Benjamin Derman
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
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21
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Kerckhove N, Tougeron D, Lepage C, Pezet D, Le Malicot K, Pelkowski M, Pereira B, Balayssac D. Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy: DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial. BMC Cancer 2022; 22:742. [PMID: 35799138 PMCID: PMC9264497 DOI: 10.1186/s12885-022-09806-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer's disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. METHODS The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming's one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. DISCUSSION This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. TRIAL REGISTRATION NCT05254639 , clincialtrials.gov, Registered 24 February 2022.
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Affiliation(s)
- Nicolas Kerckhove
- UMR 1107 NEURODOL, service de pharmacologie médicale, CHU Clermont-Ferrand, Université Clermont Auvergne, INSERM, 63000, Clermont-Ferrand, France.
| | - David Tougeron
- Service d'Hépato gastroentérologie, CHU Poitiers, 86000, Poitiers, France
| | - Côme Lepage
- Service d'Hépatogastroentérologie et oncologie digestive, CHU Dijon, Université de Bourgogne, Dijon, France
- UMR LNC 1231, EPICAD INSERM, Université de Bourgogne, Dijon, France
| | - Denis Pezet
- Service de chirurgie digestive, U1071, M2iSH, USC-INRA 2018, CHU Clermont-Ferrand, Université Clermont Auvergne, INSERM, INRA, 63000, Clermont-Ferrand, France
| | - Karine Le Malicot
- UMR LNC 1231, EPICAD INSERM, Université de Bourgogne, Dijon, France
- Fédération Francophone de Cancérologie Digestive (FFCD), 21079, Dijon, France
| | - Manon Pelkowski
- UMR LNC 1231, EPICAD INSERM, Université de Bourgogne, Dijon, France
- Fédération Francophone de Cancérologie Digestive (FFCD), 21079, Dijon, France
| | - Bruno Pereira
- Direction de la recherche clinique et de l'innovation, CHU Clermont-Ferrand, 63000, Clermont-Ferrand, France
| | - David Balayssac
- UMR 1107 NEURODOL, service de pharmacologie médicale, CHU Clermont-Ferrand, Université Clermont Auvergne, INSERM, 63000, Clermont-Ferrand, France
- Direction de la recherche clinique et de l'innovation, CHU Clermont-Ferrand, 63000, Clermont-Ferrand, France
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22
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Non-Pharmacological Self-Management Strategies for Chemotherapy-Induced Peripheral Neuropathy in People with Advanced Cancer: A Systematic Review and Meta-Analysis. Nutrients 2022; 14:nu14122403. [PMID: 35745132 PMCID: PMC9228711 DOI: 10.3390/nu14122403] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/12/2022] [Accepted: 06/07/2022] [Indexed: 02/01/2023] Open
Abstract
Non-pharmacological self-management interventions for chemotherapy-induced peripheral neurotherapy (CIPN) are of clinical interest; however, no systematic review has synthesized the evidence for their use in people with advanced cancer. Five databases were searched from inception to February 2022 for randomized controlled trials assessing the effect of non-pharmacological self-management interventions in people with advanced cancer on the incidence and severity of CIPN symptoms and related outcomes compared to any control condition. Data were pooled with meta-analysis. Quality of evidence was appraised using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2), with data synthesized narratively. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was applied to assess the certainty of the evidence. Thirteen studies were included, which had a high (69%) or unclear (31%) risk of bias. Greatest confidence was found for physical exercise decreasing CIPN severity (SMD: −0.89, 95% CI: −1.37 to −0.41; p = 0.0003; I2 = 0%; n = 2 studies, n = 76 participants; GRADE level: moderate) and increasing physical function (SMD: 0.51, 95% CI: 0.02 to 1.00; p = 0.04; I2 = 42%; n = 3 studies, n = 120; GRADE level: moderate). One study per intervention provided preliminary evidence for the positive effects of glutamine supplementation, an Omega-3 PUFA-enriched drink, and education for symptom self-management via a mobile phone game on CIPN symptoms and related outcomes (GRADE: very low). No serious adverse events were reported. The strongest evidence with the most certainty was found for physical exercise as a safe and viable adjuvant to chemotherapy treatment for the prevention and management of CIPN and related physical function in people with advanced cancer. However, the confidence in the evidence to inform conclusions was mostly very low to moderate. Future well-powered and appropriately designed interventions for clinical trials using validated outcome measures and clearly defined populations and strategies are warranted.
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23
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Selvy M, Mattévi C, Dalbos C, Aissouni Y, Chapuy E, Martin PY, Collin A, Richard D, Dumontet C, Busserolles J, Condé S, Balayssac D. Analgesic and preventive effects of donepezil in animal models of chemotherapy-induced peripheral neuropathy: Involvement of spinal muscarinic acetylcholine M2 receptors. Biomed Pharmacother 2022; 149:112915. [PMID: 35635358 DOI: 10.1016/j.biopha.2022.112915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/25/2022] [Accepted: 03/30/2022] [Indexed: 11/02/2022] Open
Abstract
BACKGROUND Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN. METHODS using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities. The involvement of muscarinic M2 acetylcholine receptors (m2AChRs) in analgesic effects was investigated at the spinal level. The absence of interference of donepezil with the cytotoxic effect of chemotherapy has been controlled in cancer cell lines. RESULTS the analgesic efficacy of donepezil was demonstrated for all CIPN models, mainly on tactile hypersensitivity (maximal efficacy at 60 min, p < 0.05 vs. vehicle group). This effect was suppressed by an intrathecal injection of methoctramine (m2AChR antagonist). Regarding preventive effects, donepezil limited tactile hypersensitivity induced by paclitaxel, but not for other CIPN models. Donepezil did not modify the viability of cancer cells or the efficacy of anticancer drugs. CONCLUSIONS donepezil had a broad analgesic effect on animal models of CIPN and this effect involved spinal m2AChRs. This work validates the repositioning of donepezil in the management of CIPN.
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Affiliation(s)
- Marie Selvy
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Chirurgie et d'oncologie digestive, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Catherine Mattévi
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Chirurgie et d'oncologie digestive, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Cristelle Dalbos
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Youssef Aissouni
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Eric Chapuy
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Pierre-Yves Martin
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Aurore Collin
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Damien Richard
- CHU Clermont-Ferrand, Laboratoire de Pharmacologie et de Toxicologie, Clermont-Ferrand F-63000, France.
| | - Charles Dumontet
- Cancer Research Center of Lyon (CRCL), Inserm 1052/CNRS, Université de Lyon, France - Hospices Civils de Lyon, Lyon 69000, France.
| | - Jérôme Busserolles
- Université Clermont Auvergne, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - Sakahlé Condé
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Neurologie, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
| | - David Balayssac
- Université Clermont Auvergne, CHU Clermont-Ferrand, Délégation à la Recherche Clinique et à l'Innovation, INSERM U1107 NEURO-DOL, Clermont-Ferrand F-63000, France.
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24
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Huehnchen P, Schinke C, Bangemann N, Dordevic AD, Kern J, Maierhof SK, Hew L, Nolte L, Körtvelyessy P, Göpfert JC, Ruprecht K, Somps CJ, Blohmer JU, Sehouli J, Endres M, Boehmerle W. Neurofilament proteins as potential biomarker in chemotherapy-induced polyneuropathy. JCI Insight 2022; 7:154395. [PMID: 35133982 PMCID: PMC8986065 DOI: 10.1172/jci.insight.154395] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 02/02/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. As sensory symptoms are challenging to assess objectively in clinical routine, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as translational surrogate marker for CIPN. METHODS NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSN) to paclitaxel. Breast and ovarian cancer patients undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced, which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single molecule array technology (SIMOA). RESULTS NFL is released from iPSC-DSN upon paclitaxel incubation in a dose- and time-dependent manner and inversely correlates with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in chemotherapy patients without CIPN or controls, resulting in an 86 % sensitivity and 87 % specificity. A NFLs increase of +36 pg/ml from baseline was associated with a predicted CIPN probability of >0.5. CONCLUSION NFLs correlates with CIPN development and severity, which may guide neurotoxic chemotherapy in the future. TRIAL REGISTRATION NCT02753036FUNDING. DFG (EXC 257 NeuroCure), BMBF (01 EO 0801), AnimalFreeResearch Organization, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283).
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Affiliation(s)
- Petra Huehnchen
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Schinke
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Nikola Bangemann
- Gynecology and Systemic Gynecology, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany
| | - Adam D Dordevic
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Johannes Kern
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Smilla K Maierhof
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Lois Hew
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Luca Nolte
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Peter Körtvelyessy
- Department of Experimental Neurology, Charite Universitätsmedizin Berlin, Berlin, Germany
| | - Jens C Göpfert
- Naturwissenschaftliches und Medizinisches Institut, Universität Tübingen, Reutlingen, Germany
| | - Klemens Ruprecht
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christopher J Somps
- Drug Safety Research and Development, Pfizer, Groton, United States of America
| | - Jens-Uwe Blohmer
- Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jalid Sehouli
- Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Matthias Endres
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Wolfgang Boehmerle
- Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
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25
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Relation between auditory difficulties and bortezomib-induced peripheral neuropathy in multiple myeloma: a single-center cross-sectional study. Eur Arch Otorhinolaryngol 2022; 279:2197-2201. [DOI: 10.1007/s00405-021-07234-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/20/2021] [Indexed: 11/03/2022]
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26
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Akhilesh, Uniyal A, Gadepalli A, Tiwari V, Allani M, Chouhan D, Ummadisetty O, Verma N, Tiwari V. Unlocking the potential of TRPV1 based siRNA therapeutics for the treatment of chemotherapy-induced neuropathic pain. Life Sci 2022; 288:120187. [PMID: 34856209 DOI: 10.1016/j.lfs.2021.120187] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 01/23/2023]
Abstract
Chemotherapy-induced neuropathic pain (CINP) is among the most common clinical complications associated with the use of anti-cancer drugs. CINP occurs in nearly 68.1% of the cancer patients receiving chemotherapeutic drugs. Most of the clinically available analgesics are ineffective in the case of CINP patients as the pathological mechanisms involved with different chemotherapeutic drugs are distinct from each other. CINP triggers the somatosensory nervous system, increases the neuronal firing and activation of nociceptive mediators including transient receptor protein vanilloid 1 (TRPV1). TRPV1 is widely present in the peripheral nociceptive nerve cells and it has been reported that the higher expression of TRPV1 in DRGs serves a critical role in the potentiation of CINP. The therapeutic glory of TRPV1 is well recognized in clinics which gives a promising insight into the treatment of pain. But the adverse effects associated with some of the antagonists directed the scientists towards RNA interference (RNAi), a tool to silence gene expression. Thus, ongoing research is focused on developing small interfering RNA (siRNA)-based therapeutics targeting TRPV1. In this review, we have discussed the involvement of TRPV1 in the nociceptive signaling associated with CINP and targeting this nociceptor, using siRNA will potentially arm us with effective therapeutic interventions for the clinical management of CINP.
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Affiliation(s)
- Akhilesh
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ankit Uniyal
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Anagha Gadepalli
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Vineeta Tiwari
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Meghana Allani
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Deepak Chouhan
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Obulapathi Ummadisetty
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Nimisha Verma
- Department of Anaesthesiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Vinod Tiwari
- Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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27
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Kerckhove N, Selvy M, Lambert C, Gonneau C, Feydel G, Pétorin C, Vimal-Baguet A, Melnikov S, Kullab S, Hebbar M, Bouché O, Slimano F, Bourgeois V, Lebrun-Ly V, Thuillier F, Mazard T, Tavan D, Benmammar KE, Monange B, Ramdani M, Péré-Vergé D, Huet-Penz F, Bedjaoui A, Genty F, Leyronnas C, Busserolles J, Trévis S, Pinon V, Pezet D, Balayssac D. Colorectal Cancer Survivors Suffering From Sensory Chemotherapy-Induced Peripheral Neuropathy Are Not a Homogenous Group: Secondary Analysis of Patients' Profiles With Oxaliplatin-Induced Peripheral Neuropathy. Front Pharmacol 2021; 12:744085. [PMID: 34803689 PMCID: PMC8599933 DOI: 10.3389/fphar.2021.744085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Oxaliplatin, a pivotal drug in the management of colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN) in a third of cancer survivors. Based on a previous cross-sectional study assessing oxaliplatin-related sensory CIPN in colorectal cancer survivors, a secondary analysis was designed to explore the possibility that different clusters of patients may co-exist among a cohort of patients with oxaliplatin-related CIPN. Other objectives were to characterize these clusters considering CIPN severity, anxiety, depression, health-related quality of life (HRQOL), patients’ characteristics and oxaliplatin treatments. Among the 96 patients analyzed, three clusters were identified (cluster 1: 52, cluster 2: 34, and cluster 3: 10 patients). Clusters were significantly different according to CIPN severity and the proportion of neuropathic pain (cluster 1: low, cluster 2: intermediate, and cluster 3: high). Anxiety, depressive disorders and HRQOL alteration were lower in cluster 1 in comparison to clusters 2 and 3, but not different between clusters 2 and 3. This study underlines that patients with CIPN are not a homogenous group, and that CIPN severity is associated with psychological distress and a decline of HRQOL. Further studies are needed to explore the relation between clusters and CIPN management.
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Affiliation(s)
- Nicolas Kerckhove
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.,Délégation à La Recherche Clinique et à L'Innovation, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Institut Analgesia, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Marie Selvy
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Céline Lambert
- Délégation à La Recherche Clinique et à L'Innovation, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Coralie Gonneau
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Gabrielle Feydel
- Délégation à La Recherche Clinique et à L'Innovation, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Caroline Pétorin
- Service Oncologie Digestive, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Agnès Vimal-Baguet
- Service Oncologie Digestive, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Sergey Melnikov
- Service Chirurgie Générale et Viscérale, Centre Hospitalier de Saint-Flour, Saint-Flour, France
| | - Sharif Kullab
- Service Oncologie, Centre Hospitalier de Moulins Yzeure, Moulins, France
| | | | - Olivier Bouché
- Service Oncologie Digestive, CHU Reims, Université de Reims Champagne-Ardenne, Reims, France
| | - Florian Slimano
- Service Pharmacie, CHU Reims, BioSpect, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France
| | - Vincent Bourgeois
- Service Oncologie Digestive, Centre Hospitalier de Boulogne sur Mer, Boulogne-Sur-Mer, France
| | | | | | | | - David Tavan
- Service Gastro-entérologie, Infirmerie Protestante de Lyon, Caluire et Cuire, France
| | | | - Brigitte Monange
- Service Oncologie, Centre Hospitalier Emile Roux, Le Puy-en-Velay, France
| | - Mohamed Ramdani
- Service Gastro-entérologie, Centre Hospitalier de Béziers, Béziers, France
| | - Denis Péré-Vergé
- Service Hépato-gastro-entérologie, Centre Hospitalier Saint-Joseph Saint-Luc, Lyon, France
| | - Floriane Huet-Penz
- Service Gastro Entérologie, Centre Hospitalier Alpes Leman, Contamine sur Arve, France
| | - Ahmed Bedjaoui
- Service Gastro-entérologie, Centre Hospitalier Intercommunal Les Hôpitaux Du Léman, Thonon Les Bains, France
| | - Florent Genty
- Service Chirurgie Digestive et Viscérale, Centre Hospitalier de Vichy, Vichy, France
| | - Cécile Leyronnas
- Service Oncologie, Groupe Hospitalier Mutualiste de Grenoble, Grenoble, France
| | - Jérôme Busserolles
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.,Institut Analgesia, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Sophie Trévis
- Service Pharmacie, CHU Clermont-Ferrand, Clermont-Ferrand, Clermont-Ferrand, France
| | - Vincent Pinon
- Service Pharmacie, CHU Clermont-Ferrand, Clermont-Ferrand, Clermont-Ferrand, France
| | - Denis Pezet
- INSERM, M2iSH, USC-INRA 2018, Université Clermont Auvergne, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - David Balayssac
- INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.,Délégation à La Recherche Clinique et à L'Innovation, CHU Clermont-Ferrand, Clermont-Ferrand, France
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Chiang JCB, Goldstein D, Park SB, Krishnan AV, Markoulli M. Corneal nerve changes following treatment with neurotoxic anticancer drugs. Ocul Surf 2021; 21:221-237. [PMID: 34144206 DOI: 10.1016/j.jtos.2021.06.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/20/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022]
Abstract
Survival rates of cancer has improved with the development of anticancer drugs including systemic chemotherapeutic agents. However, long-lasting side effects could impact treated patients. Neurotoxic anticancer drugs are specific agents which cause chemotherapy-induced peripheral neuropathy (CIPN), a debilitating condition that severely deteriorates quality of life of cancer patients and survivors. The ocular surface is also prone to neurotoxicity but investigation into the effects of neurotoxic chemotherapy on the ocular surface has been more limited compared to other systemic etiologies such as diabetes. There is also no standardized protocol for CIPN diagnosis with an absence of a reliable, objective method of observing nerve damage structurally. As the cornea is the most densely innervated region of the body, researchers have started to focus on corneal neuropathic changes that are associated with neurotoxic chemotherapy treatment. In-vivo corneal confocal microscopy enables rapid and objective structural imaging of ocular surface microscopic structures such as corneal nerves, while esthesiometers provide means of functional assessment by examining corneal sensitivity. The current article explores the current guidelines and gaps in our knowledge of CIPN diagnosis and the potential role of in-vivo corneal confocal microscopy as a diagnostic or prognostic tool. Corneal neuropathic changes with neurotoxic anticancer drugs from animal research progressing through to human clinical studies are also discussed, with a focus on how these data inform our understanding of CIPN.
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Affiliation(s)
- Jeremy Chung Bo Chiang
- School of Optometry & Vision Science, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
| | - David Goldstein
- Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia
| | - Susanna B Park
- Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Arun V Krishnan
- Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
| | - Maria Markoulli
- School of Optometry & Vision Science, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
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