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Yamashita T, Saji S, Takano T, Naito Y, Tsuneizumi M, Yoshimura A, Takahashi M, Tsurutani J, Iwatani T, Kitada M, Tada H, Mori N, Higuchi T, Iwasa T, Araki K, Koizumi K, Hasegawa H, Uchida Y, Morita S, Masuda N. Trastuzumab-Pertuzumab Plus Eribulin or Taxane as First-Line Chemotherapy for Human Epidermal Growth Factor 2-Positive Locally Advanced/Metastatic Breast Cancer: The Randomized Noninferiority Phase III EMERALD Trial. J Clin Oncol 2025; 43:1302-1313. [PMID: 39787453 PMCID: PMC11974627 DOI: 10.1200/jco-24-01888] [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: 08/28/2024] [Revised: 11/07/2024] [Accepted: 11/19/2024] [Indexed: 01/12/2025] Open
Abstract
PURPOSE Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC. METHODS In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.gov identifier: NCT03264547/UMIN000027938), patients were randomly assigned (1:1) to receive eribulin 1.4 mg/m2 once daily on days 1 and 8 (eribulin group) or a taxane (docetaxel 75 mg/m2 once on day 1 or paclitaxel 80 mg/m2 once daily on days 1, 8, and 15; taxane group) intravenously in a 21-day cycle, each with HP on day 1. The primary end point was progression-free survival (PFS; intention-to-treat population). Secondary end points included objective response rate, overall survival (OS), patient-reported quality of life (QoL), and safety. Noninferiority was tested using the stratified Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events, with a noninferiority HR margin of 1.33. RESULTS Between August 2017 and June 2021, 446 patients (median age, 56.0 years) were enrolled. The median PFS was 14.0 and 12.9 months in the eribulin group (n = 224) and taxane group (n = 222 [docetaxel/paclitaxel, n = 186/36]), respectively (HR, 0.95 [95% CI, 0.76 to 1.19]), which confirmed the noninferiority of the study regimen. The median OS was 65.3 months in the taxane group but has not been reached in the eribulin group. Median time to QoL deterioration was numerically longer with eribulin than with taxane. Adverse event (AE) rates were similar, despite the longer duration of eribulin use. Infusion reaction, skin-related AEs, diarrhea, and edema were more common with taxane, whereas neutropenia was more common with eribulin. CONCLUSION The results suggested that eribulin + HP is an option for first-line treatment of locally advanced/metastatic HER2+ BC.
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Affiliation(s)
- Toshinari Yamashita
- Department of Breast Surgery and Oncology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Shigehira Saji
- Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan
| | - Toshimi Takano
- Department of Breast Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Yoichi Naito
- Department of General Internal Medicine, National Cancer Center Hospital East, Chiba, Japan
| | - Michiko Tsuneizumi
- Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Japan
| | - Akiyo Yoshimura
- Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Masato Takahashi
- Department of Breast Surgery, Hokkaido University Hospital, Hokkaido, Japan
| | - Junji Tsurutani
- Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
| | - Tsuguo Iwatani
- Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan
| | - Masahiro Kitada
- Department of Breast Disease Center, Asahikawa Medical University Hospital, Hokkaido, Japan
| | - Hiroshi Tada
- Department of Surgery, Division of Breast and Endocrine Surgery, Tohoku University Hospital, Miyagi, Japan
| | - Natsuko Mori
- Department of Breast Surgery, Seirei Hamamatsu General Hospital, Shizuoka, Japan
| | - Toru Higuchi
- Department of Breast Unit, Japanese Red Cross Saitama Hospital, Saitama, Japan
| | - Tsutomu Iwasa
- Department of Medical Oncology, Kindai University Hospital, Osaka, Japan
| | - Kazuhiro Araki
- Department of Breast Medical Oncology, Gunma Prefectural Cancer Center, Gunma, Japan
| | - Kei Koizumi
- Department of Surgery 1, Division of Breast Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | | | | | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norikazu Masuda
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Kim L, Nan G, Kim HY, Cha M, Lee BH. Modulation of chemotherapy-induced peripheral neuropathy by JZL195 through glia and the endocannabinoid system. Biomed Pharmacother 2024; 180:117515. [PMID: 39362070 DOI: 10.1016/j.biopha.2024.117515] [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: 06/26/2024] [Revised: 09/12/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN.
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Affiliation(s)
- Leejeong Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Guanghai Nan
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hee Young Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Myeounghoon Cha
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Bae Hwan Lee
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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Zhong C, Zheng Q, Zhao B, Ren T. A real-world pharmacovigilance study using disproportionality analysis of United States Food and Drug Administration Adverse Event Reporting System events for vinca alkaloids: comparing vinorelbine and Vincristine. Expert Opin Drug Saf 2024; 23:1427-1437. [PMID: 39340205 DOI: 10.1080/14740338.2024.2410436] [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: 08/12/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Vinca alkaloids are widely used in cancer treatment for their ability to target microtubule dynamics. While their efficacy in treating certain cancers is well-established, the full spectrum of their adverse event profiles remains an area of ongoing research. METHODS We analyzed AEs related to vinorelbine and vincristine using a retrospective case/non-case approach with data from the FDA Adverse Event Reporting System (FAERS). We applied various algorithms to detect AE signals: the reporting odds ratio (ROR) and proportional reporting ratio (PRR) measured disproportionality and association strength; the Bayesian confidence propagation neural network (BCPNN) calculated the Information Component (IC) for associations against background rates; and the multi-item gamma Poisson shrinker (MGPS) yielded empirical Bayes geometric mean (EBGM) values, accounting for reporting variability. RESULTS Both medications significantly involve the blood and lymphatic systems, with vinorelbine reporting 401 cases in this System Organ Class (SOC), exhibiting a ROR of 17.4, PRR of 12.4, IC of 3.63, and EBGM of 12.38. An intersection analysis of Preferred Terms (PTs) has uncovered previously unreported AEs shared by both drugs, including posterior reversible encephalopathy syndrome and inappropriate antidiuretic hormone secretion. CONCLUSIONS This analysis highlights the need for ongoing research of the risks associated with vinorelbine and vincristine.
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Affiliation(s)
- Cheng Zhong
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Zheng
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Zhao
- Xiamen Key Laboratory of Natural Medicine Research and Development, Xiamen, China
- Xiamen Health and Medical Big Data Center, Xiamen, China
- Xiamen Medicine Research Institute, Xiamen, China
| | - Tao Ren
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Stem Cell Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Xiamen, China
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Xu Y, Luo J, Guo Y, Zhou J, Shen L, Gu F, Shi C, Yao L, Hua M. Chemical compounds, anti-tumor and anti-neuropathic pain effect of hemp essential oil in vivo. Fitoterapia 2024; 177:106092. [PMID: 38914272 DOI: 10.1016/j.fitote.2024.106092] [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: 02/23/2024] [Revised: 05/18/2024] [Accepted: 06/22/2024] [Indexed: 06/26/2024]
Abstract
Hemp (Cannabis sativa L.), an annual dioecious plant, has shown extensive application in the fields of fibers, food, oil, medicine, etc. Currently, most attention has been paid to the therapeutic properties of phytocannabinoids. However, the pharmaceutical research on essential oil from hemp is still lacking. In this study, hemp essential oil (HEO) was extracted from hemp flowers and leaves, and the components were analyzed by GC-MS. Quatitative analysis of three main compounds β-caryophyllene, β-caryophyllene oxide, α -humulene were determined by GC-FID. The anti-tumor and anti-neuropathic pain effects of HEO were evaluated. In the paclitaxel induced neuropathic mice model, HEO reduced the serum level of inflammatory cytokines TNF-α to achieve the analgesic effect, which was tested by evaluating mechanical and thermal hyperalgesia. Further investigation with cannabinoid receptor 2 (CB2 R) antagonist AM630 revealed the mechanism of reversing mechanical hyperalgesia may be related to CB2 R. In Lewis lung cancer grafted mice model, the tumor growth was significantly inhibited, the levels of tumor inflammatory cytokines TNF-α and IL-6 were downregulated, immune organ index was modified and immune-related CD4+, CD8+ T lymphocytes level, CD4+/CD8+ ratio were increased when administered with HEO. These results reveal that HEO plays a role not only in tumor chemotherapy induced peripheral neuropathy treatment, but also in anti-tumor treatment which offers key information for new strategies in cancer treatment and provides reference for the medicinal development of hemp.
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Affiliation(s)
- Yunhui Xu
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Jiajia Luo
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Yuhan Guo
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Jing Zhou
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Longhai Shen
- Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai 200437, China
| | - Fenghua Gu
- Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai 200437, China
| | - Chenfeng Shi
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Lijuan Yao
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Moli Hua
- National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
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Bartkowiak-Wieczorek J, Bienert A, Czora-Poczwardowska K, Kujawski R, Szulc M, Mikołajczak P, Wizner AM, Jamka M, Hołysz M, Wielgus K, Słomski R, Mądry E. Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat. Biomolecules 2024; 14:1065. [PMID: 39334832 PMCID: PMC11430414 DOI: 10.3390/biom14091065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024] Open
Abstract
INTRODUCTION Cannabis sativa L. (CSL) extract has pain-relieving potential due to its cannabinoid content, so the effects of two CSL extracts on alleviating neuropathic pain were investigated in vivo. Methods and groups: Male Wistar rats (n = 130) were divided into groups and received vincristine (0.1 mg/kg) and gabapentin (60 mg/kg) to induce and relieve neuropathic pain or CSL extracts (D and B). The mRNA and protein expression of the cannabinoid receptors type 1 and 2 (CB1R, CB2R) were evaluated in the cerebral cortex, hippocampus, and lymphocytes. Behavioural tests (Tail-Flick and von Frey) were performed on all animals. RESULTS VK-induced neuropathic pain was accompanied by decreased CB1R protein level and CB2R mRNA expression in the cortex. Gabapentin relieved pain and increased CB1R protein levels in the hippocampus compared to the vincristine group. Hippocampus CB1R protein expression increased with the administration of extract D (10 mg/kg, 40 mg/kg) and extract B (7.5 mg/kg, 10 mg/kg) compared to VK group. In the cerebral cortex CSL decreased CB1R protein expression (10 mg/kg, 20 mg/kg, 40 mg/kg of extract B) and mRNA level (5 mg/kg, 7.5 mg/kg of extract B; 20 mg/kg of extract D) compared to the VK-group.CB2R protein expression increased in the hippocampus after treatment with extract B (7.5 mg/kg) compared to the VK-group. In the cerebral cortex extract B (10 mg/kg, 20 mg/kg) increased CB2R protein expression compared to VK-group. CONCLUSION Alterations in cannabinoid receptor expression do not fully account for the observed behavioural changes in rats. Therefore, additional signalling pathways may contribute to the initiation and transmission of neuropathic pain. The Cannabis extracts tested demonstrated antinociceptive effects comparable to gabapentin, highlighting the antinociceptive properties of Cannabis extracts for human use.
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Affiliation(s)
| | - Agnieszka Bienert
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (A.B.); (A.-M.W.)
| | - Kamila Czora-Poczwardowska
- Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.C.-P.); (R.K.); (M.S.); (P.M.)
| | - Radosław Kujawski
- Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.C.-P.); (R.K.); (M.S.); (P.M.)
| | - Michał Szulc
- Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.C.-P.); (R.K.); (M.S.); (P.M.)
| | - Przemysław Mikołajczak
- Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.C.-P.); (R.K.); (M.S.); (P.M.)
| | - Anna-Maria Wizner
- Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (A.B.); (A.-M.W.)
| | - Małgorzata Jamka
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland; (M.J.); (K.W.)
| | - Marcin Hołysz
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Karolina Wielgus
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland; (M.J.); (K.W.)
| | - Ryszard Słomski
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants National Research Institute, 60-630 Poznan, Poland;
| | - Edyta Mądry
- Physiology Department, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
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Xu IRL, Danzi MC, Ruiz A, Raposo J, De Jesus YA, Reilly MM, Cortese A, Shy ME, Scherer SS, Hermann D, Fridman V, Baets J, Saporta M, Seyedsadjadi R, Stojkovic T, Claeys KG, Patel P, Feely S, Rebelo A, Dohrn MF, Züchner S. A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A. J Peripher Nerv Syst 2024; 29:202-212. [PMID: 38581130 PMCID: PMC11209807 DOI: 10.1111/jns.12621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/01/2024] [Accepted: 03/07/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. METHODS We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. RESULTS We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. INTERPRETATION Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.
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Affiliation(s)
- Isaac R. L. Xu
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Matt C. Danzi
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Ariel Ruiz
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Jacquelyn Raposo
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Yeisha Arcia De Jesus
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Mary M Reilly
- Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square
| | - Andrea Cortese
- Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square
| | - Michael E Shy
- Department of Neurology, University of Iowa, Iowa City, Iowa, USA
| | - Steven S. Scherer
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
| | - David Hermann
- Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 673, Rochester, New York, 14642, USA
| | - Vera Fridman
- Department of Neurology, University of Colorado Anschutz Medical Campus, 12631 E 17th Avenue, Mailstop B185, Room 5113C, Aurora, CO, 80045, USA
| | - Jonathan Baets
- Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Antwerp, Belgium
- Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Antwerp, Belgium
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Mario Saporta
- Department of Neurology, University of Miami Miller School of Medicine, United States
| | - Reza Seyedsadjadi
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tanya Stojkovic
- AP-HP, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75013 Paris, France
| | - Kristl G. Claeys
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium
- Department of Neurosciences, Laboratory for Muscle Diseases and Neuropathies, KU Leuven, Leuven, Belgium
| | - Pooja Patel
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Shawna Feely
- Department of Neurology, University of Iowa, Iowa City, Iowa, USA
| | - Adriana Rebelo
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | | | - Maike F. Dohrn
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
- Department of Neurology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Stephan Züchner
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
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Freire AADS, Guimarães AS, Lobo PLD, Rodrigues LLFR. Chemotherapy-related trigeminal and glossopharyngeal nerves neurotoxicity: a cohort study. Oral Surg Oral Med Oral Pathol Oral Radiol 2024; 137:501-507. [PMID: 38553303 DOI: 10.1016/j.oooo.2024.02.005] [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: 05/13/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 06/19/2024]
Abstract
BACKGROUND AND OBJECTIVES The association between orofacial neurotoxicity and chemotherapy treatment is still unclear. In this context, the purpose of this study is to relate the orofacial alterations that manifest during antineoplastic pharmacological treatment, highlighting the drugs commonly related to orofacial neuropathy and the adequate instrument to verify the alterations at clinical levels. METHODS This prospective cohort study, addressed patients who would start therapy with taxanes, platinum, or related therapy. The collection of signs and symptoms was divided into 3 different times (baseline, second or third cycle of antineoplastic chemotherapy treatment, and sixth cycle). A total of 40 patients were submitted to the application of the Short McGill pain questionnaire and Neutoxicity Induced by Antineoplastics questionnaire (QNIA). To verify sensory alterations in the face, a clinical evaluation was performed with the help of Semmes-Weinstein monofilaments. RESULTS Taxanes show greater orofacial neurotoxic potential, being associated with sensory alterations assessed by monofilaments (P = .003) and the presence of orofacial pain analyzed by the Short McGill pain questionnaire (P = .001). These medications related to neuropathy in the orofacial region measured through the QNIA, demonstrating a predominantly acute nature (P < .001). CONCLUSION It is suggested that chemotherapy may induce neurotoxicity in the orofacial region.
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Affiliation(s)
| | - Antônio Sérgio Guimarães
- Laboratory of Neuroimmune Interface of Pain Research, São Leopoldo Mandic College of Dentistry, Campinas, Brazil
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Li T, Trinh T, Bosco A, Kiernan MC, Goldstein D, Park SB. Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes. Support Care Cancer 2024; 32:278. [PMID: 38592525 PMCID: PMC11003903 DOI: 10.1007/s00520-024-08484-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. METHODS Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann-Whitney U tests for non-parametric data. RESULTS The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. CONCLUSION VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life.
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Affiliation(s)
- Tiffany Li
- Brain and Mind Centre, The University of Sydney, Sydney, Australia
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 94 Mallett St Camperdown, Sydney, NSW, 2050, Australia
| | - Terry Trinh
- Prince of Wales Clinical School, University of New South Wales, Kensington, Australia
| | - Annmarie Bosco
- Prince of Wales Clinical School, University of New South Wales, Kensington, Australia
- Prince of Wales Hospital, Randwick, Australia
| | - Matthew C Kiernan
- Brain and Mind Centre, The University of Sydney, Sydney, Australia
- Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia
| | - David Goldstein
- Prince of Wales Clinical School, University of New South Wales, Kensington, Australia
- Prince of Wales Hospital, Randwick, Australia
| | - Susanna B Park
- Brain and Mind Centre, The University of Sydney, Sydney, Australia.
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 94 Mallett St Camperdown, Sydney, NSW, 2050, Australia.
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9
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Yeung N, Li T, Lin HM, Timmins HC, Goldstein D, Harrison M, Friedlander M, Mahon KL, Giles C, Meikle PJ, Park SB, Horvath LG. Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy. JCO Precis Oncol 2024; 8:e2300690. [PMID: 38691814 DOI: 10.1200/po.23.00690] [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: 12/13/2023] [Revised: 02/11/2024] [Accepted: 03/07/2024] [Indexed: 05/03/2024] Open
Abstract
PURPOSE Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.
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Affiliation(s)
- Nicole Yeung
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Tiffany Li
- Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia
- The University of Sydney, Camperdown, NSW, Australia
| | - Hui-Ming Lin
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia
| | - Hannah C Timmins
- Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia
- The University of Sydney, Camperdown, NSW, Australia
| | - David Goldstein
- Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
| | | | - Michael Friedlander
- Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Kate L Mahon
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- The University of Sydney, Camperdown, NSW, Australia
- Chris O'Brien Lifehouse, Camperdown, NSW, Australia
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Corey Giles
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia
| | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia
| | - Susanna B Park
- Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Lisa G Horvath
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- The University of Sydney, Camperdown, NSW, Australia
- St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia
- Chris O'Brien Lifehouse, Camperdown, NSW, Australia
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia
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10
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Gehr NL, Karlsson P, Timm S, Christensen S, Hvid CA, Peric J, Hansen TF, Lauritzen L, Finnerup NB, Ventzel L. Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro). BMC Cancer 2024; 24:168. [PMID: 38308227 PMCID: PMC10837958 DOI: 10.1186/s12885-024-11856-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/08/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.
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Affiliation(s)
- Nina Lykkegaard Gehr
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark.
| | - Páll Karlsson
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Signe Timm
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Signe Christensen
- Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Jana Peric
- Department of Oncology, Soenderborg Hospital, University Hospital of Southern Denmark, Soenderborg, Denmark
| | - Torben Frøstrup Hansen
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Lotte Lauritzen
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Nanna Brix Finnerup
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Lise Ventzel
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
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11
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Molinares D, Kurtevski S, Zhu Y. Chemotherapy-Induced Peripheral Neuropathy: Diagnosis, Agents, General Clinical Presentation, and Treatments. Curr Oncol Rep 2023; 25:1227-1235. [PMID: 37702983 DOI: 10.1007/s11912-023-01449-7] [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] [Accepted: 08/10/2023] [Indexed: 09/14/2023]
Abstract
PURPOSE OF REVIEW This review aims to discuss pathophysiology, diagnosis, clinical presentation, and treatment of chemotherapy-induced peripheral neuropathy. Agent-specific presentation and pathophysiology is also being discussed. RECENT FINDINGS As new systemic oncological treatments continue to be developed, the number of cancer survivors continues to grow. Survivors are living longer with the long-term side effects of oncological treatments. We reviewed the pathophysiology of agent-specific chemotherapy-induced peripheral neuropathy and the updates in its treatment and preventative tools. Chemotherapy-induced peripheral neuropathy is a debilitating long-term side effect that often impairs cancer survivors' function and quality of life. The increasing life expectancy of cancer survivors has resulted in increased prevalence of this condition. Understanding its intricacies can provide physicians with better treatment tools and research opportunities to develop or identify new therapeutic agents.
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Affiliation(s)
- Diana Molinares
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, 1611 NW 12th avenue, Miami, FL, 33136, USA.
| | - Sara Kurtevski
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, 1611 NW 12th avenue, Miami, FL, 33136, USA
| | - Yingrong Zhu
- Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, 1611 NW 12th avenue, Miami, FL, 33136, USA
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12
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Davey MG, Abbas R, Kerin EP, Casey MC, McGuire A, Waldron RM, Heneghan HM, Newell J, McDermott AM, Keane MM, Lowery AJ, Miller N, Kerin MJ. Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer. Breast Cancer Res Treat 2023; 202:73-81. [PMID: 37540289 PMCID: PMC10504160 DOI: 10.1007/s10549-023-07033-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 06/30/2023] [Indexed: 08/05/2023]
Abstract
PURPOSE Prescribing NAC for breast cancer is a pragmatic treatment strategy for several reasons; however, certain patients suffer chemotherapy-induced toxicities. Unfortunately, identifying patients at risk of toxicity often proves challenging. MiRNAs are small non-coding RNA molecules which modulate genetic expression. The aim of this study was to determine whether circulating miRNAs are sensitive biomarkers that can identify the patients likely to suffer treatment-related toxicities to neoadjuvant chemotherapy (NAC) for primary breast cancer. METHODS This secondary exploratory from the prospective, multicentre translational research trial (CTRIAL ICORG10/11-NCT01722851) recruited 101 patients treated with NAC for breast cancer, from eight treatment sites across Ireland. A predetermined five miRNAs panel was quantified using RQ-PCR from patient bloods at diagnosis. MiRNA expression was correlated with chemotherapy-induced toxicities. Regression analyses was performed using SPSS v26.0. RESULTS One hundred and one patients with median age of 55 years were recruited (range: 25-76). The mean tumour size was 36 mm and 60.4% had nodal involvement (n = 61) Overall, 33.7% of patients developed peripheral neuropathies (n = 34), 28.7% developed neutropenia (n = 29), and 5.9% developed anaemia (n = 6). Reduced miR-195 predicted patients likely to develop neutropenia (P = 0.048), while increased miR-10b predicted those likely to develop anaemia (P = 0.049). Increased miR-145 predicted those experiencing nausea and vomiting (P = 0.019), while decreased miR-21 predicted the development of mucositis (P = 0.008). CONCLUSION This is the first study which illustrates the value of measuring circulatory miRNA to predict patient-specific toxicities to NAC. These results support the ideology that circulatory miRNAs are biomarkers with utility in predicting chemotherapy toxicity as well as treatment response.
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Affiliation(s)
- Matthew G Davey
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland.
- Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin, D02 YN77, Ireland.
| | - Ray Abbas
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Eoin P Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Maire Caitlin Casey
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Andrew McGuire
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Ronan M Waldron
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Helen M Heneghan
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - John Newell
- School of Mathematics, Statistics and Applied Mathematics, University of Galway, Galway, H91 TK33, Ireland
| | - Ailbhe M McDermott
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Maccon M Keane
- Department of Medical Oncology, Galway University Hospital, Galway, H71 YR71, Ireland
| | - Aoife J Lowery
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Nicola Miller
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
| | - Michael J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Galway, H91 YR71, Ireland
- Cancer Trials Ireland, Innovation House, Old Finglas Road, Dublin, D11 KXN4, Ireland
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13
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Abe T, Sakagami H, Amano S, Uota S, Bandow K, Uesawa Y, U S, Shibata H, Takemura Y, Kimura Y, Takao K, Sugita Y, Sato A, Tanuma SI, Takeshima H. A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs. MEDICINES (BASEL, SWITZERLAND) 2023; 10:43. [PMID: 37505064 PMCID: PMC10386476 DOI: 10.3390/medicines10070043] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/29/2023]
Abstract
Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.
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Affiliation(s)
- Tomoyuki Abe
- Division of Geriatric Dentistry, Meikai University School of Dentistry, Saitama 350-0283, Japan
| | - Hiroshi Sakagami
- Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, Japan
| | - Shigeru Amano
- Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, Japan
| | - Shin Uota
- Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, Japan
| | - Kenjiro Bandow
- Division of Biochemistry, Meikai University School of Dentistry, Saitama 350-0283, Japan
| | - Yoshihiro Uesawa
- Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-858, Japan
| | - Shiori U
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Hiroki Shibata
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Yuri Takemura
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Yu Kimura
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Koichi Takao
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Yoshiaki Sugita
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
| | - Akira Sato
- Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
| | - Sei-Ichi Tanuma
- Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, Japan
| | - Hiroshi Takeshima
- Division of Geriatric Dentistry, Meikai University School of Dentistry, Saitama 350-0283, Japan
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14
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Kanda K, Ishida K, Kyota A, Ishihara C, Fujimoto K, Hosokawa M, Mochizuki R. Randomized clinical trial quantifying the effectiveness of a self-monitoring intervention in cancer patients with peripheral neuropathy: A quantitative study. Asia Pac J Oncol Nurs 2023; 10:100198. [PMID: 36949819 PMCID: PMC10025959 DOI: 10.1016/j.apjon.2023.100198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
Objective The aim of this study was to quantitatively evaluate the efficacy of a self-monitoring intervention for the management of persistent chemotherapy-induced peripheral neuropathy (CIPN). Methods A randomized controlled clinical trial was conducted on 65 outpatients receiving taxane or platinum-based anticancer drugs. Participants were assigned to the control group (CG; n = 32) or the self-monitoring group (SMG; n = 33) and followed for 6 weeks. Non-interveners were blinded. Participants in the intervention group self-monitored and recorded. The researchers provided feedback on the recorded symptoms and coping strategies once every 3 weeks. The efficacy of the 6-week self-monitoring intervention was assessed, using various measures, at baseline (T0), 3 weeks (T1), and 6 weeks (T2). Scores of CIPN, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, Distress and Impact Thermometer, Self-Efficacy Scale for Advanced Cancer, and Functional Assessment of Cancer Therapy-General of both groups were compared. Safety behavior in daily life was also compared. The study was conducted from August 9, 2017 to March 30, 2020 in outpatient clinics at three hospitals. Analysis was conducted using the t-test, Mann-Whitney U test, χ2 test, and two-way repeated-measures analysis of variance (two-way RMANOVA). Results No significant differences were noted between the two groups in the CIPN score, the Distress and Impact Thermometer score, and in safety behavior in daily life. The mean Self-Efficacy Scale for Advanced Cancer score at T1 differed between the two groups (CG mean ± SD: 358.44 ± 109.90; SMG mean ± SD: 421.21 ± 85.54), which was significantly higher in the SMG (P = 0.012). Two-way RMANOVA revealed an interaction between the CG and SMG (F = 5.689, P = 0.004). Quality of life scores were higher in the SMG than in the CG at T0, T1, and T2. Two-way RMANOVA analysis showed an effect of the intervention (F = 7.914, P = 0.007). Conclusions The self-monitoring intervention maintained the participants' quality of life. This finding suggests its effectiveness in patients with peripheral neuropathy.
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Affiliation(s)
- Kiyoko Kanda
- Nursing Department, Takasaki University of Health and Welfare, Takasaki-shi, Japan
- Corresponding author.
| | | | - Ayumi Kyota
- Gunma University, Graduate School of Health Sciences, Maebashi-shi, Japan
| | | | - Keiko Fujimoto
- Nursing Department, Takasaki University of Health and Welfare, Takasaki-shi, Japan
| | - Mai Hosokawa
- Iwate Prefectural University, Faculty of Nursing/Graduate School of Nursing, Takizawa, Japan
| | - Ruka Mochizuki
- Jikei University School of Medicine, School of Nursing, Chouhu-shi, Japan
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15
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Martins D, O’Sullivan DE, Boyne DJ, Cheung WY, Allonby O, Habash M, Brenner DR, Riemer J, McGee J. Understanding Characteristics, Treatment Patterns, and Clinical Outcomes for Individuals with Advanced or Recurrent Endometrial Cancer in Alberta, Canada: A Retrospective, Population-Based Cohort Study. Curr Oncol 2023; 30:2277-2289. [PMID: 36826137 PMCID: PMC9955469 DOI: 10.3390/curroncol30020176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Endometrial cancer (EC) incidence has increased in recent decades. However, population-based outcomes data are limited. In this retrospective cohort study, we examined characteristics, treatment patterns, and clinical outcomes, including time to next treatment (TNNT) and overall survival (OS), among advanced/recurrent (A/R) EC patients between 2010 and 2018 in Alberta, Canada. Kaplan-Meier statistics evaluated TTNT and OS, stratified by patient (A/R) and treatment. A total of 1053 patients were included: 620 (58.9%) advanced and 433 (41.1%) recurrent. A total of 713 (67.7%) patients received first-line therapy: 466 (75.2%) advanced and 247 (57.0%) recurrent. Platinum-based chemotherapy (PBCT) was the most common first-line regimen (overall: 78.6%; advanced: 96.1%; recurrent: 45.3%). The median TTNT and OS from first-line therapy were 19.9 months (95% confidence interval [CI]: 17.5-23.5) and 35.9 months (95% CI: 31.5-53.5), respectively. Following first-line PBCT, the median OS from second-line chemotherapy (N = 187) was 10.4 months (95% CI: 8.9-13.3) and higher for those rechallenged with PBCT (N = 72; 38.5%) versus no rechallenge (N = 115; 61.5%) (13.3 months [95% CI: 11.2-20.9] vs. 6.4 months [95% CI: 4.6-10.4; p < 0.001]). The findings highlight poor outcomes in A/R EC, particularly following first-line therapy, and that additional tolerable therapeutic options are needed to improve patient outcomes.
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Affiliation(s)
| | - Dylan E. O’Sullivan
- Oncology Outcomes Initiative, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Devon J. Boyne
- Oncology Outcomes Initiative, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Winson Y. Cheung
- Oncology Outcomes Initiative, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | | | - Darren R. Brenner
- Oncology Outcomes Initiative, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | - Jacob McGee
- Department of Obstetrics and Gynecology, Schulich Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
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16
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Gut microbiota in chronic pain: Novel insights into mechanisms and promising therapeutic strategies. Int Immunopharmacol 2023. [DOI: 10.1016/j.intimp.2023.109685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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17
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Towards a mechanistic understanding of axon transport and endocytic changes underlying paclitaxel-induced peripheral neuropathy. Exp Neurol 2023; 359:114258. [PMID: 36279934 DOI: 10.1016/j.expneurol.2022.114258] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 10/11/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022]
Abstract
Paclitaxel is a common chemotherapeutic agent widely used to treat solid cancer. However, it frequently causes peripheral sensory neuropathy, resulting in sensory abnormalities and pain in patients receiving treatment for cancer. As one of the most widely used chemotherapeutics, many preclinical studies on paclitaxel-induced peripheral neuropathy (PIPN) have been performed. Yet, there remain no effective options for treatment or prevention. Due to paclitaxel's ability to bind to and stabilize microtubules, a change in microtubule dynamics and subsequent disruptions in axonal transport has been predicted as a major underlying cause of paclitaxel-induced toxicity. However, the systemic understanding of PIPN mechanisms is largely incomplete, and various phenotypes have not been directly attributed to microtubule-related effects. This review aims to provide an overview of the literature involving paclitaxel-induced alteration in microtubule dynamics, axonal transport, and endocytic changes. It also aims to provide insights into how the microtubule-mediated hypothesis may relate to various phenotypes reported in PIPN studies.
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18
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Klazas M, Naamneh MS, Zheng W, Lazarovici P. Gabapentin Increases Intra-Epidermal and Peptidergic Nerve Fibers Density and Alleviates Allodynia and Thermal Hyperalgesia in a Mouse Model of Acute Taxol-Induced Peripheral Neuropathy. Biomedicines 2022; 10:biomedicines10123190. [PMID: 36551946 PMCID: PMC9775678 DOI: 10.3390/biomedicines10123190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/05/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
The clinical pathology of Taxol-induced peripheral neuropathy (TIPN), characterized by loss of sensory sensitivity and pain, is mirrored in a preclinical pharmacological mice model in which Gabapentin, produced anti-thermal hyperalgesia and anti-allodynia effects. The study aimed to investigate the hypothesis that gabapentin may protect against Taxol-induced neuropathic pain in association with an effect on intra-epidermal nerve fibers density in the TIPN mice model. A TIPN study schedule was induced in mice by daily injection of Taxol during the first week of the experiment. Gabapentin therapy was performed during the 2nd and 3rd weeks. The neuropathic pain was evaluated during the whole experiment by the Von Frey, tail flick, and hot plate tests. Intra-epidermal nerve fibers (IENF) density in skin biopsies was measured at the end of the experiment by immunohistochemistry of ubiquitin carboxyl-terminal hydrolase PGP9.5 pan-neuronal and calcitonin gene-related (CGRP) peptides-I/II- peptidergic markers. Taxol-induced neuropathy was expressed by 80% and 73% reduction in the paw density of IENFs and CGPR, and gabapentin treatment corrected by 83% and 46% this reduction, respectively. Gabapentin-induced increase in the IENF and CGRP nerve fibers density, thus proposing these evaluations as an additional objective end-point tool in TIPN model studies using gabapentin as a reference compound.
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Affiliation(s)
- Michal Klazas
- Pharmacy Unit, School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel
| | - Majdi Saleem Naamneh
- Pharmacology Unit, School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel
| | - Wenhua Zheng
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
| | - Philip Lazarovici
- Pharmacology Unit, School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel
- Correspondence: ; Tel.: +972-2-6758729; Fax: +972-2-6757490
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Vesteghem C, Szejniuk WM, Brøndum RF, Falkmer UG, Azencott CA, Bøgsted M. Dynamic Risk Prediction of 30-Day Mortality in Patients With Advanced Lung Cancer: Comparing Five Machine Learning Approaches. JCO Clin Cancer Inform 2022; 6:e2200054. [DOI: 10.1200/cci.22.00054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
PURPOSE Administering systemic anticancer treatment (SACT) to patients near death can negatively affect their health-related quality of life. Late SACT administrations should be avoided in these cases. Machine learning techniques could be used to build decision support tools leveraging registry data for clinicians to limit late SACT administration. MATERIALS AND METHODS Patients with advanced lung cancer who were treated at the Department of Oncology, Aalborg University Hospital and died between 2010 and 2019 were included (N = 2,368). Diagnoses, treatments, biochemical data, and histopathologic results were used to train predictive models of 30-day mortality using logistic regression with elastic net penalty, random forest, gradient tree boosting, multilayer perceptron, and long short-term memory network. The importance of the variables and the clinical utility of the models were evaluated. RESULTS The random forest and gradient tree boosting models outperformed other models, whereas the artificial neural network–based models underperformed. Adding summary variables had a modest effect on performance with an increase in average precision from 0.500 to 0.505 and from 0.498 to 0.509 for the gradient tree boosting and random forest models, respectively. Biochemical results alone contained most of the information with a limited degradation of the performances when fitting models with only these variables. The utility analysis showed that by applying a simple threshold to the predicted risk of 30-day mortality, 40% of late SACT administrations could have been prevented at the cost of 2% of patients stopping their treatment 90 days before death. CONCLUSION This study demonstrates the potential of a decision support tool to limit late SACT administration in patients with cancer. Further work is warranted to refine the model, build an easy-to-use prototype, and conduct a prospective validation study.
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Affiliation(s)
- Charles Vesteghem
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
| | - Weronika M. Szejniuk
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
- Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
| | - Rasmus F. Brøndum
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
| | - Ursula G. Falkmer
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
- Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
| | - Chloé-Agathe Azencott
- CBIO Mines ParisTech, PSL Research University, Paris, France
- Institut Curie, Paris, France
- INSERM U900, Paris, France
| | - Martin Bøgsted
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
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Shin GJE, Abaci HE, Smith MC. Cellular Pathogenesis of Chemotherapy-Induced Peripheral Neuropathy: Insights From Drosophila and Human-Engineered Skin Models. FRONTIERS IN PAIN RESEARCH 2022; 3:912977. [PMID: 35875478 PMCID: PMC9304629 DOI: 10.3389/fpain.2022.912977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and complex condition arising from chemotherapy cancer treatments. Currently, there are no treatment or prevention options in the clinic. CIPN accompanies pain-related sensory functions starting from the hands and feet. Studies focusing on neurons in vitro and in vivo models significantly advanced our understanding of CIPN pathological mechanisms. However, given the direct toxicity shown in both neurons and non-neuronal cells, effective in vivo or in vitro models that allow the investigation of neurons in their local environment are required. No single model can provide a complete solution for the required investigation, therefore, utilizing a multi-model approach would allow complementary advantages of different models and robustly validate findings before further translation. This review aims first to summarize approaches and insights from CIPN in vivo models utilizing small model organisms. We will focus on Drosophila melanogaster CIPN models that are genetically amenable and accessible to study neuronal interactions with the local environment in vivo. Second, we will discuss how these findings could be tested in physiologically relevant vertebrate models. We will focus on in vitro approaches using human cells and summarize the current understanding of engineering approaches that may allow the investigation of pathological changes in neurons and the skin environment.
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Affiliation(s)
- Grace Ji-eun Shin
- Zuckerman Mind Brain and Behavior Institute, Jerome L. Greene Science Center, Columbia University, New York, NY, United States
- *Correspondence: Grace Ji-eun Shin
| | - Hasan Erbil Abaci
- Department of Dermatology, Columbia University Medical Center, Saint Nicholas Avenue, New York, NY, United States
| | - Madison Christine Smith
- Zuckerman Mind Brain and Behavior Institute, Jerome L. Greene Science Center, Columbia University, New York, NY, United States
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21
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The growing importance of neuro-oncology for neurologists. Neurol Sci 2022; 43:2919-2921. [DOI: 10.1007/s10072-022-06002-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 10/18/2022]
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22
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Mizrahi D, Goldstein D, Kiernan MC, Robinson L, Pitiyarachchi O, McCullough S, Mendoza-Jones P, Grimison P, Boyle F, Park SB. Development and consensus process for a clinical pathway for the assessment and management of chemotherapy-induced peripheral neuropathy. Support Care Cancer 2022; 30:5965-5974. [PMID: 35394563 PMCID: PMC9135801 DOI: 10.1007/s00520-022-07024-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/29/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cancer patients treated with neurotoxic chemotherapy are at risk of developing neurological symptoms that can impact functional capacity and quality of life. However, there are no standardised pathways to assess and manage chemotherapy-induced peripheral neurotoxicity (CIPN). This study aimed to determine consensus on statements regarding a CIPN assessment and management clinical pathway. METHODS A CIPN clinical pathway (CIPN-path) was developed and reviewed by an expert multi-disciplinary panel and consumers. Agreement with 18 statements regarding four content themes (pretreatment review, screening and assessment, management and referral, and CIPN-path feasibility) were assessed by 70 Australian respondents (68 health professionals, 2 consumers), using a 2-stage Delphi survey process to reach consensus. Respondents rated statements using a 5-point Likert scale to determine the level of agreement, with consensus defined as ≥ 80% of respondents agreeing with each statement. RESULTS The consensus was reached for 14 of 18 items after stage 1 and all items after stage 2. Feedback was obtained for all items to refine the CIPN-path. There was an agreement on important characteristics of the CIPN-path, including pretreatment screening, regular patient-reported assessment, and a stepped-care approach to investigating and managing symptom burden. There was a lack of agreement on who should oversee CIPN assessment, which may differ according to the structure and resources of each site. CONCLUSIONS There was an overall agreement concerning the CIPN-path to assess and manage CIPN, which may be adapted accordingly to the resources of each clinic. The CIPN-path may assist teams across different health services in identifying CIPN symptoms, aiding decision-making, and reducing morbidity from CIPN.
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Affiliation(s)
- David Mizrahi
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia.,Faculty of Medicine and Health, Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
| | - David Goldstein
- Faculty of Medicine and Health, Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia.,Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia
| | - Matthew C Kiernan
- Brain and Mind Centre, The University of Sydney, Sydney, Australia.,Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Louisa Robinson
- Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia
| | | | - Susan McCullough
- Translational Cancer Research Network Consumer Advisory Panel, Sydney, Australia
| | - Phil Mendoza-Jones
- Translational Cancer Research Network Consumer Advisory Panel, Sydney, Australia
| | - Peter Grimison
- Chris O'Brien Lifehouse, Sydney, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Frances Boyle
- Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.,Patricia Ritchie Centre for Cancer Care and Research, Mater Hospital, North Sydney, Australia
| | - Susanna B Park
- Brain and Mind Centre, The University of Sydney, Sydney, Australia.
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Nadalutti CA, Ayala-Peña S, Santos JH. Mitochondrial DNA damage as driver of cellular outcomes. Am J Physiol Cell Physiol 2022; 322:C136-C150. [PMID: 34936503 PMCID: PMC8799395 DOI: 10.1152/ajpcell.00389.2021] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Mitochondria are primarily involved in energy production through the process of oxidative phosphorylation (OXPHOS). Increasing evidence has shown that mitochondrial function impacts a plethora of different cellular activities, including metabolism, epigenetics, and innate immunity. Like the nucleus, mitochondria own their genetic material, but this organellar genome is circular, present in multiple copies, and maternally inherited. The mitochondrial DNA (mtDNA) encodes 37 genes that are solely involved in OXPHOS. Maintenance of mtDNA, through replication and repair, requires the import of nuclear DNA-encoded proteins. Thus, mitochondria completely rely on the nucleus to prevent mitochondrial genetic alterations. As most cells contain hundreds to thousands of mitochondria, it follows that the shear number of organelles allows for the buffering of dysfunction-at least to some extent-before tissue homeostasis becomes impaired. Only red blood cells lack mitochondria entirely. Impaired mitochondrial function is a hallmark of aging and is involved in a number of different disorders, including neurodegenerative diseases, diabetes, cancer, and autoimmunity. Although alterations in mitochondrial processes unrelated to OXPHOS, such as fusion and fission, contribute to aging and disease, maintenance of mtDNA integrity is critical for proper organellar function. Here, we focus on how mtDNA damage contributes to cellular dysfunction and health outcomes.
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Affiliation(s)
- Cristina A. Nadalutti
- 1Mechanistic Toxicology Branch, Division of the National Toxicology
Program (DNTP), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Sylvette Ayala-Peña
- 2Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Janine H. Santos
- 1Mechanistic Toxicology Branch, Division of the National Toxicology
Program (DNTP), National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, North Carolina
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Dahlmanns M, Yakubov E, Dahlmanns JK. Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction. Front Oncol 2021; 11:783067. [PMID: 34926298 PMCID: PMC8671613 DOI: 10.3389/fonc.2021.783067] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma represents the most devastating form of human brain cancer, associated with a very poor survival rate of patients. Unfortunately, treatment options are currently limited and the gold standard pharmacological treatment with the chemotherapeutic drug temozolomide only slightly increases the survival rate. Experimental studies have shown that the efficiency of temozolomide can be improved by inducing ferroptosis – a recently discovered form of cell death, which is different from apoptosis, necrosis, or necroptosis and, which is characterized by lipid peroxidation and reactive oxygen species accumulation. Ferroptosis can also be activated to improve treatment of malignant stages of neuroblastoma, meningioma, and glioma. Due to their role in cancer treatment, ferroptosis-gene signatures have recently been evaluated for their ability to predict survival of patients. Despite positive effects during chemotherapy, the drugs used to induce ferroptosis – such as erastin and sorafenib – as well as genetic manipulation of key players in ferroptosis – such as the cystine-glutamate exchanger xCT and the glutathione peroxidase GPx4 – also impact neuronal function and cognitive capabilities. In this review, we give an update on ferroptosis in different brain tumors and summarize the impact of ferroptosis on healthy tissues.
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Affiliation(s)
- Marc Dahlmanns
- Institute for Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Eduard Yakubov
- Department of Neurosurgery, Paracelsus Medical University, Nuremberg, Germany
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25
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[Neurological symptoms associated with cancer treatment]. DER NERVENARZT 2021; 92:1305-1314. [PMID: 34821945 PMCID: PMC8648645 DOI: 10.1007/s00115-021-01223-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 10/14/2021] [Indexed: 11/04/2022]
Abstract
Die onkologische Behandlung ist biomarkerbasierter, molekular maßgeschneiderter und effektiver geworden. Aufbauend auf der zunehmenden Entschlüsselung zellbiologischer und molekularer Mechanismen steigt auch die Zahl zielgerichteter medikamentöser Therapien. Es steigt zudem die Zahl der Langzeitüberlebenden. Eine neuro(onko)logische Betreuung wird immer wichtiger, nicht nur wegen vermehrter direkter tumorbedingter Symptome – wie etwa der höheren Inzidenz einer Metastasierung in das Zentralnervensystem –, sondern weil im Zuge dieser modernen onkologischen systemischen Therapieformen ein breites Spektrum therapieassoziierter neurologischer Symptome auftritt, die einer sorgfältigen und raschen neurologischen/neuroonkologischen Evaluation und Therapiekonzeption bedürfen. Das Ziel dieses Artikels ist es, das Bewusstsein für die häufigsten therapieassoziierten neurologischen Symptome zu schärfen.
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