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1
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Jia L, Meng Q, Xu X. Autophagy-related miRNAs, exosomal miRNAs, and circRNAs in tumor progression and drug-and radiation resistance in colorectal cancer. Pathol Res Pract 2024; 263:155597. [PMID: 39426141 DOI: 10.1016/j.prp.2024.155597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 07/16/2024] [Accepted: 09/20/2024] [Indexed: 10/21/2024]
Abstract
Targeted therapies are often more tolerable than traditional cytotoxic ones. Nurses play a critical role in providing patients and caregivers with information about the disease, available therapies, and the kind, severity, and identification of any potential adverse events. By doing this, it may be possible to ensure that any adverse effects are managed quickly, maximizing the therapeutic benefit. In colorectal cancer (CRC), autophagy-related activities are significantly influenced by miRNAs and exosomal miRNAs. CRC development and treatment resistance have been associated with the cellular process of autophagy. miRNAs, which are short non-coding RNA molecules, have the ability to control the expression of genes by binding to the 3' untranslated region (UTR) of target mRNAs and either preventing or suppressing translation. It has been discovered that several miRNAs are significant regulators of CRC autophagy. By preventing autophagy, these miRNAs enhance the survival and growth of cancer cells. Exosomes are small membrane vesicles that are released by cells and include miRNAs among other bioactive compounds. Exosomes have the ability to modify recipient cells' biological processes by delivering their cargo, which includes miRNAs. It has been demonstrated that exosomal miRNAs control autophagy in CRC in both autocrine and paracrine ways. We will discuss the potential roles of miRNAs, exosomal miRNAs, and circRNAs in CRC autophagy processes and how nursing care can reduce unfavorable outcomes.
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Affiliation(s)
- Liting Jia
- Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 102413, China
| | - Qingyun Meng
- Gastroenterology Department, Qingdao Municipal Hospital, Qingdao 266000, China
| | - Xiaofeng Xu
- Thoracic Surgery, Qingdao Municipal Hospital, Qingdao 266000, China.
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2
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Rauth S, Malafa M, Ponnusamy MP, Batra SK. Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights. Gastroenterology 2024; 167:867-884. [PMID: 38759843 PMCID: PMC11793124 DOI: 10.1053/j.gastro.2024.05.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/23/2024] [Accepted: 05/01/2024] [Indexed: 05/19/2024]
Abstract
Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.
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Affiliation(s)
- Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, Nebraska
| | - Mokenge Malafa
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, Nebraska.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center at Omaha, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center at Omaha, Omaha, Nebraska.
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3
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Dicovitsky RH, Schappa JT, Schulte AJ, Lang HP, Kuerbitz E, Roberts S, DePauw TA, Lewellen M, Winter AL, Stuebner K, Buettner M, Reid K, Bergsrud K, Pracht S, Chehadeh A, Feiock C, O’Sullivan MG, Carlson T, Armstrong AR, Meritet D, Henson MS, Weigel BJ, Modiano JF, Borgatti A, Vallera DA. Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model. Toxins (Basel) 2024; 16:376. [PMID: 39330834 PMCID: PMC11436214 DOI: 10.3390/toxins16090376] [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: 04/25/2024] [Revised: 07/15/2024] [Accepted: 08/20/2024] [Indexed: 09/28/2024] Open
Abstract
EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated Pseudomonas toxin. Its purpose was to simultaneously target tumors and their vasculature in the tumor microenvironment. In prior studies on mice and dogs, the drug proved efficacious. Here, we report the safety of eBAT in normal wildtype, uPAR knockout, and immunoreplete and immunodeficient tumor-bearing mice, as well as in dogs with spontaneous sarcoma that more closely mirror human cancer onset. In immunocompetent mice, tumor-bearing mice, uPAR knockout mice, and mice receiving species-optimized eBAT, toxicities were mild and self-limiting. Likewise, in dogs with life-threatening sarcoma given dosages found to be biologically active, eBAT was well tolerated. In mice receiving higher doses, eBAT was associated with dose-dependent evidence of liver injury, including portal biliary hyperplasia, oval cell proliferation, lymphoplasmacytic inflammation, periportal hepatocellular microvesicular change, hemorrhage, necrosis, and apoptosis. The results support continuing the clinical development of eBAT as a therapeutic agent for individuals with sarcoma and other cancers.
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Affiliation(s)
- Rose H. Dicovitsky
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
| | - Jill T. Schappa
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Experimental Surgical Services, Department of Surgery, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ashley J. Schulte
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Haeree P. Lang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Comparative Molecular Biosciences Graduate Program and DVM-PhD Dual Degree Program, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Ellen Kuerbitz
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
| | - Sarah Roberts
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
| | - Taylor A. DePauw
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Microbiology, Immunology, and Cancer Biology Graduate Program, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
| | - Mitzi Lewellen
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Amber L. Winter
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Kathy Stuebner
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Michelle Buettner
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Kelly Reid
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Kelly Bergsrud
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Sara Pracht
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Andrea Chehadeh
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Caitlin Feiock
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - M. Gerard O’Sullivan
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA;
| | - Tim Carlson
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA;
| | - Alexandra R. Armstrong
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
| | - Danielle Meritet
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Michael S. Henson
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Brenda J. Weigel
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jaime F. Modiano
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
- Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Antonella Borgatti
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; (R.H.D.); (J.T.S.); (A.J.S.); (H.P.L.); (E.K.); (S.R.); (T.A.D.); (M.L.); (C.F.); (A.R.A.); (M.S.H.); (J.F.M.); (A.B.)
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Daniel A. Vallera
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA; (A.L.W.); (K.S.); (M.B.); (K.R.); (K.B.); (S.P.); (A.C.); (M.G.O.); (B.J.W.)
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Radiation Oncology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
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Dan H, Jiang Q, Jia X, Qi G, Zong D, Li Z. Dermatologic toxicities in epidermal growth factor receptor: a comprehensive pharmacovigilance study from 2013 to 2023. Front Med (Lausanne) 2024; 10:1283807. [PMID: 38327269 PMCID: PMC10848916 DOI: 10.3389/fmed.2023.1283807] [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: 08/27/2023] [Accepted: 12/26/2023] [Indexed: 02/09/2024] Open
Abstract
Epidermal growth factor receptor inhibitors (EGFRIs) induced cutaneous toxicity is a common adverse event (AE), although it is not as severe as major cancers, we still need to pay enough attention to them. Therefore, it is necessary to evaluate the diversity of EGFRI class drugs. The objective of this study was to conduct a scientific and systematic investigation into the correlation between EGFRI and cutaneous toxicities. The data accessed from the FDA adverse event reporting system database (FAERS) encompass a time frame spanning from January 2013 to March 2023. By utilizing reporting odds ratios (RORs), information components (ICs), proportional reporting ratios (PRRs), and chi-squared (χ2), the relationship between drugs and adverse reactions was evaluated through disproportionality analysis. Within the FAERS database, a total of 29,559 skin adverse events were recorded. A robust indication of the correlation between EGFRI and elderly patients (≥65 years) was identified. Among EGFRIs, erlotinib accounted for the largest proportion of skin adverse events (39.72%). Rash, dry skin, and pruritus ranked top among all preferred terms, and signals such as rash, skin lesions, and acneiform dermatitis were detected in every single drug. Clinicians should guide patients customize the treatment plan for each patient.
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Affiliation(s)
- Hanyu Dan
- Medical Information Analysis Laboratory, College of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China
| | - Qiang Jiang
- Medical Information Analysis Laboratory, College of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiangnan Jia
- Medical Information Analysis Laboratory, College of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China
| | - Guanpeng Qi
- School of Artificial Intelligence and Computer Science, Jiangnan University, Wuxi, China
| | - Dongsheng Zong
- Medical Information Analysis Laboratory, College of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China
| | - Zuojing Li
- Medical Information Analysis Laboratory, College of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China
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De Luca E, Sollena P, Di Nardo L, D'Argento E, Vita E, Tortora G, Peris K. Facial Papulopustular Eruption during the COVID-19 Pandemic in Patients Treated with EGFR Inhibitors. Dermatol Res Pract 2024; 2024:8859032. [PMID: 38249546 PMCID: PMC10796184 DOI: 10.1155/2024/8859032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 09/16/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Papulopustular rash (PPR) is the most frequent cutaneous adverse event during treatment with epidermal growth factor receptor inhibitors (EGFRis). Although often mild in severity, it can impair patients' quality of life and may also be a reason for discontinuing or changing the dose of the antineoplastic treatment. During COVID-19 pandemics, the use of surgical masks drastically increased and it had an impact on the face skin microenvironment, favoring the worsening of dermatological pathologies. We reported the relapse of PPR in patients treated with EGFR inhibitors who consistently wore face masks (>6 hours/day). All the patients developed the PPR within 6 months of starting mask use. Compared to the PPR occurred previously, after mask use, the skin eruption was more severe and affected mainly those regions of the face which came into contact with the mask. Patients received topical or systemic treatment, obtaining complete response in 65.7% of the cases. The establishment of an early treatment for the PPR allows continuing the oncologic treatment, without any suspension which could result in a decreased oncologic outcome. In conclusion, when using these devices, it is recommended to use special precautions, particularly in oncologic patients, by using a daily prophylactic skincare and replacing masks regularly with regular and frequent breaks.
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Affiliation(s)
- Eleonora De Luca
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Pietro Sollena
- Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Lucia Di Nardo
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ettore D'Argento
- Oncologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Emanuele Vita
- Oncologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Giampaolo Tortora
- Oncologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Ketty Peris
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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Yang F, Smith MJ. Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling. Free Radic Biol Med 2024; 210:158-171. [PMID: 37989446 DOI: 10.1016/j.freeradbiomed.2023.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/18/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023]
Abstract
Coronary ischemia-reperfusion (IR) injury results from a blockage of blood supply to the heart followed by restoration of perfusion, leading to oxidative stress induced pathological processes. Nuclear factor erythroid 2-related factor 2 (NRF2), a master antioxidant transcription factor, plays a key role in regulating redox signaling. Over the past decades, the field of metallomics has provided novel insights into the mechanism of pro-oxidant and antioxidant pathological processes. Both redox-active (e.g. Fe and Cu) and redox-inert (e.g. Zn and Mg) metals play unique roles in establishing redox balance under IR injury. Notably, Zn protects against oxidative stress in coronary IR injury by serving as a cofactor of antioxidant enzymes such as superoxide dismutase [Cu-Zn] (SOD1) and proteins such as metallothionein (MT) and KEAP1/NRF2 mediated antioxidant defenses. An increase in labile Zn2+ inhibits proteasomal degradation and ubiquitination of NRF2 by modifying KEAP1 and glycogen synthase kinase 3β (GSK3β) conformations. Fe and Cu catalyse the formation of reactive oxygen species via the Fenton reaction and also serve as cofactors of antioxidant enzymes and can activate NRF2 antioxidant signaling. We review the evidence that Zn and redox-active metals Fe and Cu affect redox signaling in coronary cells during IR and the mechanisms by which oxidative stress influences cellular metal content. In view of the unique double-edged characteristics of metals, we aim to bridge the role of metals and NRF2 regulated redox signaling to antioxidant defenses in IR injury, with a long-term aim of informing the design and application of novel therapeutics.
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Affiliation(s)
- Fan Yang
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
| | - Matthew J Smith
- MSD R&D Innovation Centre, 120 Moorgate, London EC2M 6UR, United Kingdom.
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Marini M, Titiz M, Souza Monteiro de Araújo D, Geppetti P, Nassini R, De Logu F. TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches. Biomolecules 2023; 13:1557. [PMID: 37892239 PMCID: PMC10605459 DOI: 10.3390/biom13101557] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
Ion channels play a crucial role in a wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family of channels has emerged as a promising therapeutic target due to its involvement in several stages of cancer development and dissemination. TRP channels are expressed in a large variety of cells and tissues, and by increasing cation intracellular concentration, they monitor mechanical, thermal, and chemical stimuli under physiological and pathological conditions. Some members of the TRP superfamily, namely vanilloid (TRPV), canonical (TRPC), melastatin (TRPM), and ankyrin (TRPA), have been investigated in different types of cancer, including breast, prostate, lung, and colorectal cancer. TRP channels are involved in processes such as cell proliferation, migration, invasion, angiogenesis, and drug resistance, all related to cancer progression. Some TRP channels have been mechanistically associated with the signaling of cancer pain. Understanding the cellular and molecular mechanisms by which TRP channels influence cancer provides new opportunities for the development of targeted therapeutic strategies. Selective inhibitors of TRP channels are under initial scrutiny in experimental animals as potential anti-cancer agents. In-depth knowledge of these channels and their regulatory mechanisms may lead to new therapeutic strategies for cancer treatment, providing new perspectives for the development of effective targeted therapies.
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Affiliation(s)
| | | | | | | | - Romina Nassini
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, 50139 Florence, Italy; (M.M.); (M.T.); (D.S.M.d.A.); (P.G.); (F.D.L.)
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8
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Fowler M, Tobback H, Karuri A, Fernández-Ortega P. Nursing care and management of adverse events for patients with BRAF V600E-mutant metastatic colorectal cancer receiving encorafenib in combination with cetuximab: a review. Support Care Cancer 2023; 31:204. [PMID: 36881161 PMCID: PMC9989561 DOI: 10.1007/s00520-023-07579-9] [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: 07/08/2022] [Accepted: 01/05/2023] [Indexed: 03/08/2023]
Abstract
Encorafenib is a B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) inhibitor, approved in the EU and USA, in combination with the epidermal growth factor receptor (EGFR) inhibitor cetuximab, for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC). In the pivotal BEACON CRC trial, patients achieved longer survival with encorafenib in combination with cetuximab vs. conventional chemotherapy. This targeted therapy regimen is also generally better tolerated than cytotoxic treatments. However, patients may present with adverse events unique to the regimen and characteristic of BRAF and EGFR inhibitors, which produce their own set of challenges. Nurses play an essential role in navigating the care of patients with BRAFV600E-mutant mCRC and managing adverse events that patients may experience. This includes early and efficient identification of treatment-related adverse events, subsequent management of adverse events and education of patients and their caregivers around key adverse events. This manuscript aims to provide support to nurses managing patients with BRAFV600E-mutant mCRC receiving encorafenib in combination with cetuximab, by summarising potential adverse events and providing guidance on how to manage them. Special attention will be paid to the presentation of key adverse events, dose modifications that may be required, practical recommendations and supportive care measures.
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Affiliation(s)
- Matthew Fowler
- University Hospitals of Derby and Burton NHSFT, Uttoxeter Road, DE22 3NE, Derby, UK.
| | | | | | - Paz Fernández-Ortega
- Institut Català d'Oncologia, Granvia de l'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain
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9
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Chen C, Shi Q, Xu J, Ren T, Huang Y, Guo W. Current progress and open challenges for applying tyrosine kinase inhibitors in osteosarcoma. Cell Death Dis 2022; 8:488. [PMID: 36509754 PMCID: PMC9744866 DOI: 10.1038/s41420-022-01252-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/06/2022] [Accepted: 11/10/2022] [Indexed: 12/15/2022]
Abstract
Osteosarcoma (OS) is a mesenchymal-origin tumor that constitutes the most common primary malignant bone tumor. The survival rate of the patients has significantly improved since the introduction of neoadjuvant chemotherapy and extensive resection, but it has stagnated in recent 40 years. Tyrosine kinase inhibitors (TKIs) have played a key part in the treatment of malignant tumors. In advanced OS, TKIs including anlotinib, apatinib, sorafenib, etc. have significantly improved the progression-free survival of patients, while the overall survival remains unchanged. The main reason is the rapid and inevitable progress of acquired drug resistance of OS. However, as the application of TKIs in OS and other tumors is still in the exploratory phase, its drug resistance mechanism and corresponding solutions are rarely reported. Hence, in this review, we summarize knowledge of the applications of TKIs, the mechanism of TKIs resistance, and the attempts to overcome TKIs resistance in OS, which are the three potentially novel insights of TKIs in OS. Because most evidence is derived from studies using animal and cell models, we also reviewed clinical trials and related bioinformatics data available in public databases, which partially improved our understanding of TKIs applications.
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Affiliation(s)
- Chenglong Chen
- grid.414360.40000 0004 0605 7104Department of Orthopedics, Beijing Jishuitan Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Qianyu Shi
- grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Jiuhui Xu
- grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Tingting Ren
- grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Yi Huang
- grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, People’s Republic of China
| | - Wei Guo
- grid.411634.50000 0004 0632 4559Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital, Beijing, People’s Republic of China ,grid.411634.50000 0004 0632 4559Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, People’s Republic of China
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10
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Dettling DE, Kwok E, Quach L, Datt A, Degenhardt JD, Panchal A, Seto P, Krakow JL, Wall R, Hillier BJ, Zhu Y, Vinogradova M, DuBridge RB, May C. Regression of EGFR positive established solid tumors in mice with the conditionally active T cell engager TAK-186. J Immunother Cancer 2022; 10:jitc-2021-004336. [PMID: 35728872 PMCID: PMC9214390 DOI: 10.1136/jitc-2021-004336] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
Background Despite clinical success with T cell engagers (TCEs) targeting hematological malignancies, achieving a safe and efficacious dose in patients with solid tumors remains challenging. Due to potency, low levels of target antigen expression on normal tissues may not be tolerated. To overcome this, we engineered a novel conditionally active TCE design called COBRA (Conditional Bispecific Redirected Activation). Administered as prodrugs, COBRAs bind to cell surface antigens on both normal and tumor tissues but are preferentially activated within the tumor microenvironment. Methods A COBRA was engineered to target EGFR, TAK-186. The potency of precleaved TAK-186 relative to a non-cleavable control was assessed in vitro. Mice bearing established solid tumors expressing a range of EGFR levels were administered a single bolus of human T cells, and concurrently treated with TAK-186 and associated controls intravenously. We assessed the plasma and tumor exposure of intact and cleaved TAK-186. Results TAK-186 shows potent redirected T cell killing of antigen expressing tumor cells. In vivo efficacy studies demonstrate regressions of established solid tumors, dependent on intratumoral COBRA cleavage. Pharmacokinetic studies reveal TAK-186 is stable in circulation, but once activated is rapidly cleared due to loss of its albumin-binding half-life extension domain. Conclusions The studies shown support the advancement of TAK-186, and the pursuit of additional COBRA TCEs for the treatment of solid tumors.
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Affiliation(s)
- Danielle E Dettling
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Eilene Kwok
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Lucy Quach
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Aakash Datt
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Jeremiah D Degenhardt
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Anand Panchal
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Pui Seto
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Jessica L Krakow
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Russell Wall
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Brian J Hillier
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Ying Zhu
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Maia Vinogradova
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Robert B DuBridge
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
| | - Chad May
- Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA
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11
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Herpers B, Eppink B, James MI, Cortina C, Cañellas-Socias A, Boj SF, Hernando-Momblona X, Glodzik D, Roovers RC, van de Wetering M, Bartelink-Clements C, Zondag-van der Zande V, Mateos JG, Yan K, Salinaro L, Basmeleh A, Fatrai S, Maussang D, Lammerts van Bueren JJ, Chicote I, Serna G, Cabellos L, Ramírez L, Nuciforo P, Salazar R, Santos C, Villanueva A, Stephan-Otto Attolini C, Sancho E, Palmer HG, Tabernero J, Stratton MR, de Kruif J, Logtenberg T, Clevers H, Price LS, Vries RGJ, Batlle E, Throsby M. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. NATURE CANCER 2022; 3:418-436. [PMID: 35469014 DOI: 10.1038/s43018-022-00359-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 03/04/2022] [Indexed: 12/19/2022]
Abstract
Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.
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Affiliation(s)
- Bram Herpers
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | - Mark I James
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Carme Cortina
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Adrià Cañellas-Socias
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Sylvia F Boj
- Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands
| | - Xavier Hernando-Momblona
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Dominik Glodzik
- Wellcome Sanger Institute, Hinxton, UK
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | | | - Marc van de Wetering
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | | | | | - Jara García Mateos
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | - Kuan Yan
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | | | | | | | | | - Irene Chicote
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Garazi Serna
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Laia Cabellos
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Lorena Ramírez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ramon Salazar
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Santos
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Alberto Villanueva
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
- Xenopat SL, Parc Cientific de Barcelona (PCB), Barcelona, Spain
| | - Camille Stephan-Otto Attolini
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Hector G Palmer
- CIBERONC, Madrid, Spain
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Josep Tabernero
- CIBERONC, Madrid, Spain
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | | | | | | | - Hans Clevers
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Leo S Price
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.
- CIBERONC, Madrid, Spain.
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
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12
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Li Y, Fu R, Jiang T, Duan D, Wu Y, Li C, Li Z, Ni R, Li L, Liu Y. Mechanism of Lethal Skin Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors and Related Treatment Strategies. Front Oncol 2022; 12:804212. [PMID: 35223483 PMCID: PMC8866822 DOI: 10.3389/fonc.2022.804212] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/17/2022] [Indexed: 02/01/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancers such as non-small cell lung cancer, head and neck cancer, breast cancer, pancreatic cancer. Adverse reactions such as skin toxicity, interstitial lung disease, hepatotoxicity, ocular toxicity, hypomagnesemia, stomatitis, and diarrhea may occur during treatment. Because the EGFR signaling pathway is important for maintaining normal physiological skin function. Adverse skin reactions occurred in up to 90% of cancer patients treated with EGFR inhibitors, including common skin toxicities (such as papulopustular exanthemas, paronychia, hair changes) and rare fatal skin toxicities (e.g., Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis). This has led to the dose reduction or discontinuation of EGFR inhibitors in the treatment of cancer. Recently, progress has been made about research on the skin toxicity of EGFR inhibitors. Here, we summarize the mechanism of skin toxicity caused by EGFR inhibitors, measures to prevent severe fatal skin toxicity, and provide reference for medical staff how to give care and treatment after adverse skin reactions.
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Affiliation(s)
- Yanping Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Ruoqiu Fu
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Tingting Jiang
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Dongyu Duan
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Yuanlin Wu
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Chen Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Ziwei Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Rui Ni
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Li Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Yao Liu
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
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13
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Bavbek S, Pagani M, Alvarez‐Cuesta E, Castells M, Dursun AB, Hamadi S, Madrigal‐Burgaleta R, Sanchez‐Sanchez S, Vultaggio A. Hypersensitivity reactions to biologicals: An EAACI position paper. Allergy 2022; 77:39-54. [PMID: 34157134 DOI: 10.1111/all.14984] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/31/2021] [Accepted: 06/15/2021] [Indexed: 12/15/2022]
Abstract
Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research.
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Affiliation(s)
- Sevim Bavbek
- Division of Immunology and Allergy Department of Chest Diseases School of Medicine Ankara University Ankara Turkey
| | - Mauro Pagani
- Medical Department Medicine Ward ASST di Mantova Mantova Italy
| | | | - Mariana Castells
- Division of Allergy and Immunology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
| | - Adile Berna Dursun
- Department of Immunology and Allergic Diseases Recep Tayyip Erdoğan University Rize Turkey
| | - Sahar Hamadi
- Division of Allergy and Immunology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
| | - Ricardo Madrigal‐Burgaleta
- Allergy & Severe Asthma Service St Bartholomew's Hospital Barts Health NHS Trust London UK
- Drug Desensitisation Centre Catalan Institute of Oncology Barcelona Spain
| | | | - Alessandra Vultaggio
- Department of Biomedicine Azienda Ospedaliera Universitaria Careggi Florence Italy
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Xie L, Xu J, Guo W, Wang Z, Yao Y, Li J, Lin J, Xiao J, Yu X, Zhang W, Cai Z, Hua Y, Chen J, Shao Z, Wu D, Wu S, Tu Z, Zhang X. Management of Apatinib-Related Adverse Events in Patients With Advanced Osteosarcoma From Four Prospective Trials: Chinese Sarcoma Study Group Experience. Front Oncol 2021; 11:696865. [PMID: 34367981 PMCID: PMC8339966 DOI: 10.3389/fonc.2021.696865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 06/29/2021] [Indexed: 02/05/2023] Open
Abstract
Four prospective trials have reported apatinib-related efficacy in osteosarcoma, with a high response rate of 43.2%. Currently, Adverse Events (AEs) have increasingly gained attention, as treatment with multiple tyrosine kinase inhibitors (TKIs) is potentially lifelong. For this reason, a consensus meeting of the Chinese Sarcoma Study Group (CSSG), which is a multidisciplinary panel composed of pediatric, medical and surgical oncologists specializing in sarcoma, nurse specialists, oncological senior pharmacists and gastroenterologists, was held to develop comprehensive guidelines on AEs emerging due to apatinib treatment to better assist in the prevention, management, and understanding of AE development. We summarized all AEs that arose in ≥10% of the participants as well as rare AEs that required extra caution to prevent that were observed in these four published prospective trials and arranged these AEs into 14 disorder systems according to CTCAE 5.0. In this review, we discuss strategies for the management of AEs in patients with advanced osteosarcoma, with the aim of maximizing treatment benefits and minimizing the need for apatinib treatment discontinuation. We also focus on providing recommendations for the prophylaxis and treatment of advanced osteosarcoma using apatinib to achieve optimal outcomes.
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Affiliation(s)
- Lu Xie
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China
| | - Jie Xu
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China
| | - Zhen Wang
- Orthopedic Oncology, Xijing Hospital Air Force Medical University of PLA (The Fourth Military Medical University), Xi'an, China
| | - Yang Yao
- Medical Oncology, Shanghai Sixth People's Hospital, Shanghai, China
| | - Jianmin Li
- Orthopedic Oncology, Qilu Hospital of Shandong University, Jinan, China
| | - Jianhua Lin
- Musculoskeletal Tumor Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jianru Xiao
- Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai, China
| | - Xiuchun Yu
- Orthopedic Oncology, Jinan Military General Hospital, Jinan, China
| | - Weibin Zhang
- Orthopedic Oncology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
| | - Zhendong Cai
- Orthopedic Oncology, Shanghai General Hospital, Shanghai, China
| | - Yingqi Hua
- Orthopedic Oncology, Shanghai General Hospital, Shanghai, China
| | - Jing Chen
- Orthopedic Oncology and Medical Oncology, Wuhan Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Zengwu Shao
- Orthopedic Oncology and Medical Oncology, Wuhan Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Di Wu
- Medical Oncology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Sujia Wu
- Orthopedic Oncology, General Hospital of Eastern Theater Command, Nanjing, China
| | - Zhongqi Tu
- Orthopedic Oncology, Huaxi Hospital West China School of Medicine/West China Hospital of Sichuan University (WCSM/WCH), Chengdu, China
| | - Xiaojing Zhang
- Musculoskeletal Tumor Center, Liaoning Cancer Hospital & Institute, Shenyang, China
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15
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João Pissarra A, Abreu C, Mansinho A, Lúcia Costa A, Dâmaso S, Lobo-Martins S, Martins M, Costa L. Landscape of Current Targeted Therapies for Advanced Colorectal Cancer. COLORECTAL CANCER 2021. [DOI: 10.5772/intechopen.93978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.
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16
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Lee SF, Choi HCW, Chan SK, Lam KO, Lee VHF, Wong IOL, Chiang CL. Cost-Effectiveness of Anti-Epidermal Growth Factor Receptor Therapy Versus Bevacizumab in KRAS Wild-Type (WT), Pan-RAS WT, and Pan-RAS WT Left-Sided Metastatic Colorectal Cancer. Front Oncol 2021; 11:651299. [PMID: 34012917 PMCID: PMC8127841 DOI: 10.3389/fonc.2021.651299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/25/2021] [Indexed: 11/13/2022] Open
Abstract
Objectives We aimed to compare the economic value of chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) against chemotherapy with bevacizumab (Bev, an anti-vascular endothelial growth factor mAb) as first-line treatment in KRAS wild-type (WT), pan-RAS WT and pan-RAS WT left-sided metastatic colorectal cancer (mCRC) patients from the Hong Kong societal perspective. Materials and Methods We developed Markov models and 10-year horizon to estimate costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of chemotherapy plus anti-EGFR therapy against chemotherapy plus Bev in KRAS WT, pan-RAS WT, and pan-RAS WT left-sided mCRC. We considered two times of the local gross domestic product per capita (GDPpc) as the willingness-to-pay (WTP) threshold (2× GDPpc; US$97,832). Results Adding anti-EGFR mAb to chemotherapy provides additional 0.24 (95% confidence interval [CI] 0.19-0.29), 0.32 (95% CI 0.27-0.37), and 0.57 (95% CI 0.49-0.63) QALY compared to adding Bev in KRAS WT, pan-RAS WT, and left-sided pan-RAS WT mCRC populations respectively. The corresponding ICER is US$106,847 (95% CI 87,806-134,523), US$88,565 (95% CI 75,678-105,871), US$76,537 (95% CI 67,794-87,917) per QALY gained, respectively. Conclusions Anti-EGFR therapy is more cost-effective than Bev as a first-line targeted therapy in left-sided pan-RAS WT and pan-RAS WT, with ICER <US$100,000/QALY, compared to KRAS WT mCRC population.
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Affiliation(s)
- Shing Fung Lee
- Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hong Kong, Hong Kong
| | - Horace C W Choi
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, Hong Kong
| | - Sik Kwan Chan
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, Hong Kong
| | - Ka On Lam
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, Hong Kong.,Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Victor H F Lee
- Department of Clinical Oncology, University of Hong Kong, Hong Kong, Hong Kong.,Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Irene O L Wong
- School of Public Health, University of Hong Kong, Hong Kong, Hong Kong
| | - Chi Leung Chiang
- Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hong Kong, Hong Kong.,Department of Clinical Oncology, University of Hong Kong, Hong Kong, Hong Kong.,Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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17
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Pietropaolo G, Pugliese D, Armuzzi A, Guidi L, Gasbarrini A, Rapaccini GL, Wolf FI, Trapani V. Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy. Nutrients 2020; 12:nu12113277. [PMID: 33114586 PMCID: PMC7692710 DOI: 10.3390/nu12113277] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy.
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Affiliation(s)
- Giuseppe Pietropaolo
- Sezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Daniela Pugliese
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (A.A.); (L.G.); (A.G.); (G.L.R.)
| | - Alessandro Armuzzi
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (A.A.); (L.G.); (A.G.); (G.L.R.)
| | - Luisa Guidi
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (A.A.); (L.G.); (A.G.); (G.L.R.)
| | - Antonio Gasbarrini
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (A.A.); (L.G.); (A.G.); (G.L.R.)
| | - Gian Lodovico Rapaccini
- UOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (A.A.); (L.G.); (A.G.); (G.L.R.)
| | - Federica I. Wolf
- Sezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Correspondence: (F.I.W.); (V.T.)
| | - Valentina Trapani
- Sezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Correspondence: (F.I.W.); (V.T.)
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18
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Abstract
Astrocytes, initially described as merely support cells, are now known as a heterogeneous population of cells actively involved in a variety of biological functions such as: neuronal migration and differentiation; regulation of cerebral blood flow; metabolic control of extracellular potassium concentration; and modulation of synapse formation and elimination; among others. Cerebellar glial cells have been shown to play a significant role in proliferation, differentiation, migration, and synaptogenesis. However, less evidence is available about the role of neuron-astrocyte interactions during cerebellar development and their impact on diseases of the cerebellum. In this review, we will focus on the mechanisms underlying cellular interactions, specifically neuron-astrocyte interactions, during cerebellar development, function, and disease. We will discuss how cerebellar glia, astrocytes, and Bergmann glia play a fundamental role in several steps of cerebellar development, such as granule cell migration, axonal growth, neuronal differentiation, and synapse formation, and in diseases associated with the cerebellum. We will focus on how astrocytes and thyroid hormones impact cerebellar development. Furthermore, we will provide evidence of how growth factors secreted by glial cells, such as epidermal growth factor and transforming growth factors, control cerebellar organogenesis. Finally, we will argue that glia are a key mediator of cerebellar development and that identification of molecules and pathways involved in neuron-glia interactions may contribute to a better understanding of cerebellar development and associated disorders.
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19
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Annunziata MC, De Stefano A, Fabbrocini G, Leo S, Marchetti P, Romano MC, Romano I. Current Recommendations and Novel Strategies for the Management of Skin Toxicities Related to Anti-EGFR Therapies in Patients with Metastatic Colorectal Cancer. Clin Drug Investig 2020; 39:825-834. [PMID: 31264159 DOI: 10.1007/s40261-019-00811-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The use of targeted therapies, when added to conventional chemotherapy, has significantly improved clinical outcomes and survival of cancer patients. While targeted therapies do not have the systemic adverse reactions of chemotherapy, they are associated with toxicities that can be severe and impair patient quality of life and adherence to anti-cancer treatment. Panitumumab and cetuximab, two monoclonal antibodies against epidermal growth factor receptor (EGFR), are recommended for the treatment of metastatic colorectal cancer (mCRC). The majority of patients with mCRC who are treated with anti-EGFR therapy develop skin toxicities, including papulopustular rash (the most common), xerosis, painful cracks and fissures on the palms and soles of the feet, paronychia, pruritus, and abnormal hair and eyelash growth; they are also more prone to skin infections. Given the involvement of EGFR in normal epidermis physiology, development and function, skin toxicities caused by anti-EGFR therapy are not unexpected. In recent years, recommendations have been formulated for the prevention and treatment of anti-EGFR therapy-related skin toxicities. Indeed, proper and timely management of these toxicities is important for ensuring uninterrupted anti-cancer treatment and optimal outcomes. Here, we review the current knowledge of anti-EGFR therapy-related skin toxicities and the latest recommendations for their management. We also present a treatment approach for papulopustular rash based on the combination of fusidic acid plus betamethasone in a lipid-enriched topical formulation. The effectiveness of this approach is documented by the presentation of five cases successfully treated in clinical practice for anti-EGFR therapy-related rash.
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Affiliation(s)
- Maria Carmela Annunziata
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Alfonso De Stefano
- SC Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Gabriella Fabbrocini
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Silvana Leo
- Medical Oncology Unit, Ospedale Vito Fazzi, Lecce, Italy
| | - Paolo Marchetti
- Oncology Unit, Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy.
- IDI-IRCCS, Rome, Italy.
| | | | - Ivana Romano
- Dermatologist, UOC Oncologia, Ospedale "Sacro Cuore di Gesù" Gallipoli - Progetto Lilt, Lecce, Italy
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20
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Bouché O, Ben Abdelghani M, Labourey JL, Triby S, Bensadoun RJ, Jouary T, Des Guetz G. Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer. World J Gastroenterol 2019; 25:4007-4018. [PMID: 31413534 PMCID: PMC6689814 DOI: 10.3748/wjg.v25.i29.4007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/07/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown.
AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management.
METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up.
RESULTS Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low.
CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.
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Affiliation(s)
- Olivier Bouché
- Department of Gastroenterology and Digestive Oncology, Hôpital Robert Debré, CHU Reims, Reims 51000, France
| | | | | | - Simon Triby
- Medical Department, AMGEN France, Boulogne-Billancourt 92100, France
| | | | - Thomas Jouary
- Dermatology Department, Hôpital Saint-André, CHU de Bordeaux, Bordeaux 33000, France
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21
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Shah RR, Shah DR. Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology. Drug Saf 2019; 42:181-198. [PMID: 30649743 DOI: 10.1007/s40264-018-0772-x] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) have dramatically improved progression-free survival in non-small-cell lung cancer (NSCLC) patients who carry sensitizing EGFR-activating mutations and in patients with breast and pancreatic cancers. However, EGFR-TKIs are associated with significant and disabling undesirable effects that adversely impact on quality of life and compliance. These effects include dermatological reactions, diarrhoea, hepatotoxicity, stomatitis, interstitial lung disease and ocular toxicity. Each individual EGFR-TKI is also associated with additional adverse effect(s) that are not shared widely by the other members of its class. Often, these effects call for dose reduction, treatment discontinuation or pharmacotherapeutic intervention. Since dermatological effects result from on-target effects on wild-type EGFR, rash is often considered to be a biomarker of efficacy. A number of studies have reported better outcomes in patients with skin reactions compared with those without. This has led to a 'dosing-to-rash' strategy to optimize therapeutic outcomes. Although conceptually attractive, there is currently insufficient evidence-based support for this strategy. While skin reactions following EGFR-TKIs are believed to result from an effect on wild-type EGFR, their efficacy is related to effects on mutant variants of EGFR. It is noteworthy that newer EGFR-TKIs that spare wild-type EGFR are associated with fewer dermatological reactions. Furthermore, secondary mutations such as T790M in exon 20 often lead to development of resistance to the clinical activity and efficacy of first- and second-generation EGFR-TKIs. This has stimulated the search for later-generations of EGFR-TKIs with the ability to overcome this resistance and with greater target selectivity to spare wild-type EGFR in expectations of an improved safety profile. However, available data reviewed herein indicate that not only are these newer agents associated with the aforementioned adverse effects typical of earlier agents, but they are also susceptible to resistance due to tertiary mutations, most frequently C797S. At least three later-generation EGFR-TKIs, canertinib, naquotinib and rociletinib, have been discontinued from further development in NSCLC following concerns about their safety and risk/benefit.
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22
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Gaiser MR, Lorenzen S, Merx K, Trojan J, Ocvirk J, Ettrich TJ, Al-Batran SE, Schulz H, Homann N, Feustel HP, Schatz M, Kripp M, Schulte N, Heeger S, Vlassak S, Koch W, Hofheinz RD. Evaluation of EGFR inhibitor-mediated acneiform skin toxicity within the double-blind randomized EVITA trial: A thorough gender-specific analysis using the WoMo score. Cancer Med 2019; 8:4169-4175. [PMID: 31199595 PMCID: PMC6675717 DOI: 10.1002/cam4.2132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/13/2019] [Accepted: 03/13/2019] [Indexed: 12/16/2022] Open
Abstract
Acne‐like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double‐blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1‐treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender‐specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)‐related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non‐parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.
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Affiliation(s)
- Maria R Gaiser
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Kirsten Merx
- Interdisciplinary Tumor Center Mannheim, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jörg Trojan
- Medical Clinic I, University Hospital Frankfurt, Frankfurt, Germany
| | | | | | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research (IKF) at Nordwest Hospital, UCT-University Cancer Center, Frankfurt, Germany
| | | | - Nils Homann
- Medical Clinic II Wolfsburg, Wolfsburg, Germany
| | | | - Michael Schatz
- Medizinische Klinik II, ViDia Christliche Kliniken Karlsruhe, Karlsruhe, Germany
| | - Melanie Kripp
- Interdisciplinary Tumor Center Mannheim, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Nadine Schulte
- Interdisciplinary Tumor Center Mannheim, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | | | | | | | - Ralf-Dieter Hofheinz
- Interdisciplinary Tumor Center Mannheim, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
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23
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Zou ZG, Rios FJ, Montezano AC, Touyz RM. TRPM7, Magnesium, and Signaling. Int J Mol Sci 2019; 20:E1877. [PMID: 30995736 PMCID: PMC6515203 DOI: 10.3390/ijms20081877] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/12/2019] [Accepted: 04/12/2019] [Indexed: 12/17/2022] Open
Abstract
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme that possesses an ion channel permeable to the divalent cations Mg2+, Ca2+, and Zn2+, and an α-kinase that phosphorylates downstream substrates. TRPM7 and its homologue TRPM6 have been implicated in a variety of cellular functions and is critically associated with intracellular signaling, including receptor tyrosine kinase (RTK)-mediated pathways. Emerging evidence indicates that growth factors, such as EGF and VEGF, signal through their RTKs, which regulate activity of TRPM6 and TRPM7. TRPM6 is primarily an epithelial-associated channel, while TRPM7 is more ubiquitous. In this review we focus on TRPM7 and its association with growth factors, RTKs, and downstream kinase signaling. We also highlight how interplay between TRPM7, Mg2+ and signaling kinases influences cell function in physiological and pathological conditions, such as cancer and preeclampsia.
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Affiliation(s)
- Zhi-Guo Zou
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Centre, University of Glasgow, Glasgow G12 8TA, UK.
| | - Francisco J Rios
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Centre, University of Glasgow, Glasgow G12 8TA, UK.
| | - Augusto C Montezano
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Centre, University of Glasgow, Glasgow G12 8TA, UK.
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Centre, University of Glasgow, Glasgow G12 8TA, UK.
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24
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Peng Y, Li Q, Zhang J, Shen W, Zhang X, Sun C, Cui H. Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors. Biosci Trends 2018; 12:537-552. [PMID: 30555112 DOI: 10.5582/bst.2018.01246] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The past decades have witnessed a rapid increase in the use of molecularly targeted therapies. One class of agents includes the epidermal growth factor receptor inhibitors (EGFRIs), which afford patients longer progression-free survival (PFS) times, especially among non-small cell lung cancer (NSCLC) and metastatic colorectal carcinoma (mCRC). Certain adverse effects, particularly skin toxicity, are mainly manifested as rash, xerosis, pruritus, nails changes, hair changes and mucositis. Previous studies reported the adverse events occurred based on the cutaneous inflammation reaction. Treatment recommended glucocorticoids and antibiotics. It is suggested that skin toxicity is an important issue because it usually affects patients' quality of life (QoL) and still causes dose reduction or discontinuation of targeted therapies. For these reasons, more and more oncologists and dermatologists recognize the importance of recognition and management of skin toxicities with the expansion in availability of EGFRIs. In this review, we conducted a systematic review of recent data to examine the types and frequencies of dermatologic toxicities associated with anti-epidermal growth factor receptor (EGFR) therapies in NSCLC and mCRC. In addition, we would like to explore the management and treatment options currently used by clinicians based on the possible mechanism.
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Affiliation(s)
- Yanmei Peng
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Qiang Li
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Jingyi Zhang
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Wen Shen
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Xu Zhang
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Chenyao Sun
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital
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25
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An Update of Efficacy and Safety of Cetuximab in Metastatic Colorectal Cancer: A Narrative Review. Adv Ther 2018; 35:1497-1509. [PMID: 30218345 DOI: 10.1007/s12325-018-0791-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is the second most common cancer, representing 13% of all diagnosed cancers. Cetuximab is a recombinant chimeric monoclonal IgG1 antibody and epidermal growth factor receptor (EGFR) inhibitor. Cetuximab is approved for the first-line treatment in combination with chemotherapy or as a single agent in patients who have failed or are intolerant to chemotherapy in patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer. Cetuximab efficacy emerged from studies that were conducted to approve the drug. Cetuximab is well tolerated; its toxicities are caused by its mechanism of action and the most common adverse reaction is skin toxicity. The main purpose of this manuscript is to present an update on the evidence-based summary of efficacy and safety and on the cost-effectiveness of cetuximab. Furthermore, it suggests a management of adverse drug reactions to improve the tolerability of the drug.
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26
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Iskandar AS, Hwang A, Dasanu CA. EGFR inhibitor-induced cut-like skin lesions of the fingers. BMJ Case Rep 2018; 2018:bcr-2017-224144. [PMID: 30068575 DOI: 10.1136/bcr-2017-224144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Cetuximab and osimertinib are epidermal growth factor receptors (EGFRs) inhibitors used in the treatment of several malignancies. These agents have been associated with several skin lesions, the most common being papulopustular acneiform rash involving the face, neck, chest and back. Herein, we describe a unique toxic effect of these agents involving the fingertips and lateral aspects of fingers in a small patient series. The lesions presented approximately 4 weeks into treatment were cut-like and caused local discomfort/pain. Application of a colloidal solution allowed for partial resolution of these lesions in one patient, while discontinuation of the drug led to the disappearance of the lesions in another. Thus, we call for awareness of this unique skin toxicity with the use of EGFR inhibitors in patients with cancer.
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Affiliation(s)
- Andrew S Iskandar
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, California, USA
| | - Andrew Hwang
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, California, USA
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27
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McGregor M, Price TJ. Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC. Future Oncol 2018; 14:2437-2459. [PMID: 29737864 DOI: 10.2217/fon-2017-0711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The humanized monoclonal antibody panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of panitumumab continues to evolve as understanding of sequencing of therapies grows. There is evidence for use as maintenance therapy and conversion therapy for unresectable liver metastases. Future research is likely to focus on biomarkers for improved patient selection and the development of novel therapeutic strategies to overcome resistance.
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Affiliation(s)
- Mark McGregor
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, Flinders Medical Centre, Adelaide, Australia
| | - Timothy J Price
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, The Queen Elizabeth Hospital & University of Adelaide, Woodville, Adelaide, Australia
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Hofheinz RD, Lorenzen S, Trojan J, Ocvirk J, Ettrich T, Al-Batran SE, Schulz H, Homann N, Feustel HP, Schatz M, Kripp M, Schulte N, Tetyusheva M, Heeger S, Vlassak S, Merx K. EVITA—a double-blind, vehicle-controlled, randomized phase II trial of vitamin K1 cream as prophylaxis for cetuximab-induced skin toxicity. Ann Oncol 2018; 29:1010-1015. [DOI: 10.1093/annonc/mdy015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Wollina U, Tchernev G, Lotti T. Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer. Open Access Maced J Med Sci 2017; 6:152-155. [PMID: 29484016 PMCID: PMC5816291 DOI: 10.3889/oamjms.2018.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Revised: 11/14/2017] [Accepted: 10/29/2017] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in humans. Targeted therapy with monoclonal antibody cetuximab is an option in case of advanced tumor or metastasis. AIM: We present and update of the use of cetuximab in NMSC searching PUBMED 2011-2017. METHODS: The monoclonal antibody cetuximab against epidermal growth factor receptor (EGFR) has been investigated for its use in NMSC during the years 2011 to 2017 by a PUBMED research using the following items: “Non-melanoma skin cancer AND cetuximab,” “cutaneous squamous cell carcinoma AND cetuximab,” and “basal cell carcinoma AND cetuximab”, and “cetuximab AND skin toxicity”. Available data were analyzed including case reports. RESULTS: Current evidence of cetuximab efficacy in NMSC was mainly obtained in cutaneous SCC and to a lesser extend in BCC. Response rates vary for neoadjuvant, adjuvant, mono- and combined therapy with cetuximab. Management of cutaneous toxicities is necessary. Guidelines are available. CONCLUSIONS: Cetuximab is an option for recurrent or advanced NMSC of the skin. It seems to be justified particularly in very high-risk tumors. There is a need for phase III trials.
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Affiliation(s)
- Uwe Wollina
- Department of Dermatology and Allergology, Städtisches Klinikum Dresden, 01067 Dresden, Germany
| | - Georgi Tchernev
- Medical Institute of the Ministry of Interior, Dermatology, Venereology and Dermatologic Surgery.,Onkoderma, Private Clinic for Dermatologic Surgery, Dermatology and Surgery, Sofia 1407, Bulgaria
| | - Torello Lotti
- University G. Marconi of Rome, Dermatology and Venereology, Rome 00192, Italy
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AIO LQ-0110: a randomized phase II trial comparing oral doxycycline versus local administration of erythromycin as preemptive treatment strategies of panitumumab-mediated skin toxicity in patients with metastatic colorectal cancer. Oncotarget 2017; 8:105061-105071. [PMID: 29285233 PMCID: PMC5739620 DOI: 10.18632/oncotarget.21249] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/08/2017] [Indexed: 11/25/2022] Open
Abstract
Background Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b.i.d. (standard arm) or erythromycin ointment 2% followed by doxycycline in case of insufficient activity. The primary endpoint was the percentage of patients developing no skin toxicity ≥ grade 2 at any time during the first 8 weeks of panitumumab treatment. Skin toxicity was assessed using the NCI CTCAE v 4.0. Secondary endpoints comprised the assessment of skin toxicity using a more thorough grading system (WoMo score), evaluation of skin-related (DLQI) and global quality of life (EORTC QLQ C30). Results In total, 88 patients were included in this trial. 69% of the patients in the erythromycin arm suffered from skin toxicity of grade ≥ 2 versus 63% in the standard arm (P = n.s.). However, as per WoMo score significantly more patients in the erythromycin arm developed moderate or severe skin toxicity at earlier time points. Skin related and overall quality of life was comparable between both arms. Conclusions Based on this data erythromycin cannot be regarded as an alternative to doxycycline as prevention of EGFR-related skin toxicity.
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