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1
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Kagaya M, Uesawa Y. Nuclear Receptors and Stress Response Pathways Associated with the Development of Oral Mucositis Induced by Antineoplastic Agents. Pharmaceuticals (Basel) 2024; 17:1086. [PMID: 39204191 PMCID: PMC11358984 DOI: 10.3390/ph17081086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Oral mucositis (OM) is one of the common adverse events associated with cancer treatment that decreases the quality of life and affects treatment outcomes. However, the medications used to manage OM are generally only palliative, and our knowledge of the syndrome is limited. The etiology of the syndrome is thought to be complex and multifactorial. We investigated the trends and characteristics of OM and estimated molecular initiating events (MIEs) associated with the development of the syndrome using the FDA Adverse Event Reporting System. The study of trends and characteristics suggested that OM is significantly more likely to occur in females and nonelderly patients and is likely to be induced by protein kinase inhibitors such as afatinib and everolimus. Next, we used Toxicity Predictor, an in-house quantitative structure-activity relationship system, to estimate OM-associated MIEs. The results revealed that the agonist activity of the human pregnane X receptor, thyroid-stimulating hormone-releasing hormone receptor, and androgen receptor may be associated with OM development. Our study findings are expected to help avoid the risk of OM induction during the drug discovery process and clinical use of antineoplastic agents.
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Affiliation(s)
| | - Yoshihiro Uesawa
- Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
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2
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Mohammed AI, Fedoruk L, Fisher N, Liu AX, Khanna S, Naylor K, Gong Z, Celentano A, Alrashdan MS, Cirillo N. Systemic Anti-Inflammatory Agents in the Prevention of Chemoradiation-Induced Mucositis: A Review of Randomised Controlled Trials. Biomolecules 2024; 14:560. [PMID: 38785967 PMCID: PMC11117894 DOI: 10.3390/biom14050560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/25/2024] Open
Abstract
Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice.
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Affiliation(s)
- Ali I. Mohammed
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Lexi Fedoruk
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Nicholas Fisher
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Andy Xiaoqian Liu
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Samar Khanna
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Kaelan Naylor
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Ziyi Gong
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Antonio Celentano
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
| | - Mohammad S. Alrashdan
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Department of Oral Medicine and Oral Surgery, Faculty of Dentistry, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Nicola Cirillo
- Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Carlton, VIC 3053, Australia; (A.I.M.); (L.F.); (N.F.); (A.X.L.); (S.K.); (K.N.); (Z.G.); (A.C.)
- School of Dentistry, University of Jordan, Amman 11942, Jordan
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3
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Solé S, Becerra S, Carvajal C, Bettolli P, Letelier H, Santini A, Vargas L, Cifuentes A, Larsen F, Jara N, Oyarzún J, Bustamante E, Martínez B, Rosenberg D, Galván T. Clinical relevance of the use of Dentoxol ® for oral mucositis induced by radiotherapy: A phase II clinical trial. World J Clin Oncol 2022; 13:813-821. [PMID: 36337310 PMCID: PMC9630999 DOI: 10.5306/wjco.v13.i10.813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/22/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe oral mucositis associated with cancer therapy is a frequent complication that may affect a patient's systemic condition, resulting in interruption and/or prolongation of cancer therapy. Dentoxol® is a medical solution in the form of a mouthwash that has been shown to result in statistically significant improvement in the prevention of severe oral mucositis. However, knowing the measures of the clinical significance of this therapy is important for accurate decision-making.
AIM To describe the clinical impact of Dentoxol® use in severe oral mucositis.
METHODS Clinical significance was measured using the results obtained in a randomized controlled clinical trial previously conducted by the same group of researchers. The measures of clinical significance evaluated were the absolute risk or incidence, relative risk, absolute risk reduction, relative risk reduction, number needed to treat, and odds ratio.
RESULTS The data obtained show that the impact of Dentoxol® on reducing the severity of oral mucositis has important clinical relevance.
CONCLUSION The results of this study justify the incorporation of Dentoxol® mouth rinse into clinical protocols as a complement to cancer therapy to prevent and/or treat oral mucositis secondary to radiotherapy.
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Affiliation(s)
- Sebastián Solé
- Department of Radiotherapy, Radiomedicine Institute, Américo Vespucio Norte 1314 Vitacura, 7630370, Santiago, Chile
| | - Sergio Becerra
- National Institute of Cancer, Santiago, Servicio de Salud Metropolitano Norte, Av Profesor Zañartu 1010, Independencia, 8380455, Santiago, Chile
| | - Claudia Carvajal
- National Institute of Cancer, Santiago, Servicio de Salud Metropolitano Norte, Av Profesor Zañartu 1010, Independencia, 8380455, Santiago, Chile
| | - Piero Bettolli
- Oncologic Institute Arturo López Pérez Foundation, José Manuel Infante 805, Providencia, 7500691, Santiago, Chile
| | - Hernán Letelier
- Hospital Base Valdivia, Bueras 1003 s/n XIV Región, 5100238, Valdivia, Chile
| | - Alejandro Santini
- Oncologic Center of Antofagasta, Los Pumas 10255, Antofagasta, 1267348, Antofagasta, Chile
| | - Lorena Vargas
- Department of Radiotherapy, Radiomedicine Institute, Américo Vespucio Norte 1314 Vitacura, 7630370, Santiago, Chile
| | - Alexander Cifuentes
- National Institute of Cancer, Santiago, Servicio de Salud Metropolitano Norte, Av Profesor Zañartu 1010, Independencia, 8380455, Santiago, Chile
| | - Francisco Larsen
- Department of Radiotherapy, Radiomedicine Institute, Américo Vespucio Norte 1314 Vitacura, 7630370, Santiago, Chile
| | - Natalia Jara
- Department of Radiotherapy, Radiomedicine Institute, Américo Vespucio Norte 1314 Vitacura, 7630370, Santiago, Chile
| | - Jorge Oyarzún
- Hospital Base Valdivia, Bueras 1003 s/n XIV Región, 5100238, Valdivia, Chile
| | - Eva Bustamante
- Oncologic Institute Arturo López Pérez Foundation, José Manuel Infante 805, Providencia, 7500691, Santiago, Chile
| | - Benjamín Martínez
- Universidad Mayor, Santiago, Av Libertador Bernardo O´Higgins 2013, 8340585, Santiago, Chile
| | - David Rosenberg
- Ingalfarma, Dr Manuel Barros Borgoño 71, Oficina 1308, Providencia, 7500593, Santiago, Chile
| | - Tomas Galván
- Ingalfarma, Dr Manuel Barros Borgoño 71, Oficina 1308, Providencia, 7500593, Santiago, Chile
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Shetty SS, Maruthi M, Dhara V, de Arruda JAA, Abreu LG, Mesquita RA, Teixeira AL, Silva TA, Merchant Y. Oral mucositis: Current knowledge and future directions. Dis Mon 2022; 68:101300. [PMID: 34758917 DOI: 10.1016/j.disamonth.2021.101300] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Oral mucositis secondary to head and neck chemoradiation displays a complex molecular pathogenesis involving epithelial and microvascular injury, release of pro-inflammatory cytokines, and host-microbiome communications. These processes lead to oxidative stress and the release of reactive oxygen species that stifle the structural integrity of the oral mucosa, with emergence of erosions and ulcers. The consequences are malnutrition, psychological/psychiatric symptoms, poor quality of life, and occurrence of opportunistic infections. The latter pose a major challenge due to the risk of interruption of anti-neoplastic therapy, tumour recurrence and, ultimately, death. This article aims to present the clinical characteristics, molecular pathogenesis, and an overview of the predisposing factors and current management of oral mucositis. It is anticipated that the future direction of the management of oral mucositis will focus on evidence-based prehabilitation and pre- and per-chemoradiation therapy monitoring.
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Affiliation(s)
- Sameep S Shetty
- Department of Oral and Maxillofacial Surgery, Manipal College of Dental Sciences, Mangalore, Manipal Academy of Higher Education, A Constituent of MAHE, Manipal 576104, India.
| | - Meghana Maruthi
- Department of Dental Rehabilitative Oncology, HealthCare Global Enterprises Ltd., Bangalore, India.
| | - Vasantha Dhara
- Consultant Maxillofacial Surgeon, Hyderabad, Telangana, India.
| | - José Alcides Almeida de Arruda
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, room 3202 D, CEP: 31.270-910, Belo Horizonte, Minas Gerais, Brazil.
| | - Lucas Guimarães Abreu
- Department of Child's and Adolescent's Oral Health, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Ricardo Alves Mesquita
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Antonio Lucio Teixeira
- Faculdade Santa Casa BH, Belo Horizonte, Brazil. Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
| | - Tarcília Aparecida Silva
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, room 3204, CEP: 31.270-910, Belo Horizonte, Minas Gerais, Brazil.
| | - Yash Merchant
- Consultant Maxilofacial Surgeon, Pune, Maharashtra, India.
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Al-Zubidi N, Page JC, Gombos DS, Srivastava A, Appelbaum E, Gidley PW, Chambers MS, Nader ME. Immune-Related Oral, Otologic, and Ocular Adverse Events. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:399-416. [PMID: 34972977 DOI: 10.1007/978-3-030-79308-1_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Emerging immunotherapeutic agents, including immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), have revolutionized cancer treatment. The first immune checkpoint inhibitor (ICI) ipilimumab, an anti-CTLA-4, was approved in 2011. Since then, the US Food and Drug Administration (FDA) has approved more than half a dozen immune checkpoint inhibitors to treat various malignancies. These agents are part of a broader class of chemotherapy agents termed immunotherapy, which selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. While the effects of traditional chemotherapy are well known, the toxicity profile of emerging immune therapies is not fully elucidated. They have been associated with atypical side effects labeled collectively as immune-related adverse events (irAEs).
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Affiliation(s)
- Nagham Al-Zubidi
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Cody Page
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dan S Gombos
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Akanksha Srivastava
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eric Appelbaum
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul W Gidley
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark S Chambers
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marc-Elie Nader
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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6
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Koushik K, Janaki MG, Kumawat R, Paramesh R, Palaniyamma D. Safety and efficacy of Oro-T oral rinse in oral mucositis during cancer radiotherapy and/or chemotherapy: Cumulative analysis of two studies. J Cancer Res Ther 2021; 17:1503-1509. [PMID: 34916385 DOI: 10.4103/jcrt.jcrt_988_17] [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: 11/04/2022]
Abstract
Introduction Oral mucositis is inflammation of the mucosa of the mouth which ranges from redness to severe ulceration. It results from the local effects of radiation to the oral mucosa. Objectives The study is cumulative analysis of two studies (one comparative and the other open labeled) evaluated in individuals with oral mucositis during cancer radiotherapy and/or chemotherapy for the safety and efficacy of Oro-T mouthwash in a comparative design with normal saline. Methodology Both the studies were similar with respect to clinical and laboratory parameters for analysis. The participants were advised to use 10 ml of Oro-T for 1 min 4 times daily for 6 weeks starting from day 1 of standard care. Patients were followed up, and the results were assessed from baseline on visit days: At entry and at the end of every week for 6 weeks. Clinical assessment of oral condition was done objectively (by the investigator) and also subjectively. Clinical symptoms such as sore throat, number of ulcer, burning sensation, pain, difficulty in chewing, difficulty in drinking, and mucositis grading along with Patient Reported Outcome Measures Scale were evaluated at each interval. Data was available for 40 subjects in Oro-T and 15 subjects in NS groups respectively. Results and Conclusion The significant positive outcome was reported both subjectively and objectively in Oro-T group as compared to NS group with the delay in the onset of symptoms and less severe manifestation of oral mucositis with an improvement in quality of life. No adverse effects were reported that prompted discontinuation of study medication. Overall compliance to study medication was good.
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Affiliation(s)
- Kirthi Koushik
- Department of Radiotherapy, M S Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
| | - M G Janaki
- Department of Radiotherapy, M S Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
| | - Rajesh Kumawat
- Head Medical Services and Clinical Development, The Himalaya Drug Company, Bengaluru, Karnataka, India
| | - Rangesh Paramesh
- Chief Scientific officer, The Himalaya Drug Company, Bengaluru, Karnataka, India
| | - D Palaniyamma
- Principal Scientist-Medical Services and Clinical Development, The Himalaya Drug Company, Bengaluru, Karnataka, India
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Rao D, Behzadi F, Le RT, Dagan R, Fiester P. Radiation Induced Mucositis: What the Radiologist Needs to Know. Curr Probl Diagn Radiol 2020; 50:899-904. [PMID: 33279307 DOI: 10.1067/j.cpradiol.2020.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/16/2020] [Indexed: 11/22/2022]
Abstract
Radiation induced oral mucositis (RIOM) is a common and debilitating complication of radiation therapy for head and neck cancers. RIOM can lead to oral pain, dysphagia, and reduced oral intake, which can be severe enough to necessitate placement of a feeding tube or utilization of total parenteral nutrition. When severe, RIOM can cause premature termination of radiation therapy and can alter treatment plans leading to suboptimal treatment doses. While patient reporting of RIOM symptoms has been the gold standard of documenting RIOM progression, little has been described in the radiology literature concerning the typical imaging findings of RIOM. Herein, we review the pathophysiology and clinical presentation that underlies the development of RIOM with illustrative cases to highlight the relevant imaging findings related to RIOM for the practicing radiologist.
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Affiliation(s)
- Dinesh Rao
- Department of Radiology, UF Health Jacksonville, Jacksonville, FL
| | - Fardad Behzadi
- Department of Internal Medicine, Aventura Hospital and Medical Center, Aventura, FL
| | - Rebecca T Le
- Department of Radiology, UF Health Jacksonville, Jacksonville, FL; Department of Radiology, Rochester General Hospital, Rochester, NY.
| | - Roi Dagan
- Department of Radiation Oncology, UF Proton Center, Jacksonville, FL
| | - Peter Fiester
- Department of Radiology, UF Health Jacksonville, Jacksonville, FL
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Efficacy and safety of Dentoxol® in the prevention of radiation-induced oral mucositis in head and neck cancer patients (ESDOM): a randomized, multicenter, double-blind, placebo-controlled, phase II trial. Support Care Cancer 2020; 28:5871-5879. [PMID: 32266567 PMCID: PMC7686187 DOI: 10.1007/s00520-020-05358-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/12/2020] [Indexed: 01/02/2023]
Abstract
PURPOSE The aim of this study was to assess the efficacy and safety of Dentoxol mouthrinse in reducing the severity of oral mucositis (OM) secondary to radiation therapy (RT) for head and neck cancer. METHODS A randomized, double-blind, placebo-controlled, multicenter phase II clinical trial was conducted. Subjects were asked to use Dentoxol (n = 55) or control (n = 53) mouthrinse 5 times/day during RT. Twice a week, OM was assessed clinically using the WHO scale and the Oral Mucositis Daily Questionnaire (OMDQ) was completed. RESULTS The incidence of severe OM was 40.7% in the Dentoxol group and 51% in the control group (p = 0.265). Comparing all recorded clinical assessments, severe OM was seen in 13.3% of all assessments in the Dentoxol group vs. 21.8% in the control group (p = 0.000). There was a statistically significant lower proportion of assessments showing severe OM in the Dentoxol group at weeks 4, 5, and 6 of RT. The mean duration of severe OM was 11.95 days in the Dentoxol group vs. 14.59 days in the control group (p = 0.502). There was no difference between groups in mouth pain and its impact on function. The use of Dentoxol was safe and was not linked to any serious adverse events. CONCLUSION The use of Dentoxol 5 times/day is safe and resulted in significantly fewer time-points with severe OM and a delay in the onset of severe OM, compared with a control rinse. A phase III clinical trial is warranted to confirm efficacy and address the limitations of this study.
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9
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Esteves I, Santos FPS, Ribeiro AAF, Seber A, Sugawara EK, Sobrinho JJDN, Barros JC, Oliveira JSR, Fernandes JF, Hamerschlak N, Andersson BS, de Lima M, Kerbauy FR. Targeted-dose of busulfan: Higher risk of sinusoidal obstructive syndrome observed with systemic exposure dose above 5000 µMol⸱min. A historically controlled clinical trial. Hematol Oncol 2020; 38:773-781. [PMID: 32779746 DOI: 10.1002/hon.2789] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 07/22/2020] [Accepted: 08/07/2020] [Indexed: 11/12/2022]
Abstract
Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.
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Affiliation(s)
- Iracema Esteves
- Hospital Israelita Albert Einstein, São Paulo, Brazil.,Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | | | | | | | | | | | - José Carlos Barros
- Transplantation, Hospital Dr. Euryclides de Jesus Zerbini, São Paulo, Brazil
| | | | - Juliana Folloni Fernandes
- Hospital Israelita Albert Einstein, São Paulo, Brazil.,Bone Marrow Transplantation Unit, Itaci Hospital, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | | | - Borje S Andersson
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marcos de Lima
- Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA
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Widjaja NA, Pratama A, Prihaningtyas R, Irawan R, Ugrasena I. Efficacy Oral Glutamine to Prevent Oral Mucositis and Reduce Hospital Costs During Chemotherapy in Children with Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev 2020; 21:2117-2121. [PMID: 32711440 PMCID: PMC7573404 DOI: 10.31557/apjcp.2020.21.7.2117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Indexed: 11/25/2022] Open
Abstract
Objective: To investigate the use of glutamine administered orally during Methotrexate chemotherapy to prevent oral mucositis and reduce hospital costs in children with acute lymphoblastic leukemia (ALL). Methods: Twenty-four children received oral glutamine (400 mg/kg body weight per day) and twenty four received placebo on days of chemotherapy administration and for at least 14 additional days. Oral mucositis was graded daily at each day of treatment till completion of therapy. The study groups were compared for the oral mucositis development using the WHO scale. Results: Oral mucositis occurred in 4.2 % of the glutamine group and 62.5% in the placebo group. The use of glutamine was directly associated with prevention of oral mucositis than placebo (OR 0,026; 95% CI: 0,003-0,228). The duration of length hospital stay was lower in the glutamine group than in the placebo group ((8 vs 12 days); p = 0,005). Hospital cost per day for glutamine group was 40 USD per day while placebo group was 48 USD per day. Conclusions: There was significant difference in the prevention of oral mucositis by oral glutamine vs placebo. The hospital cost for glutamine supplementation was lower than control group.
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Affiliation(s)
- Nur Aisiyah Widjaja
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ardha Pratama
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Rendi Prihaningtyas
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Roedi Irawan
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Idg Ugrasena
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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11
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Anderson PM, Lalla RV. Glutamine for Amelioration of Radiation and Chemotherapy Associated Mucositis during Cancer Therapy. Nutrients 2020; 12:nu12061675. [PMID: 32512833 PMCID: PMC7352314 DOI: 10.3390/nu12061675] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
Glutamine is a major dietary amino acid that is both a fuel and nitrogen donor for healing tissues damaged by chemotherapy and radiation. Evidence supports the benefit of oral (enteral) glutamine to reduce symptoms and improve and/or maintain quality of life of cancer patients. Benefits include not only better nutrition, but also decreased mucosal damage (mucositis, stomatitis, pharyngitis, esophagitis, and enteritis). Glutamine supplementation in a high protein diet (10 grams/day) + disaccharides, such as sucrose and/or trehalose, is a combination that increases glutamine uptake by mucosal cells. This increased topical effect can reduce painful mucosal symptoms and ulceration associated with chemotherapy and radiation in the head and neck region, esophagus, stomach and small intestine. Topical and oral glutamine seem to be the preferred routes for this amino acid to promote mucosal healing during and after cancer treatment.
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Affiliation(s)
- Peter M. Anderson
- Cleveland Clinic Pediatric Hematology/Oncology and Bone Marrow Transplant, Pediatric Institute and Taussig Cancer Institute, Cleveland, OH 44195, USA
- Correspondence: ; Tel.: +1-216-308-2706
| | - Rajesh V. Lalla
- UConn Health, School of Dental Medicine, Farmington, CT 06030 USA;
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Immune-Related Oral, Otologic, and Ocular Adverse Events. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:295-307. [PMID: 32301024 DOI: 10.1007/978-3-030-41008-7_17] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Emerging immunotherapy agents, such as immune checkpoint inhibitors, have shown remarkable promise in the treatment of various malignancies. These drugs selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. Due to the novelty of these therapeutic agents, their toxicity profile is less well understood.Meta-analysis results reveal that the overall prevalence of oral mucositis, stomatitis, and xerostomia is lower with checkpoint inhibitors compared to conventional chemotherapy, and head and neck radiation therapy. However, the widespread use of immunotherapy reveals new oral mucosal barrier adverse events, including bullous pemphigoid, mucous membrane pemphigoid, and lichenoid mucositis. Audiovestibular dysfunction can occur from autoimmune-mediated pathways of immunotherapy (adoptive cell) with limited treatment options. Such auditory complications can lead to speech recognition deficits and sensorineural hearing loss. Ocular toxicities are among the most common adverse events resulting from the use of these agents. The majority of ocular immune-related adverse events (irAEs) are mild, low-grade, non-sight threatening, such as blurred vision, conjunctivitis, and ocular surface disease. Serious and sight-threatening events, including corneal perforation, optic neuropathy, and retinal vascular occlusion, can occur but are infrequent. In this chapter, we review the current evidence on the clinical manifestations of oral, audiovestibular, and ocular immune-related adverse events (i.e., irAEs).
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Berger K, Staudenmaier T, Cenzer I, Crispin A, Strobach D, Ostermann H. Epidemiology, patient adherence, and costs of oral mucositis in routine care in stem cell transplantation. Support Care Cancer 2019; 28:3113-3123. [DOI: 10.1007/s00520-019-05107-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 09/30/2019] [Indexed: 12/30/2022]
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Carreón-Burciaga RG, Castañeda-Castaneira E, González-González R, Molina-Frechero N, Gaona E, Bologna-Molina R. Severity of Oral Mucositis in Children following Chemotherapy and Radiotherapy and Its Implications at a Single Oncology Centre in Durango State, Mexico. Int J Pediatr 2018; 2018:3252765. [PMID: 29861749 PMCID: PMC5971240 DOI: 10.1155/2018/3252765] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/12/2018] [Accepted: 03/29/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mucositis is an adverse effect of chemotherapy (QT) and/or radiotherapy (RT). The purpose of this study was to investigate the occurrence of oral mucositis in children undergoing cancer treatment. METHODS Fifty-one children with cancer who had received QT, RT, or both (QT-RT) underwent clinical evaluations; World Health Organization criteria were used to establish the degree and severity of mucositis. The correlations between the clinical data, type of cancer, and therapy were statistically analysed. RESULTS Mucositis was present in 88.23% of the patients; 57.78%, 7.78%, and 24.44% received QT, RT, and QT-RT, respectively. Severity scores of 1 and 2 were the most common; scores of 3-4 were observed in patients who received QT-RT or more than 7 treatment cycles. There was a significant association between mucositis, the type of treatment, and the number of cycles received (p < 0.05). CONCLUSION It is important to implement therapeutic protocols that help maintain excellent oral health and reduce the risk of oral mucositis. Stomatologists should be consulted to assess patients' oral cavities and provide preventive treatment prior to QT and/or RT administration. It is important to integrate a stomatologist into the oncological working group to focus on preventing and managing oral mucositis.
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Affiliation(s)
- Ramón G. Carreón-Burciaga
- Research Department, Faculty of Dentistry, University of Juarez of Durango State, Durango, DGO, Mexico
| | - Enrique Castañeda-Castaneira
- Division of Biological Sciences and Health, Metropolitan Autonomous University, Xochimilco, Ciudad de México, Mexico
| | - Rogelio González-González
- Research Department, Faculty of Dentistry, University of Juarez of Durango State, Durango, DGO, Mexico
| | - Nelly Molina-Frechero
- Division of Biological Sciences and Health, Metropolitan Autonomous University, Xochimilco, Ciudad de México, Mexico
| | - Enrique Gaona
- Division of Biological Sciences and Health, Metropolitan Autonomous University, Xochimilco, Ciudad de México, Mexico
| | - Ronell Bologna-Molina
- Molecular Pathology Area, School of Dentistry, University of the Republic, Montevideo, Uruguay
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Staudenmaier T, Cenzer I, Crispin A, Ostermann H, Berger K. Burden of oral mucositis in stem cell transplant patients-the patients' perspective. Support Care Cancer 2017; 26:1577-1584. [PMID: 29197961 DOI: 10.1007/s00520-017-4000-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/24/2017] [Indexed: 11/26/2022]
Abstract
PURPOSE Purpose of this study was to determine the impact of Oral Mucositis (OM) on health-related quality of life (HRQoL) and quality of life associated symptoms and functions in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS Prospective, non-interventional single-center observational study at a German tertiary teaching hospital. Inpatient allogenic and autologous stem cell transplant patients ≥18-year-old with high-dose chemotherapy. OM was assessed with the WHO Oral Toxicity Scale, pain according to the Numeric Rating Scale (NRS) and the performance status using the ECOG Score. QOL was captured with the EORTC QLQ-C30 and the QLQ-OH15 questionnaires. RESULTS Forty-five stem cell transplant patients (20 autologous, 25 allogenic) were enrolled between August 2016 and February 2017. Twenty-six (58%, 95% CI: 42% - 72%) patients developed OM (10 grade I, 4 grade II, 8 grade III, 4 grade IV). OM affected patients suffered more from pain, sore mouth and sensitive mouth. A lower physical functioning (34.5 vs 7.5, p = 0.003) and a lower oral health-related quality of life (24.3 vs 7.7, p = 0.006) was found in patients with OM development. There was found a positive correlation between the grade of OM and the NRS-value (r = 0.93, 95% CI: 0.89-0.96, p < 0.001). CONCLUSION OM is associated with health-related quality of life and quality of life associated functions and symptoms. More research should be performed to find ways to prevent OM and to stabilize patients' quality of life during HSCT.
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Affiliation(s)
- Tim Staudenmaier
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Irena Cenzer
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Crispin
- Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Helmut Ostermann
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Karin Berger
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
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The Effect of Orally-Administered Zinc in the Prevention of Chemotherapy-Induced Oral Mucositis in Patients with Acute Myeloid Leukemia. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.9252] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Abstract
Dermatologists face a wide range of pain control challenges in daily practice, from the transient pain of dermatologic surgery to the persistent pain that plagues some chronic dermatologic conditions. Although the pathophysiology of pain is well described and the profound impact of dermatological pain on patients' quality of life is well appreciated, there is an identified need for clear therapeutic plans for providing symptomatic pain relief of common painful dermatoses. In this paper, we will review and clearly outline approaches to pain management of a number of common painful dermatoses such as herpes zoster and post-herpetic neuralgia, ulcers, oral dermatoses, dysesthesias, and many others.
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Aoyama T, Nishikawa K, Takiguchi N, Tanabe K, Imano M, Fukushima R, Sakamoto J, Oba MS, Morita S, Kono T, Tsuburaya A. Double-blind, placebo-controlled, randomized phase II study of TJ-14 (hangeshashinto) for gastric cancer chemotherapy-induced oral mucositis. Cancer Chemother Pharmacol 2014; 73:1047-54. [PMID: 24652604 PMCID: PMC4000413 DOI: 10.1007/s00280-014-2440-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 03/06/2014] [Indexed: 11/20/2022]
Abstract
BACKGROUND Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with gastric cancer. METHODS We randomly assigned patients with gastric cancer who developed moderate-to-severe oral mucositis (CTCAE v4.0 grade ≧1) during any cycle of chemotherapy to receive either TJ-14 or a placebo as a double-blind trial. The patients received a placebo or TJ-14 for 2-6 weeks according to the chemotherapy regimen from the beginning of the next course of chemotherapy. The primary end point was the incidence of grade ≧2 oral mucositis in the protocol treatment course, and the secondary end points were the time to disappearance of oral mucositis and the incidence of adverse events. RESULTS Following the key opening of the blinding protocol, we analyzed 91 eligible patients (TJ-14: 45, placebo: 46) using a "per protocol set" analysis. The incidence of ≧grade 2 COM was 40.0 % in the TJ-14 group and 41.3 % in the placebo group (p = 0.588). The median duration of ≧grade 2 COM was 14 days in the TJ-14 group and 16 days in the placebo group (p = 0.894). Meanwhile, the median duration of any grade of COM was 9 days in the TJ-14 group and 17 days in the placebo group among the patients who developed grade 1 symptoms during the screening cycle [hazard ratio 0.60; 95 % CI (0.23-1.59), p = 0.290]. CONCLUSIONS Although TJ-14 treatment did not reduce the incidence of ≥2 COM in the patients who developed mucositis during chemotherapy for gastric cancer, a trend was observed in which TJ-14 reduced the risk of COM in the patients who developed grade 1 COM during the screening cycle. Further, phase III studies with a larger sample size are needed to clarify the protective effects of TJ-14 for COM.
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Affiliation(s)
- Toru Aoyama
- Department of Surgery, Miura City Hospital, Miura, Japan,
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19
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Padmini C, Bai KY. Oral and dental considerations in pediatric leukemic patient. ISRN HEMATOLOGY 2014; 2014:895721. [PMID: 24724033 PMCID: PMC3960739 DOI: 10.1155/2014/895721] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Accepted: 01/17/2014] [Indexed: 11/24/2022]
Abstract
Throughout the world, there have been drastic decline in mortality rate in pediatric leukemic population due to early diagnosis and improvements in oncology treatment. The pediatric dentist plays an important role in the prevention, stabilization, and treatment of oral and dental problems that can compromise the child's health and quality of life during, and follow up of the cancer treatment. This manuscript discusses recommendations and promotes dental care of the pediatric leukemic patients.
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Affiliation(s)
- Chiyadu Padmini
- Department of Pedodontics and Preventive Dentistry, Malla Reddy Institute of Dental Sciences, Hyderabad, Andhra Pradesh, India ; NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India
| | - K Yellamma Bai
- NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India ; Department of Pedodontics and Preventive Dentistry, Mally Reddy Women's Dental College, Hyderabad, Andhra Pradesh, India
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20
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Kono T, Kaneko A, Matsumoto C, Miyagi C, Ohbuchi K, Mizuhara Y, Miyano K, Uezono Y. Multitargeted Effects of Hangeshashinto for Treatment of Chemotherapy-Induced Oral Mucositis on Inducible Prostaglandin E2 Production in Human Oral Keratinocytes. Integr Cancer Ther 2014; 13:435-45. [DOI: 10.1177/1534735413520035] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Objective. Chemotherapy-induced oral mucositis (COM) is characterized by painful inflammation with prolonged damage that involves the pathological pain-evoking prostaglandin E2 (PGE2). We previously found that gargling with hangeshashinto (HST), a traditional Japanese medicine, was effective for the treatment of COM. However, little is known regarding the mechanisms. Our aim was to identify the active ingredients and clarify the characteristic effects of HST on the PGE2 system. Methods. Prostanoids produced by human oral keratinocytes (HOK) stimulated with IL-1β were measured by enzyme immunoassay. Active ingredients that regulate PGE2 production were identified and quantified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and a culture system of HOK cells. Results. Inducible PGE2, PGD2, and PGF2α, metabolites of cyclooxygenase (COX) pathways, were reduced by HST (10-300 µg/mL) without inducing cytotoxicity. The active ingredients of HST were quantified by LC-MS/MS, and [6]-shogaol, [6]-gingerol, wogonin, baicalein, baicalin, and berberine were shown to reduce PGE2 production. A mixture of these 6 ingredients at concentrations equal to 300 µg/mL of HST strongly suppressed PGE2 production to the same level as HST. [6]-Shogaol and [6]-gingerol did not decrease COX-2 mRNA expression and mostly inhibited PGE2 metabolic activity in an assay using intact HOK cells, suggesting that they regulate PGE2 synthesis at the posttranscriptional level. Wogonin, baicalin, and berberine inhibited expression of COX-2 mRNA without affecting PGE2 metabolic activity. Moreover, wogonin, but not [6]-shogaol, suppressed phosphorylation of mitogen-activated protein kinases (p38s and JNKs). Conclusions. These lines show that HST includes several PGE2-regulating ingredients that have different mechanisms and can function as a multicomponent and multitarget agent for treatment of COM, indicating that HST may be beneficial in a new medical strategy for COM treatment.
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Affiliation(s)
- Toru Kono
- Hokkaido University, Sapporo, Japan
- Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Atsushi Kaneko
- Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan
| | - Chinami Matsumoto
- Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan
| | - Chika Miyagi
- Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan
| | - Katsuya Ohbuchi
- Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan
| | - Yasuharu Mizuhara
- Tsumura Research Laboratories, Tsumura and Co, Inashiki-gun, Ibaraki, Japan
| | - Kanako Miyano
- National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Yasuhito Uezono
- National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
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Ghosh S, Wadhwa P, Kumar A, Pai K, Seshadri S, Manohar C. Abnormal radiological features in a multiple myeloma patient: a case report and radiological review of myelomas. Dentomaxillofac Radiol 2012; 40:513-8. [PMID: 22065801 DOI: 10.1259/dmfr/74265829] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Multiple myeloma is the prototype of malignant monoclonal gammopathies. The most common skeletal sites are pelvis, skull, spine, ribs and femoral and humeral shafts. The classic radiographic presentation of multiple myeloma is lytic skeletal lesions. Other types of presentation include sclerotic and porotic changes. Primary sclerotic manifestations are rare and occur in only 3% of cases. Although exceptional, multiple myeloma must be borne in mind in the presence of bone sclerosis. This report presents a patient with multiple myeloma with a sunburst/hair-on-end pattern on the radiograph and sclerotic skeletal lesions.
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Affiliation(s)
- S Ghosh
- Center for Dental Education & Research, All India Institute of Medical Sciences, New Delhi, India.
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Oral mucositis in children suffering from acute lymphoblastic leukaemia. Contemp Oncol (Pozn) 2012; 16:12-5. [PMID: 23788849 PMCID: PMC3687384 DOI: 10.5114/wo.2012.27331] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 09/12/2011] [Accepted: 12/02/2011] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Oral mucositis is the most commonly reported side effect observed in neoplastic patients treated with chemotherapy and radiotherapy of the head and neck region as well as in patients who have received a haematopoietic stem cell transplant. The aim of the study was to assess the oral mucosa status in children with acute lymphoblastic leukaemia (ALL) during antineoplastic therapy. Material and methods The clinical examination included 78 children aged 2-18 with ALL. The clinical examination was conducted using the dental preset tray. The condition of the oral mucosa was determined using the WHO scale for oral mucositis. Results In the first period of antineoplastic therapy the pathological lesions of the oral mucosa of the mucositis type were observed among the examined patients. The lesions had various levels of intensity. Pain was found to be the primary symptom of oral mucositis. In this study the following were observed: local erythema of the oral mucosa in 35%, white pseudomembranous lesions in 18%, erosions in 40% and oral ulcerative lesions in 4% of patients who underwent the antineoplastic therapy. Oral mucositis was observed in 3.17% of children after 6 months of chemotherapy. Conclusion Local treatment of oral mucositis with polyantibiotic-antifungal mixture, supporting antifungal systemic treatment, and improving the overall peripheral blood conditions in children suffering from acute lymphoblastic leukaemia improve the condition of the oral mucosa.
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23
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Lalla RV. Translating mucositis research from animal models to humans: challenges and opportunities. THE JOURNAL OF SUPPORTIVE ONCOLOGY 2011; 9:169. [PMID: 22024304 DOI: 10.1016/j.suponc.2011.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 04/22/2011] [Indexed: 10/17/2022]
Affiliation(s)
- Rajesh V Lalla
- University of Connecticut Health Center, Farmington, CT, USA.
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A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy. Support Care Cancer 2011; 20:1797-804. [PMID: 21964618 DOI: 10.1007/s00520-011-1277-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 09/13/2011] [Indexed: 10/17/2022]
Abstract
PURPOSE Misoprostol, a synthetic analog of prostaglandin E1, has anti-inflammatory and mucosa-protecting properties. The objective of this study was to evaluate the efficacy of misoprostol oral rinse in reducing the severity of oral mucosal injury caused by high-dose chemotherapy. METHODS The study used a randomized, double-blind, placebo-controlled, parallel-group design. Oncology patients receiving myeloablative high-dose chemotherapy, in preparation for a hematopoietic stem cell transplant, were randomized to misoprostol or placebo rinse. The primary outcome measure was the severity of oral mucositis, measured using the modified Oral Mucositis Index. Additional outcome measures included the severity of mouth pain (measured using a Visual Analog Scale and the Pain Affect Faces Scale), duration of hospital stay, and days on total parenteral nutrition. RESULTS This study was originally planned to accrue 160 subjects but was terminated early due to revised sponsor research priorities. The intent-to-treat population consisted of 22 subjects randomized to misoprostol rinse and 26 subjects randomized to placebo rinse. There was no significant difference between the two groups in mucositis or pain severity. In both groups, duration of hospital stay was approximately 19 days, and number of days on total parenteral nutrition was 17-18 days. There were no serious adverse events attributable to misoprostol rinse. CONCLUSIONS Although this study did not find a beneficial effect of a misoprostol rinse in mucositis secondary to high-dose chemotherapy, the small sample size limits the strength of this conclusion. Given the proposed importance of the prostaglandin pathway in the pathogenesis of oral mucositis, additional studies are warranted.
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Lopes NNF, Plapler H, Lalla RV, Chavantes MC, Yoshimura EM, da Silva MAB, Alves MTS. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters. Lasers Surg Med 2010; 42:546-52. [PMID: 20662031 DOI: 10.1002/lsm.20920] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Several studies have suggested that low-level laser therapy (LLLT) can ameliorate oral mucositis; however, the mechanisms involved are not well understood. The aim of this study was to investigate the mechanisms of action of LLLT on chemotherapy-induced oral mucositis, as related to effects on collagen expression and inflammation. MATERIALS AND METHODS A hamster cheek pouch model of oral mucositis was used with all animals receiving intraperitoneal 5-fluorouracil, followed by surface irritation. Animals were randomly allocated into three groups, and treated with an InGaAIP diode laser at a wavelength of 660 nm and output power of 35 or 100 mW laser, or no laser. Clinical severity of mucositis was assessed at four time-points by a blinded examiner. Buccal pouch tissue was harvested from a subgroup of animals in each group at four time-points. Collagen was qualitatively and quantitatively evaluated after picrosirius staining. The density of the neutrophil infiltrate was also scored. RESULTS Peak clinical severity of mucositis was reduced in the 35 mW laser group as compared to the 100 mW and control groups. The reduced peak clinical severity of mucositis in the 35 mW laser group was accompanied by a decrease in the number of neutrophils and an increase in the proportion of mature collagen as compared to the other two groups. The total quantity of collagen was significantly higher in the control (no laser) group at the day 11 time-point, as compared to the 35 mW laser group, consistent with a more prolonged inflammatory response in the control group. CONCLUSION This study supports two mechanisms of action for LLLT in reducing mucositis severity. The increase in collagen organization in response to the 35 mW laser indicates that LLLT promotes wound healing. In addition, LLLT also appears to have an anti-inflammatory effect, as evidenced by the reduction in neutrophil infiltrate.
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Affiliation(s)
- Nilza Nelly Fontana Lopes
- Department of Experimental Surgery, Federal University of São Paulo, São Paulo CEP 04023-062, Brazil.
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Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Support Care Cancer 2009; 18:95-103. [PMID: 19404685 DOI: 10.1007/s00520-009-0635-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2008] [Accepted: 03/30/2009] [Indexed: 10/20/2022]
Abstract
GOALS Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis. MATERIALS AND METHODS We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day -10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1beta, and TNF-alpha. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients. MAIN RESULTS Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant. CONCLUSIONS Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis.
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Abstract
There are many types of diseases associated with the oral cavity. As an adjunct to professional oral dental care, various drug delivery systems have been developed to improve the treatment or prevention of these diseases. In this manuscript, the current status of drug delivery strategies for these common orofacial diseases is reviewed. Biomineral-binding drug delivery and on-demand drug release are suggested to be considered in the future design of drug delivery systems for orofacial diseases. Apparently, this research field deserves much more attention from both pharmaceutical scientists and dental health professionals.
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Affiliation(s)
- Xin-Ming Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA
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Figliolia SLC, Oliveira DT, Pereira MC, Lauris JRP, Maurício AR, Oliveira DT, Mello de Andrea ML. Oral mucositis in acute lymphoblastic leukaemia: analysis of 169 paediatric patients. Oral Dis 2008; 14:761-6. [PMID: 18761642 DOI: 10.1111/j.1601-0825.2008.01468.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Chemotherapy-induced oral mucositis is a frequent therapeutic challenge in cancer patients. The purpose of this retrospective study was to estimate the prevalence and risk factors of oral mucositis in 169 acute lymphoblastic leukaemia (ALL) patients treated according to different chemotherapeutic trials at the Darcy Vargas Children's Hospital from 1994 to 2005. Demographic data, clinical history, chemotherapeutic treatment and patients' follow-up were recorded. The association of oral mucositis with age, gender, leucocyte counts at diagnosis and treatment was assessed by the chi-squared test and multivariate regression analysis. Seventy-seven ALL patients (46%) developed oral mucositis during the treatment. Patient age (P = 0.33), gender (P = 0.08) and leucocyte counts at diagnosis (P = 0.34) showed no correlation with the occurrence of oral mucositis. Multivariate regression analysis showed a significant risk for oral mucositis (P = 0.009) for ALL patients treated according to the ALL-BFM-95 protocol. These results strongly suggest the greater stomatotoxic effect of the ALL-BFM-95 trial when compared with Brazilian trials. We concluded that chemotherapy-induced oral mucositis should be systematically analysed prospectively in specialized centres for ALL treatment to establish the degree of toxicity of chemotherapeutic drugs and to improve the quality of life of patients based on more effective therapeutic and prophylactic approaches for prevention of its occurrence.
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Affiliation(s)
- S L C Figliolia
- Department of Stomatology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
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29
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Abstract
Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, and have a significant economic impact. The pathogenesis of oral mucositis is multifactorial and complex. This review discusses the morbidity, economic impact, pathogenesis and clinical course of mucositis. Current clinical management of oral mucositis is largely focused on palliative measures such as pain management, nutritional support and maintenance of good oral hygiene. However, several promising therapeutic agents are in various stages of clinical development for the management of oral mucositis. These agents are discussed in the context of recently updated evidence-based clinical management guidelines.
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Affiliation(s)
- Rajesh V Lalla
- Division of Oral Medicine, Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center MC 1605, 263 Farmington Avenue, Farmington, CT 06030, USA.
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30
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Stoopler ET, Vogl DT, Stadtmauer EA. Medical management update: Multiple myeloma. ACTA ACUST UNITED AC 2007; 103:599-609. [PMID: 17291793 DOI: 10.1016/j.tripleo.2006.10.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Revised: 10/20/2006] [Accepted: 10/23/2006] [Indexed: 02/08/2023]
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal proliferation of immunoglobulin-secreting plasma cells. Manifestations of MM may include anemia, osteolytic lesions, and renal dysfunction. Treatment for this disease chiefly consists of corticosteroids, bisphosphonates, chemotherapy, and hematopoietic stem-cell transplantation. This medical management update will review recent clinical and therapeutic advances in the field of MM and highlight issues that are important to the oral health care provider.
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Affiliation(s)
- Eric T Stoopler
- Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
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31
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Abstract
Mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, lead to sepsis, and have significant economic impact. Recent modeling of the toxicity has been based on the continuum of clinical signs and symptoms of mucositis involving the alimentary tract, including both oral and gastrointestinal sites. The pathogenesis of oral and gastrointestinal mucositis is multifactorial and complex. In recent years, there has been a substantial increase in both basic and clinical research related to mucosal injury in cancer patients. Since most of this research has been directed to oral mucositis, the present review principally addresses this component of the toxicity. Morbidity, economic impact, pathogenesis and clinical course of mucositis are discussed. In addition, several agents in clinical development for mucositis are discussed in the context of the current pathobiologic model as well as the recently updated evidence-based clinical management guidelines.
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Affiliation(s)
- Rajesh V Lalla
- Division of Oral Medicine, Department of Oral Health and Diagnostic Sciences and the Head and Neck/Oral Oncology Program, Neag Comprehensive Cancer Center University of Connecticut Health Center, Farmington, CT 06030, USA.
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32
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Abstract
Mucositis and xerostomia are the most common oral complications of the non-surgical therapy of cancer. Mucositis, a common sequel of radio- (DXR), chemo-(CXR) and radiochemo-therapy in patients with cancer, or patients requiring haemopoietic stem cell transplants (HSCT), has a direct and significant impact on the quality of life and cost of care, and also affects survival--because of the risk of infection. Apart from dose reduction, preventive and treatment options for mucositis are scarce, although multiple agents have been tested. Evidence suggests that cryotherapy, topical benzydamine and amifostine might provide some benefit in specific situations. The recombinant human keratinocyte growth factor Palifermin (Kepivance) was recently approved as a mucositis intervention in patients receiving conditioning regimens before HSCT for the treatment of haematological malignancies. A number of mechanistically based interventions are in various stages of development. Unfortunately, many other approaches have not been rigorously tested. This paper reviews the clinical features, prevalence, diagnosis, complications, pathogenesis, prophylaxis and management of mucositis.
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Affiliation(s)
- C Scully
- Eastman Dental Institute, University College London, University of London, London, UK.
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33
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Elad S, Ackerstein A, Bitan M, Shapira MY, Resnick I, Gesundheit B, Cohen Y, Diss O, Barak D, Dray L, Or R. A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation. Bone Marrow Transplant 2006; 37:757-62. [PMID: 16518424 DOI: 10.1038/sj.bmt.1705331] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45+/-1 in the HDC group and 1.21+/-1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7+/-3.6 and 2.33+/-2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.
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Affiliation(s)
- S Elad
- Department of Oral Medicine, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel.
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Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti-inflammatory agents in the management of alimentary mucositis. Support Care Cancer 2006; 14:558-65. [PMID: 16565821 DOI: 10.1007/s00520-006-0050-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Accepted: 02/21/2006] [Indexed: 01/02/2023]
Abstract
BACKGROUND Alimentary mucositis is a significant complication of cancer therapy, with important clinical and economic implications. MATERIALS AND METHODS In June 2005, the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology conducted an evidence-based review of the literature on alimentary mucositis. The goal of this literature review was to update previously published guidelines for the management of mucositis. RESULTS This article reports the findings of the subgroup charged with reviewing the literature related to anti-inflammatory interventions. Considerable preclinical and clinical evidence suggests that the use of anti-inflammatory agents may be a promising approach to reduce the severity of mucositis. However, there was not enough evidence to support any new guidelines advocating the use of any specific anti-inflammatory intervention. CONCLUSION Thus, there is a need for well-designed clinical trials evaluating the use of anti-inflammatory agents in the management of mucositis.
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Affiliation(s)
- Rajesh V Lalla
- Department of Oral Health and Diagnostic Sciences MC1605, University of Connecticut Health Center, 263, Farmington Avenue, Farmington, 06030-1605, USA.
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