Rechallenge After Oxaliplatin-Induced Hypersensitivity Reactions.
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ABSTRACT:
SUBMITTER: Rassy E
PROVIDER: S-EPMC9880861 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
Rechallenge After Oxaliplatin-Induced Hypersensitivity Reactions.
Rassy Elie E Le Roy Florence F Smolenschi Cristina C Valéry Marine M Boige Valérie V Ducreux Michel M Boilève Alice A
JAMA oncology 20230301 3
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Project description:An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.
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Project description:Interventions: Dexamethasone 13.2mg/body i.v.(day1) Oxaliplatin 130mg/m2 i.v. (day1) Bevaciumab 7.5mg/Kg i.v. (day1) Capecitabine2,000mg/m2,p.o.(day1-14) to be repeated every 3 weeks
Primary outcome(s): Hypersensitivity reaction incidence
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Project description:This research study will examine how often hypersensitivity, or allergic reactions, occur in patients receiving the chemotherapy medication oxaliplatin. Hypersensitivity reactions can vary from a transient skin rash and fever to more severe symptoms such as shortness of breath, chest tightness, and a more severe allergic reaction that can affect blood pressure called anaphylaxis. We will be examining how often hypersensitivity reactions occur and how severe the reactions are when they occur. We will also examine whether there are factors that place people at risk for developing hypersensitivity reactions to oxaliplatin. In an optional portion to this study, we will examine whether allergy skin testing can predict whether someone will develop a hypersensitivity reaction.
Participants who develop a moderate to severe allergic reaction to oxaliplatin will be invited to participate in an additional portion of the study examining a desensitization process. This part of the study will examine whether a desensitization process can prevent future hypersensitivity reactions to oxaliplatin in patients who previously developed moderate to severe hypersensitivity reactions and allow therapy with oxaliplatin to continue.
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Project description:Oxaliplatin is a key drug for colorectal cancer and causes peripheral neuropathy. Oxaliplatin-induced laryngopharyngeal dysesthesia is an acute peripheral neuropathy similar to a hypersensitivity reaction. Hypersensitivity reactions to oxaliplatin do not require immediate discontinuation, but re-challenge and desensitization therapy can be very burdensome for patients. We encountered 2 cases in which laryngopharyngeal dysesthesia could be differentiated from hypersensitivity reactions to oxaliplatin, and treatment could continue. The first case was that of a 58-year-old woman who developed dyspnea during the first course of combination therapy with capecitabine and oxaliplatin as the primary treatment for advanced rectal cancer. After laryngopharyngeal dysesthesia was differentiated from hypersensitivity reaction based on these typical symptoms, she was considered to have grade 3 (Common Terminology Criteria for Adverse Events [CTCAE] ver. 5) laryngopharyngeal dysesthesia. The second course of oxaliplatin was extended from 2 to 4 h, but symptoms recurred. The third course was performed with a reduced dose of oxaliplatin from 130 mg/m2 to 100 mg/m2, and the patient could complete the treatment without symptom recurrence. The second case involved a 76-year-old woman who developed grade 3 laryngopharyngeal dysesthesia during the first course of combination therapy with capecitabine and oxaliplatin as the primary treatment for localized colon cancer. Based on the experience of the first case, we reduced the oxaliplatin dose from 130 mg/m2 to 100 mg/m2 for the second course, and the patient completed the treatment without symptoms. This dose reduction was effective for grade 3 laryngopharyngeal dysesthesia caused by oxaliplatin without reducing therapeutic efficacy.
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Project description:Hypersensitivity reactions to medications constitute a growing problem in the clinical practice. In order to study the molecular basis underlying the pathogenesis of non-immediate hypersensitivity reactions to drugs, we characterized the gene expression profiles of PBMCs isolated from patients during the acute phase and upon resolution of the clinical symptoms using a cDNA array technology. Eighty five genes were found to be differentially expressed during the acute phase of drug-induced delayed hypersensitivity reactions. Furthermore, ninety two genes with distinct expression patterns during the acute phase of severe and benign diseases were identified. Keywords: Comparison between disease and healty status Expression profiles of 11835 genes were analyzed in peripheral blood mononuclear cells from 13 patients with different clinical entities . Two samples were analyze from each patient. The first blood sample was drawn during the acute phase of the disease. The second blood sample was obtained upon resolutin of the clinical symptoms. The ratio between gene expression levels in both samples was calculated for each patient.
2009-10-01 | E-GEOD-12829 | biostudies-arrayexpress
Project description:Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
| S-EPMC7156285 | biostudies-literature
Project description:Hypersensitivity reactions to medications constitute a growing problem in the clinical practice. In order to study the molecular basis underlying the pathogenesis of non-immediate hypersensitivity reactions to drugs, we characterized the gene expression profiles of PBMCs isolated from patients during the acute phase and upon resolution of the clinical symptoms using a cDNA array technology. Eighty five genes were found to be differentially expressed during the acute phase of drug-induced delayed hypersensitivity reactions. Furthermore, ninety two genes with distinct expression patterns during the acute phase of severe and benign diseases were identified. Keywords: Comparison between disease and healty status
2009-10-01 | GSE12829 | GEO
Project description:BackgroundCarbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.MethodsWe performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.ResultsThe HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).ConclusionsThe presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
| S-EPMC3113609 | biostudies-literature
Project description:Oxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission.The effect of a polyamine deficient diet was investigated in an animal model of oxaliplatin-induced acute pain hypersensitivity using behavioral tests (mechanical and cold hypersensitivity). The involvement of spinal glutamate neurotransmission was monitored by using a proton nuclear magnetic resonance spectroscopy based metabolomic approach and by assessing the expression and phosphorylation of the NR2B subunit of the NMDA receptor.A 7-day polyamine deficient diet totally prevented oxaliplatin-induced acute cold hypersensitivity and mechanical allodynia. Oxaliplatin-induced pain hypersensitivity was not associated with an increase in NR2B subunit expression or phosphorylation, but with an increase of glutamate level in the spinal dorsal horn which was completely prevented by a polyamine deficient diet. As a validation that the oxaliplatin-induced hypersensitivity could be due to an increased activity of the spinal glutamate system, an intrathecal administration of the specific NR2B antagonist, ifenprodil, totally reversed oxaliplatin-induced mechanical and cold hypersensitivity.A polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity.
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Project description:Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxaliplatin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.
| S-EPMC3377073 | biostudies-literature