RESUMO
BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome side effect in patients exposed to taxanes in the treatment of cancer and may affect quality of life dramatically. Here we assessed whether serum levels of neurofilament light (NfL) and tau (two neuroaxonal injury biomarkers) and glial fibrillary acidic protein (GFAP, a biomarker for astrocytic activation) correlate with the development of CIPN in the adjuvant setting of early breast cancer. MATERIALS AND METHODS: Using ultrasensitive single molecule array technology, serum levels of NfL, GFAP, and tau were measured before and every 3 weeks in 10 women receiving adjuvant EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) every 3 weeks × 3, followed by weekly paclitaxel 80 mg/m² × 9-12 weeks after surgery due to early breast cancer. CIPN was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and the questionnaire EORTC QLQ CIPN-20. RESULTS: Serum levels of GFAP increased successively during cycles of EC. NfL increased instead in response to the treatment of paclitaxel. NfL and GFAP continued to rise throughout exposure of cumulatively higher doses of paclitaxel and were reduced 3 months after the end of chemotherapy. Serums levels of tau were marginally affected by exposure to chemotherapy. Women with worse symptoms of CIPN had higher concentrations of NfL than women with mild symptoms of CIPN. INTERPRETATION: NfL and GFAP are promising biomarkers to identify women at risk of developing CIPN. Larger prospective studies are now needed.
Assuntos
Biomarcadores , Neoplasias da Mama , Epirubicina , Proteína Glial Fibrilar Ácida , Proteínas de Neurofilamentos , Paclitaxel , Doenças do Sistema Nervoso Periférico , Proteínas tau , Humanos , Feminino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/sangue , Proteínas de Neurofilamentos/sangue , Pessoa de Meia-Idade , Proteína Glial Fibrilar Ácida/sangue , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Proteínas tau/sangue , Adulto , Biomarcadores/sangue , Epirubicina/efeitos adversos , Epirubicina/administração & dosagem , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/administração & dosagem , Idoso , Quimioterapia Adjuvante/efeitos adversosRESUMO
BACKGROUND AND PURPOSE: A real-time biomarker in chemotherapy-induced peripheral neurotoxicity (CIPN) would be useful for clinical decision-making during treatment. Neurofilament light chain (NfL) can be detected in blood in the case of neuroaxonal damage. The aim of the study was to compare the levels of plasma NfL (pNfL) according to the type of chemotherapeutic agent and the severity of CIPN. METHODS: This single-center prospective observational longitudinal study included patients treated with paclitaxel (TX; n = 34), brentuximab vedotin (BV; n = 29), or oxaliplatin (PT; n = 19). All patients were assessed using the Total Neuropathy Score-clinical version and Common Terminology Criteria for Adverse Events before, during, and up to 6-12 months after the end of treatment. Nerve conduction studies (NCS) were performed before and after chemotherapy discontinuation. Consecutive plasma samples were analyzed for NfL levels using a Simoa® analyzer. Changes in pNfL were compared between groups and were eventually correlated with clinical and NCS data. Clinically relevant (CR) CIPN was considered to be grade ≥ 2. RESULTS: Eighty-two patients, mostly women (59.8%), were included. One third of the patients who received TX (29.4%), BV (31%), or PT (36.8%) developed CR-CIPN, respectively, without differences among them (p = 0.854). Although pNfL significantly increased during treatment and decreased throughout the recovery period in all three groups, patients receiving TX showed significantly greater and earlier changes in pNfL levels compared to the other agents (p < 0.001). CONCLUSIONS: A variable change in pNfL is observed depending on the type of agent and mechanism of neurotoxicity with comparable CIPN severity, strongly implying the need to identify different cutoff values for each agent.
Assuntos
Antineoplásicos , Proteínas de Neurofilamentos , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Idoso , Adulto , Antineoplásicos/efeitos adversos , Estudos Longitudinais , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/etiologia , Estudos Prospectivos , Biomarcadores/sangue , Oxaliplatina/efeitos adversos , Paclitaxel/efeitos adversosRESUMO
PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS: Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS: A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION: Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.
Assuntos
Hidrocarbonetos Aromáticos com Pontes , Lipidômica , Doenças do Sistema Nervoso Periférico , Triglicerídeos , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Fatores de Risco , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Adulto , Taxoides/efeitos adversos , Taxoides/uso terapêuticoRESUMO
In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.
Assuntos
Neuropatias Amiloides Familiares , Proteínas de Neurofilamentos , Qualidade de Vida , Humanos , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/diagnóstico , Masculino , Proteínas de Neurofilamentos/sangue , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/diagnóstico , Idoso de 80 Anos ou mais , Estudos Prospectivos , AdultoRESUMO
FOLFOX is a combination of chemotherapeutic agents (5-fluorouracil, leucovorin, and oxaliplatin) and is used to treat advanced colorectal cancer (CRC) but induces various side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most critical side effects that compromise the quality of life of patients with CRC undergoing FOLFOX chemotherapy. This study aimed to evaluate circulating miRNA, cortisol and catecholamine as potential biomarkers that can predict FOLFOX-CIPN symptoms. High-throughput microRNA (miRNA) sequencing was performed on the RNA circulating in the plasma of eight patients with CRC who underwent FOLFOX chemotherapy. miRNA expression profiles were evaluated according to two groups: those who underwent ≤3 cycles and those who underwent ≥6 cycles of FOLFOX chemotherapy. The identified miRNAs were validated in 27 patients with CRC who underwent FOLFOX chemotherapy using quantitative reverse transcription polymerase chain reaction. Target genes were predicted using bioinformatics and functional analyses. Cortisol and catecholamine concentrations in peripheral plasma were measured using an enzyme-linked immunosorbent assay. miR-3184-5p was differentially expressed when miRNA expression was compared between the groups that underwent ≤3 and ≥6 cycles of FOLFOX chemotherapy. Cortisol levels were significantly higher in the group that underwent ≥6 cycles of FOLFOX chemotherapy than in the group that underwent ≤3 cycles. This study suggests that miR-3184-5p may be a potential marker for predicting CIPN.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Fluoruracila , Leucovorina , MicroRNAs , Compostos Organoplatínicos , Doenças do Sistema Nervoso Periférico , Humanos , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/sangue , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , MicroRNAs/sangue , MicroRNAs/genética , Idoso , Hidrocortisona/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Adulto , Catecolaminas/sangueRESUMO
Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers.
Assuntos
Metabolômica , Oxaliplatina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Antineoplásicos/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/metabolismo , Cromatografia Líquida de Alta Pressão , Idoso , Biomarcadores/sangue , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/diagnósticoRESUMO
Deficiency for thiamine (vitamin B1), traditionally assessed via the activity of the thiamine-dependent enzyme erythrocyte transketolase, has been reported in individuals with alcohol use disorder (AUD) and in people with HIV; concentrations of the metabolically active diphosphate form, however, have yet to be reported in HIV cohorts and results in AUD are equivocal. In this cross-sectional study, samples from 170 AUD, 130 HIV, and 100 healthy control individuals were analyzed to test the hypothesis that AUD and HIV groups relative to healthy controls would show low whole blood thiamine diphosphate (TDP) concentrations related to peripheral neuropathy. TDP concentrations were not different in the 3 study groups (P = .6141) but were lower in Black (n = 172) relative to White (n = 155) individuals (P < .0001) regardless of group. In a multiple regression, race relative to diagnoses explained more than 10 times the variance in whole blood TDP concentrations (F4,395 = 3.5, P = .0086; r2 = 15.1]. Performance on a measure of peripheral neuropathy (2-point discrimination) was worse in the HIV and AUD cohorts relative to the healthy control group (P < .0001) but was not associated with TDP concentrations. These findings suggest that Black individuals carry a heightened vulnerability for low whole blood TDP concentrations, but the clinical significance and mechanisms underlying these results remain to be determined.
Assuntos
Alcoolismo , Infecções por HIV , Tiamina Pirofosfato , População Branca , Humanos , Masculino , Estudos Transversais , Tiamina Pirofosfato/sangue , Feminino , Pessoa de Meia-Idade , Adulto , Infecções por HIV/sangue , Alcoolismo/sangue , Deficiência de Tiamina/sangue , Doenças do Sistema Nervoso Periférico/sangue , Negro ou Afro-AmericanoRESUMO
BACKGROUND: Chronic liver disease has been reported to be associated with peripheral neuropathy. However, which sensory fibers are affected remains unknown. The objective of this study was to examine the function of sensory nerve fibers in patients with cirrhosis using the current perception threshold (CPT) test, as well as the correlation between blood biochemical indicators related to cirrhosis and CPT values. METHODS: We recruited 44 patients with liver cirrhosis and 37 healthy controls of the same age and gender. The Neurometer® system for the CPT test was used to stimulate the median nerve on the right index finger, as well as the deep and superficial peroneal nerves on the right hallux, using three distinct parameters (2000 Hz, 250 Hz, and 5 Hz). Comparative analysis was performed on the CPT values of the sensory nerves. Additionally, the correlation between CPT values and biochemical blood indicators in the study participants was analyzed. RESULTS: Under 2000 Hz electrical stimulation, there was a significant difference between the cirrhosis and healthy control groups in the median nerve as well as the deep and superficial peroneal nerves (p < 0.05). In addition, the median nerve CPT value of the cirrhosis group was significantly higher than that of the control group at an electrical stimulation frequency of 250 Hz (p = 0.005). There was no correlation between CPT values and blood biochemical indicators. CONCLUSION: According to the results, the sensory peripheral neuropathy in liver cirrhosis is mainly manifested as Aß fiber neuropathy.
Assuntos
Cirrose Hepática , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Cirrose Hepática/sangue , Adulto , Estimulação Elétrica , Idoso , Nervo Mediano/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Limiar Sensorial/fisiologia , Nervo Fibular/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/sangue , Fibras Nervosas/patologia , Fibras Nervosas/fisiologiaRESUMO
This study aimed to explore the efficacy and safety of Tangmaikang Granules in the treatment of diabetic peripheral neuropathy(DPN). PubMed, Cochrane Library, EMbase, SinoMed, CNKI, Wanfang and VIP were retrieved for randomized controlled trial(RCT) of Tangmaikang Granules in the treatment of DPN. Cochrane handbook 5.3 was used to evaluate the quality of the inclu-ded studies, and RevMan 5.4.1 and Stata 15.1 were employed to analyze data and test heterogeneity. GRADEpro was used to assess the quality of each outcome index. Clinical effective rate was the major outcome index, while the improvement in numbness of hands and feet, pain of extremities, sluggishness or regression of sensation, sensory conduction velocity(SCV) and motor conduction velocity(MCV) of median nerve and peroneal nerve, fasting blood glucose(FBG), 2 h postprandial blood glucose(2hPBG), and glycated hemoglobin(HbA1c) and incidence of adverse reactions were considered as the minor outcome indexes. A total of 19 RCTs with 1 602 patients were eventually included. The Meta-analysis showed that the improvements in clinical effective rate(RR=1.45, 95%CI[1.32, 1.61], P<0.000 01), pain of extremities(RR=1.70, 95%CI[1.27, 2.27], P=0.000 3), MCV of peroneal nerve(MD=4.08, 95%CI[3.29, 4.86], P<0.000 01) and HbA1c(SMD=-1.23, 95%CI[-1.80,-0.66], P<0.000 1) of Tangmaikang Granules alone or in combination in the experimental group were better than those in the control group. Compared with the conditions in the control group, numbness of hands and feet(RR=1.42, 95%CI[1.12, 1.80], P=0.003), sluggishness or regression of sensation(RR=1.41, 95%CI[1.05, 1.91], P=0.02), SCV of median nerve(MD=4.59, 95%CI[0.92, 8.27], P=0.01), SCV of peroneal nerve(MD=4.68, 95%CI[3.76, 5.60], P<0.000 01) and MCV of median nerve(MD=5.58, 95%CI[4.05, 7.11], P<0.000 01) of Tangmaikang Granules in combination in the experimental group were improved by subgroup analysis. The levels of FBG(MD=-0.57, 95%CI[-1.27, 0.12], P=0.11) and 2hPBG(MD=-0.69, 95%CI[-1.70, 0.33], P=0.18) in the experimental group were similar to those in the control group after treatment with Tangmaikang Granules alone or in combination. There was no difference in the safety(RR=1.28, 95%CI[0.58, 2.82], P=0.54) of Tangmaikang Granules in the treatment of DPN between the experimental group and the control group. Tangmaikang Granules could significantly increase clinical effective rate and nerve conduction velocity as well as improve symptoms of peripheral nerve and blood glucose level, and no serious adverse reactions were identified yet. Further validation was needed in future in large-sample, multicenter, high-quality RCTs.
Assuntos
Neuropatias Diabéticas , Medicamentos de Ervas Chinesas , Doenças do Sistema Nervoso Periférico , Humanos , Glicemia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Hemoglobinas Glicadas , Hipestesia/tratamento farmacológico , Estudos Multicêntricos como Assunto , Dor/tratamento farmacológico , Dor/etiologia , Resultado do Tratamento , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologiaRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting side effect of several first-line chemotherapeutic agents including paclitaxel, oxaliplatin and bortezomib, for which no predictive marker is currently available. We have previously shown that mitochondrial dysfunction is associated with the development and maintenance of CIPN. The aim of this study was to evaluate the potential use of mitochondrial DNA (mtDNA) levels and complex I enzyme activity as blood biomarkers for CIPN. Real-time qPCR was used to measure mtDNA levels in whole blood collected from chemotherapy- and vehicle-treated rats at three key time-points of pain-like behaviour: prior to pain development, at the peak of mechanical hypersensitivity and at resolution of pain-like behaviour. Systemic oxaliplatin significantly increased mtDNA levels in whole blood prior to pain development. Furthermore, paclitaxel- and bortezomib-treated animals displayed significantly higher levels of mtDNA at the peak of mechanical hypersensitivity. Mitochondrial complex I activity in whole blood was assessed with an ELISA-based Complex I Enzyme Activity Dipstick Assay. Complex I activity was not altered by any of the three chemotherapeutic agents, either prior to or during pain-like behaviour. These data demonstrate that blood levels of mtDNA are altered after systemic administration of chemotherapy. Oxaliplatin, in particular, is associated with higher mtDNA levels before animals show any pain-like behaviour, thus suggesting a potential role for circulating mtDNA levels as non-invasive predictive biomarker for CIPN.
Assuntos
Antineoplásicos/toxicidade , Biomarcadores/sangue , DNA Mitocondrial/sangue , DNA Mitocondrial/genética , Mitocôndrias/patologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Animais , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Ratos , Ratos Sprague-DawleyRESUMO
Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENT Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.
Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/efeitos adversos , Cloridrato de Duloxetina/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Analgésicos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Corticosterona/sangue , Cloridrato de Duloxetina/farmacologia , Feminino , Masculino , Oxaliplatina/efeitos adversos , Paclitaxel/efeitos adversos , Manejo da Dor , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos Sprague-DawleyRESUMO
Antibodies to acetylcholine receptor (AChR) are detected in the vast majority of patients with generalized myasthenia gravis (MG) and are rarely detected in significant titer in other autoimmune diseases. We report a patient with an axonal predominately sensory neuropathy for over 12 years with persistent binding and modulating AChR antibodies as well as striational muscle antibodies with no evidence of MG or any neoplastic disease.
Assuntos
Autoanticorpos/sangue , Doenças do Sistema Nervoso Periférico/sangue , Receptores Colinérgicos/biossíntese , Idoso , Autoanticorpos/imunologia , Humanos , Masculino , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/imunologia , Receptores Colinérgicos/imunologiaRESUMO
BACKGROUND: Diabetic peripheral neuropathy (DPN) is 1 of the most common clinical complications of diabetes, which seriously affects the quality of life of patients and causes a substantial economic burden on diabetes care. The pathogenesis of DPN is complex. There is no targeted treatment method, and mainstream treatment methods have low efficacy and large side effects. Traditional Chinese medicine has rich clinical experience in the prevention and treatment of diabetic peripheral neuropathy, which has dramatically improved the quality of life of patients. It is clinically proven that traditional Chinese medicine fumigants (TCMF) have apparent effects in treating diabetic peripheral neuropathy. Therefore, we aim to systematically review the effectiveness and safety of TCMF for DPN. METHODS: We will search the following databases: PubMed, Embase, Cochrane Library, MEDLINE, the China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, Cqvip Database, and Wanfang Data. Besides, we will also search for clinical trial registrations, potential grey literature, relevant conference abstracts, and reference lists of established studies. The studies published from the inception of the database to November 2020 will be retrieved. The randomized controlled trials on TCMF for DPN will be included. Also, we will search for clinical trial registrations, potential grey literature, relevant conference abstracts, and reference lists of established studies. The main result is clinical efficacy and nerve conduction velocity. Fasting blood glucose, 2âhours postprandial blood glucose, blood lipid, glycosylated hemoglobin, and adverse events are secondary results. We will perform the analyses using RevMan V.5.3 software. RESULTS: This study will provide a high-quality comprehensive evaluation of the efficacy and safety of TCMF in the treatment of DPN. CONCLUSIONS: This systematic review will evaluate the effectiveness and safety of TCMF in the treatment of DPN, and provide the latest evidence for clinical application. INPLASY REGISTRATION NUMBER: INPLASY2020110137.
Assuntos
Neuropatias Diabéticas/terapia , Fumigação/métodos , Medicina Tradicional Chinesa/métodos , Doenças do Sistema Nervoso Periférico/terapia , Glicemia/análise , Diabetes Mellitus/sangue , Diabetes Mellitus/fisiopatologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/etiologia , Hemoglobinas Glicadas/análise , Humanos , Metanálise como Assunto , Condução Nervosa , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/etiologia , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do TratamentoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) has long been recognized as a clinically significant issue in patients treated with antineoplastic drugs. This common long-term toxic side-effect which negatively impacts the outcome of the disease can lead to disability and have detrimental effects on patients' quality of life. Since axonal injury is a prominent feature of CIPN, responsible for several sensory symptoms, including pain, sensory loss and hypersensitivity to mechanical and/or cold stimuli in the hands and feet, neurophysiological assessments remain the gold standard for clinical diagnosis of CIPN. Given the large impact of CIPN on cancer patients, there is increasing emphasis on biomarkers of adverse outcomes in safety assessment and translational research, to prevent permanent neuroaxonal damage. Since the results on reliable blood molecular markers for axonal degeneration are still controversial, here we provide a brief overview of blood molecular biomarkers used for assessing and/or predicting CIPN in preclinical and clinical settings.
Assuntos
Antineoplásicos , Biomarcadores/análise , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/sangue , Animais , Antineoplásicos/efeitos adversos , Humanos , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Qualidade de VidaRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3 -/- mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell-derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. SIGNIFICANCE: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.
Assuntos
Galectinas/sangue , Macrófagos/fisiologia , Percepção da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Proteínas Sanguíneas/antagonistas & inibidores , Proteínas Sanguíneas/farmacologia , Proteínas Sanguíneas/fisiologia , Movimento Celular , Quimiotaxia , Ácido Clodrônico/farmacologia , Modelos Animais de Doenças , Docetaxel/efeitos adversos , Feminino , Galectinas/antagonistas & inibidores , Galectinas/farmacologia , Galectinas/fisiologia , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Estudos Prospectivos , Ratos , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/citologia , Nervo Isquiático/efeitos dos fármacos , Regulação para CimaRESUMO
Metformin-treated diabetics (MTD) showed a decrease in cobalamin, a rise in homocysteine, and methylmalonic acid, leading to accentuated diabetic peripheral neuropathy (DPN). This study aimed to determine whether or not metformin is a risk factor for DPN. We compared MTD to non-metformin-treated diabetics (NMTD) clinically using the Toronto Clinical Scoring System (TCSS), laboratory (methylmalonic acid, cobalamin, and homocysteine), and electrophysiological studies. Median homocysteine and methylmalonic acid levels in MTD vs. NMTD were 15.3 vs. 9.6 µmol/l; P < 0.001 and 0.25 vs. 0.13 µmol/l; P = 0.02, respectively with high statistical significance in MTD. There was a significantly lower plasma level of cobalamin in MTD than NMTD. Spearman's correlation showed a significant negative correlation between cobalamin and increased dose of metformin and a significant positive correlation between TCSS and increased dose of metformin. Logistic regression analysis showed that MTD had significantly longer metformin use duration, higher metformin dose > 2 g, higher TCSS, lower plasma cobalamin, and significant higher homocysteine. Diabetics treated with metformin for prolonged duration and higher doses were associated with lower cobalamin and more severe DPN.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Metformina/administração & dosagem , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/patologia , Feminino , Homocisteína/sangue , Humanos , Masculino , Metformina/efeitos adversos , Ácido Metilmalônico/metabolismo , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Fatores de Risco , Vitamina B 12/sangueRESUMO
BACKGROUND: Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves. OBJECTIVE: This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN. METHODS: Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up. RESULTS: Twenty-five patients with VPN were included (SVN, nâ=â10; NSVN, nâ=â15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, pâ=â0.009). Erythrocyte sedimentation rate (ESR) values over 20âmm/h were significantly more common in SVN patients (100% vs. 60%, pâ=â0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; pâ=â0.03), with a higher proportion of definite VPN cases (92 vs 46%; pâ=â0.04). CONCLUSIONS: Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.
Assuntos
Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/etiologia , Vasculite/complicações , Vasculite/diagnóstico , Adulto , Idade de Início , Biópsia , Sedimentação Sanguínea , Seguimentos , Humanos , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/patologia , Estudos Retrospectivos , Vasculite/sangue , Vasculite/patologiaRESUMO
Peripheral neuropathy (PN) is an incurable complication of multiple myeloma (MM) which adversely affects patients' quality of life. The important roles that Circular RNAs (circRNAs) play in tumor progression, and exosome-mediated intracellular communication has been recognized as a crucial factor in the pathogenesis of MM. However, the role of exosome-derived circRNAs (exo-circRNAs) in MM and MM-induced PN remains elusive. In this study, we aimed to investigate the correlation between serum exo-circRNAs and MM to preliminarily explore the role of exo-circRNAs in MM-related PN. A cohort of 25 MM patients and 5 healthy control (HC) individuals were enrolled in the study. High-throughput sequencing and qRT PCR validation of serum exo-circRNAs were used to generate the aberrantly expressed exo-circRNAs profiles. Bioinformatics analysis was done using GO, KEGG, miRanda, Targetscan and Metascape. Correlation analysis was conducted between chr2:2744228-2,744,407+ and clinical characteristics of PN. ROC curve, univariate and multivariate COX regression models were conducted to identify the prognostic potential of chr2:2744228-2,744,407+ in the MM-related PN. 265 upregulated circRNAs and 787 downregulated circRNAs, with at least a two-fold difference in expression level in MM patients vs HC, were screened. Bioinformatics analysis indicated that upregulated circRNAs had the potential to facilitate MM-related PN. Furthermore, PCR validated the abundant expression of chr2:2744228-2,744,407+ in the serum exosomes of 25 MM patients. Bioinformatics analysis indicated that chr2:2744228-2,744,407+ might induce MM related PN via the downstream miRNA and GRIN2B axis. Overexpressed chr2:2744228-2,744,407+ in the serum exosomes of MM patients might lead to the downregulation of hsa-miR-6829-3p, elevation of GRIN2B in the serum and PC12 cells, and inhibited cell viability. The correlation analysis indicated that the expression of chr 2:2744228-2,744,407+ was positively correlated with the clinical characteristics of PN. ROC curve, univariate and multivariate COX regression analysis identified that chr2:2744228-2,744,407+ is an independent prognostic factor in the MM related PN. We identified that the abnormal expression of the serum exo-circRNA was correlated with MM-related PN, implying that exo-circRNA has potential as a novel therapeutic target for MM related PN.
Assuntos
Ácidos Nucleicos Livres , Exossomos , Mieloma Múltiplo , Doenças do Sistema Nervoso Periférico , RNA Circular , RNA Neoplásico , Adulto , Animais , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Exossomos/genética , Exossomos/metabolismo , Humanos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Células PC12 , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/terapia , RNA Circular/sangue , RNA Circular/genética , RNA Neoplásico/sangue , RNA Neoplásico/genética , RatosRESUMO
PURPOSE: This study aimed to investigate the prevalence of peripheral neuropathy (PNP) and its related serum metabolites in de novo patients with Parkinson's disease (PD). PNP is a type of frequent comorbidity in PD. Although the administration of levodopa has been described as a presumptive risk factor in its development, few studies have explored its effect on unmedicated PD patients. MATERIALS AND METHODS: This study included 105 drug-naïve de novo PD patients. A standardized nerve conduction study (NCS) technique was used to evaluate motor or sensory neuropathy. We analyzed serologic tests including metabolic markers of vitamin B12, homocysteine (Hcy), and uric acid (UA). RESULTS: We found abnormal nerve conduction velocity findings in 24 out of 105 total patients. Among them, 20 patients showed a type of combined motor-sensory, while three were a type of pure sensory and one was a pure motor. Nine patients had carpal tunnel syndrome. PD with PNP group demonstrated higher serum levels of Hcy and UA compared to PD without PNP group. CONCLUSION: Our data demonstrated a potential role of Hcy and UA on PNP in de novo patients with PD. These results suggest the contribution of the inherent metabolic pathway in deterioration of the peripheral nervous system in PD.
Assuntos
Homocisteína/sangue , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/epidemiologia , Ácido Úrico/sangue , Vitamina B 12/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Doenças do Sistema Nervoso Periférico/sangue , Prevalência , Fatores de RiscoRESUMO
PURPOSE: The aim of the current study was to evaluate the effect of N-acetylcysteine (NAC) on the incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN) in breast cancer patients. METHOD: A prospective randomized controlled open label study was conducted on 75 breast cancer patients receiving adjuvant paclitaxel 80 mg/m2 weekly for 12 weeks. Eligible patients were randomized to either the low dose group; 1200 mg daily NAC, the high dose group; 1200 mg NAC twice daily or the control group; received paclitaxel only. The primary endpoint was the incidence of different grades of PIPN using National Cancer Institute's common toxicity criteria for adverse event (NCI-CTCAE) while secondary endpoints were the severity of PIPN using modified total neuropathy score (mTNS), quality of life (QOL) using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX) subscale, serum nerve growth factor (NGF), and serum malondialdehyde (MDA). RESULTS: At the end of the 12-week period, the incidence of grade (2, 3) peripheral neuropathy was significantly lower in the high dose group (28.6%) compared to the low dose group (61.9%) and the control group (100%), p value < 0.001. A significant improvement in the mTNS and QOL scores was observed after 6 and 12 weeks in the high dose group and the low dose group compared to the control, p value < 0.001. Significantly higher levels of serum NGF in the high dose group and lower level of serum MDA in the high dose and the low dose group were observed. CONCLUSION: Oral NAC (1200 mg once and twice daily) might reduce the incidence and severity of PIPN and improve the patients' QOL. TRIAL REGISTRY: Clinical Trial.gov registration number: NCT03492047.