Dolor neuropático en pacientes oncológicos en tratamiento con bortezomib / Neurpathic pain in cancer patients treated with bortezomib

Introducción: El dolor neuropático es el problema más habitual en la neuropatía inducida por quimioterapia (NIQ) y el que más interfiere en la calidad de vida de los pacientes. Su detección precoz resulta fundamental para reducir o eliminar los problemas que de este se derivan. Los objetivos de este estudio eran: 1) determinar la incidencia y las características de NIQ y dolor neuropático en pacientes con mieloma múltiple (MM) tratados con bortezomib, y 2) evaluar el impacto del dolor neuropático en las actividades de la vida diaria (AVD). Método: Todos los pacientes diagnosticados de MM candidatos a tratamiento con bortezomib atendidos en el Hospital Joan XXIII durante 2013, participaron. Los participantes eran entrevistados individualmente e informaban sobre la presencia, las características y el impacto del dolor, así como de los efectos adversos del bortezomib. Resultados: Participaron 22 personas, de las cuales la mitad presentaron NIQ, siendo el grado 2 el predominante. La localización más habitual del dolor neuropático era manos y pies; aparecía de manera espontánea y progresiva empeorando en reposo y durante la noche, con predominio de síntomas positivos. El impacto del dolor se reflejó en todas las AVD. La limitación principal fue la incapacidad para disfrutar de la vida. La neuropatía periférica ocupó el primer lugar en orden de importancia subjetiva para el paciente seguido de la fatiga y el estreñimiento. Conclusiones: Una adecuada evaluación y detección precoz del dolor neuropático es fundamental para minimizar su impacto en la calidad de vida del paciente (AU)

Introduction: The neuropathic pain is the most habitual problem in the neuropathy induced by chemotherapy (NIQ) and the one that more interferes in the quality of life of the patients. His precocious detection turns out to be fundamental to reduce or to eliminate the problems that from this one stem. The aims of this study were: 1) determine the incident and NIQ's characteristics and neuropathic pain in patients with mieloma multiple (MM) treated with bortezomib, and 2) to evaluate the impact of the neuropathic pain in the activities of the daily life (AVD). Method: All the patients diagnosed of MM candidates for treatment with bortezomib attended in the Hospital Joan XXIII during 2013, took part. The participants were interviewed individually and were reporting on the presence, the characteristics and the impact of the pain, as well as of the adverse effects of the bortezomib. Results: There took part 22 persons, of which NIQ presented the half, being the degree 2 the predominant one. The most habitual location of the neuropathic pain was hands and feet; it was appearing in a spontaneous and progressive way deteriorating in rest and during the night, with predominance of positive symptoms. The impact of the pain was reflected in all the AVD. The principal limitation was the disability to enjoy the life. The peripheral neuropathy occupied the first place in order of subjective importance for the patient followed by the fatigue and the constipation. Conclusions: A proper assessment and early detection of neuropathic pain is critical to minimizing its impact on the quality of life of patients (AU)

Neuropathic pain in cancer patients treated with bortezomib. / Dolor neuropático en pacientes oncológicos en tratamiento con bortezomib.

INTRODUCTION: The neuropathic pain is the most habitual problem in the neuropathy induced by chemotherapy (NIQ) and the one that more interferes in the quality of life of the patients. His precocious detection turns out to be fundamental to reduce or to eliminate the problems that from this one stem. The aims of this study were: 1) determine the incident and NIQ's characteristics and neuropathic pain in patients with mieloma multiple (MM) treated with bortezomib, and 2) to evaluate the impact of the neuropathic pain in the activities of the daily life (AVD). METHOD: All the patients diagnosed of MM candidates for treatment with bortezomib attended in the Hospital Joan XXIII during 2013, took part. The participants were interviewed individually and were reporting on the presence, the characteristics and the impact of the pain, as well as of the adverse effects of the bortezomib. RESULTS: There took part 22 persons, of which NIQ presented the half, being the degree 2 the predominant one. The most habitual location of the neuropathic pain was hands and feet; it was appearing in a spontaneous and progressive way deteriorating in rest and during the night, with predominance of positive symptoms. The impact of the pain was reflected in all the AVD. The principal limitation was the disability to enjoy the life. The peripheral neuropathy occupied the first place in order of subjective importance for the patient followed by the fatigue and the constipation. CONCLUSIONS: A proper assessment and early detection of neuropathic pain is critical to minimizing its impact on the quality of life of patients.

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers.

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.

Morphometry of dermal nerve fibers in human skin.

OBJECTIVE: We aimed to assess the innervation density of dermal nerves in human skin biopsies by bright-field immunohistochemistry. METHODS: The size of dermal area where nerve length was quantified was validated in 30 skin biopsy sections (5 controls and 5 patients with small-fiber neuropathy [SFN]). It was obtained dividing an area of 200-µm depth from the dermal-epidermal junction into 4 equal portions. The length of dermal nerves (DNFL) was measured into 150 sections (25 controls and 25 patients with SFN) and values per millimeter of epidermis (DNFL/mm) and dermal area (DNFL/mm2) were obtained. Age- and gender-matched normative values of intraepidermal nerve fiber (IENF) density were used as gold standard to calculate the performance of dermal nerve morphometry. RESULTS: Patients showed significantly lower DNFL (1.96 mm ± 0.96 SD), DNFL/mm (0.65 ± 0.29 SD), and DNFL/mm2 (3.75 ± 1.7 SD) than controls (DNFL 3.52 mm ± 1.31 SD, 5th percentile 2.05; DNFL/mm 1.25 ± 0.39, 5th percentile 0.71; DNFL/mm2 7.07 ± 2.41 SD, 5th percentile 3.95). Sensitivity, specificity, and percentage of individuals correctly classified were 75.8%, 73.9%, and 74.8% for DNFL, 75%, 80%, and 77.7% for DNFL/mm, and 75.8%, 80.2%, and 78.1% for DNFL/mm2. Receiver operator characteristic area analysis confirmed the excellent discrimination (0.8-0.9) between patients and controls. Dermal nerve morphometry significantly correlated with IENF density. Spearman rank correlation demonstrated good agreement for interobserver analysis (0.87-0.89), and between DNFL and IENF densities (0.71-0.73; p < 0.0001). CONCLUSIONS: We provided a reliable method to quantify the innervation density of dermal nerves that might improve the diagnostic yield of skin biopsy.