Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect.

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.

Blood molecular biomarkers for chemotherapy-induced peripheral neuropathy: From preclinical models to clinical practice.

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.

Actualización en ventilación de alta frecuencia oscilatoria en pacientes pediátricos con insuficiencia respiratoria aguda / Ventilation update high oscillatory frequency in pediatric patients with Severe respiratory insufficiency

Recientemente un grupo de expertos estableció la definición del síndrome de dificultad respiratoria aguda en niños y las recomendaciones relativas a su tratamiento. La ventilación de alta frecuencia oscilatoria es considerada por este consenso como una alternativa válida a la ventilación mecánica convencional en pacientes con este síndrome e hipoxemia resistente. La incorporación de la ventilación de alta frecuencia oscilatoria en el ámbito clínico data de la década de 1970, su utilización se sustenta en que este modo ventilatorio respeta los objetivos fisiológicos de reclutamiento y protección pulmonar. La literatura alberga numerosas publicaciones referidas a la ventilación de alta frecuencia oscilatoria en niños con síndrome de dificultad respiratoria aguda y su comparación con la ventilación mecánica convencional, la mayoría de los trabajos con diseños limitados, a excepción de dos estudios controlados y aleatorizados que objetivan menor daño inducido y menor enfermedad pulmonar crónica en los pacientes tratados con ventilación de alta frecuencia oscilatoria. A la luz de la evidencia analizada, esta ventilación en pacientes con síndrome de dificultad respiratoria aguda pediátrico sería una terapia aceptable ante el fracaso de las medidas convencionales(AU)

Recently, a group of experts established the definition of pediatric acute respiratory distress syndrome and the recommendations regarding its treatment. High-frequency oscillatory ventilation is considered by this consensus as a valid alternative to conventional mechanical ventilation in children with acute respiratory distress syndrome and refractory hypoxemia. There are numerous publications about high-frequency oscillatory ventilation in pediatric patients with this syndrome and its comparison with the conventional mechanical ventilation, most of the studies with limited designs, except for two randomized controlled studies that reported less induced injury and less chronic lung disease in patients treated with high-frequency oscillatory ventilation. Incorporation of this type of ventilation in the clinical setting dates back to the 70s, its use is supported by the fact that this ventilation mode respects the physiological aims of recruitment and lung protection. In light of the analyzed evidence, high-frequency oscillatory ventilation in children with acute respiratory distress syndrome would be an acceptable therapy when conventional measures fail.(AU)

Lesión pulmonar aguda secundaria a transfusión (TRALI): reporte de un caso y revisión de la bibliografía / Acute lung injury secondary to transfusion (TRALI): report of a case and review of the bibliography

La lesión pulmonar aguda producida por transfusión (TRALI) es un grave síndrome clínico que se presenta con hipoxemia aguda y edema pulmonar no cardiogénico dentro de las 6 h de una transfusión con productos sanguíneos. La incidencia reportada oscila entre 1 caso cada 5000-100.000 transfusiones. Se han propuesto dos teorías sobre su fisiopatología: inmunomediada y no inmune. El diagnóstico es clínico y el tratamiento, de sostén. La tasa de mortalidad puede llegar al 10%, y la morbilidad es alta. Presentamos un paciente que, durante el posoperatorio inmediato de una artrodesis posterior instrumentada por escoliosis, evoluciona con hipoxemia resistente. En la cirugía, requirió múltiples transfusiones con hemoderivados por sangrado activo, por lo que se arriba al diagnóstico de TRALI. Requirió asistencia respiratoria mecánica con altos parámetros por 72 h y sostén hemodinámico por bajo gasto cardíaco. La evolución fue favorable y recibió el alta hospitalaria a los 11 días, sin complicaciones(AU)

Transfusion-related acute lung injury (TRALI) is a serious clinical syndrome that occurs with acute hypoxemia and non-cardiogenic pulmonary edema within 6 hours of a transfusion with blood products. The reported incidence ranges from 1 case per 5,000-100,000 transfusions. Two theories have been proposed about its pathophysiology, an immune-mediated one and a non-immune one. The diagnosis is clinical, and the treatment is supportive. Mortality may reach 10%, with high morbidity. We report a patient who in the immediate postoperative period of posterior instrumented arthrodesis for scoliosis developed refractory hypoxemia. During surgery, he required multiple blood products transfusions due to active bleeding, so we diagnosed TRALI. The patient required mechanical ventilation with high parameters during 72 hours and hemodynamic support for low cardiac output. The outcome was favorable and he was discharged at day 11 without complications. (AU)

Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve.

To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established "chronic" schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.

In vivo comparative study of the cytotoxicity of a liposomal formulation of cisplatin (lipoplatin™).

PURPOSE: Cisplatin is one of the most effective cytotoxic agents in the treatment of solid malignancies, but its use is limited by several side effects. Among them, peripheral neurotoxicity can be dose limiting. A liposomal formulation of cisplatin, Lipoplatin™, was developed to reduce the systemic toxicity of cisplatin but without preventing its efficacy. The aim of this study was to use an animal model to establish, through a multimodal approach, whether chronic treatment with two different schedules of Lipoplatin™, selected within the range of its anticancer effective dose, is less neurotoxic than cisplatin administration. METHODS: Female Wistar rats were treated intraperitoneally with cisplatin at a dose of 4 mg/kg or with Lipoplatin™ at doses delivering 12 or 24 mg/kg of cisplatin once weekly for 4 weeks. General toxicity was assessed by daily observation, body weight change, hematological and blood chemistry analysis, and histopathology of liver and kidney. The onset of peripheral neurotoxicity was assessed by measuring tail nerve conduction velocity (NCV), morphological and morphometric analysis of dorsal root ganglia (DRG), and morphological analysis of the sciatic nerve. RESULTS: Cisplatin induced a statistically significant reduction in body weight, the development of renal failure, and impairment in NCV with pathological alterations in the DRG and sciatic nerve. By contrast, Lipoplatin™ was markedly less nephrotoxic, and no significant weight gain reduction was observed in animals treated with both doses of the drug. Moreover, the lowest dose induced less severe damage to the peripheral nervous system with a moderate decrease in NCV and mild pathological alterations in DRG and the sciatic nerve. CONCLUSIONS: The results suggest that Lipoplatin™ 12 mg/kg is less neurotoxic than cisplatin 4 mg/kg, thus opening up the possibility of using this new formulation in future studies where its anticancer activity and the peripheral neurotoxicity will be assessed in parallel.

Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies.

Cisplatin, paclitaxel and bortezomib belong to some of the most effective families of chemotherapy drugs for solid and haematological cancers. Epothilones represent a new family of very promising antitubulin agents. The clinical use of all these drugs is limited by their severe peripheral neurotoxicity. Several in vivo rat models have reproduced the characteristics of the peripheral neurotoxicity of these drugs. However, since only a very limited number of cancer types can be studied in immunocompetent rats, these animal models do not represent an effective way to evaluate, at the same time, the antineoplastic activity and the neurotoxic effects of the anticancer compounds. In this study, we characterized the neurophysiological impairment induced by chronic chemotherapy treatment in BALB/c mice, a strain suitable for assessing the activity of anticancer treatments. At the end of a 4-week period of treatment with cisplatin, paclitaxel, epothilone-B or bortezomib, sensory and sensory/motor nerve conduction velocities (NCV) were determined in the caudal and digital nerves and dorsal root ganglia (DRG) and sciatic nerves were collected for histopathological analysis. The electrophysiological studies revealed that all the compounds caused a statistically significant reduction in the caudal NCV, while impairment of the digital NCV was less severe. This functional damage was confirmed by the histopathological observations evidencing axonal degeneration in the sciatic nerve induced by all the drugs associated with pathological changes in DRG induced only by cisplatin and bortezomib. These results confirm the possibility to use our models to combine the study of the antineoplastic activity of anticancer drugs and of their toxic effects on the peripheral nervous system in the BALB/c mouse strain.