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Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

Changes of brain structure and function have been described in peripheral neuropathies. The aim of our study was to systematically investigate possible modifications of major large-scale brain networks using resting-state functional magnetic resonance imaging (RS-fMRI) in Charcot–Marie–Tooth disease type 1A (CMT1A) patients. In this cross-sectional study, 3-T MRI brain scans were acquired of right-handed genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing neurological impairment. RS-fMRI data were analysed using a seed-based approach, with 32 different seeds sampling the main hubs of default mode, sensorimotor, visual, salience (SN), dorsal attention, frontoparietal, language and cerebellar networks. Between-group differences in terms of functional connectivity (FC) with the explored seeds were tested voxelwise, correcting for local grey matter density to account for possible structural abnormalities, whilst the relationship between FC modifications and neurological impairment was investigated using robust correlation analyses. Eighteen CMT1A patients (34.0  11.4 years; M/F 11/7) were enrolled, along with 20 healthy controls (30.1  10.2 years; M/F 11/9). In the CMT group compared to controls, clusters of increased FC with the visual cortex (P = 0.001), SN (P < 6 9 10 4), dorsal attention network (P < 8 9 105) and language network (P < 7 9 10–4) were found, along with a single cluster of reduced FC with the visual cortex in the left lentiform nucleus (P = 10–6). A significant correlation emerged between neurophysiological impairment and increased FC with right temporal language areas (r = 0.655, P = 0.006), along with an association between walking ability and increased FC with the left supramarginal gyrus (SN) (r = 0.620, P = 0.006). Our data show evidence of diffuse functional reorganization involving multiple large-scale networks in the CMT1A brain, independent of structural modifications and partially correlating with peripheral nerve damage and functional impairment.

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Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aimof our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 +/- 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 +/- 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = -0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Background Failed back surgery syndrome (FBSS) represents one main cause of chronic neuropathic or mixed pain, functional disability and reduced Health Related Quality of Life (HRQoL). Spinal Cord Stimulation (SCS) can be a value for money option to treat patients refractory to conventional medical management (CMM). We estimated from real-world data: 1) the amount of reduced levels of HRQoL of target patients compared to general population, 2) the relationship between pain intensity, functional disability, and overall HRQoL, and 3) the improvement of patients’ health from SCS intervention, and 4) we give some insights and make some suggestions on the selection of a battery of patients’ reported health instruments for use in routine clinical practice. Methods At recruitment (before SCS) and every 6 months for 2 years after SCS a battery of questionnaires/tests were completed: the generic EQ-5D and SF-36 for HRQoL, the specific Numerical Rating Scale (NRS) to measure pain intensity, and Oswestry Disability Index (ODI) to measure functional disability. We conducted multilevel regression analyses to investigate the association of HRQoL with the NRS and ODI indexes; multiple regression analyses to compare EQ-5D data with those of the general population adjusted for age, sex and education, and statistical tests to compare the changes of HRQoL, NRS and ODI estimates at baseline with those measured during the follow-up. Results Eighty patients (40% male, mean age = 58 years) participated. HRQoL was significantly worse in the patients than in the corresponding general population. Pain, functional disability and HRQoL significantly related each other during follow-up, Significant improvements (p

Background and aim: Peripheral neuropathy is a disorder with often unknown causes. Some drugs, including statins, are proposed to be among the causes of peripheral neuropathy. This study aimed at evaluating this condition by electrodiagnostic study among patients who had received statins. Methods: This case-control study was conducted in Shiraz, Iran in 2015, and included 39 patients aged 35-55 who had received statins for at least 6 months, and 39 healthy matched controls. Using electrodiagnosis, the sensory and motor wave features (amplitude, latency and nerve conduction velocity) of the peripheral nerves (Median, Ulnar, Tibial, Sural, and Peroneal) were evaluated among the subjects. Data were analyzed using SPSS software and p

International audience; BACKGROUND:Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.METHODS:We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).RESULTS:At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P

AIM: This study aimed to confirm the role of f VEGF gene 936 C/T polymorphism and Diabetic Polyneuropathy (DPN) in the Indonesian population as well as to investigate its relationship with VEGF-A level and the role of vascular risk factors. MATERIAL AND METHODS: This was a cross-sectional study involving 152 subjects. Clinical symptoms and signs of DPN were examined using DNE and DNS scoring followed by nerve conduction study. All subjects underwent anthropometric, clinical examination and laboratory procedures to obtain body mass index, HbA1C level, lipid profile, Polymorphism of +936 C/T VEGF gene (PCR-RFLP technique), and VEGF-A plasma level (ELISA). Statistical analysis using a t-test or Mann-Whitney was performed to assess continuous data and Chi-square for categorical data. Multivariate logistic regressions were also performed to determine the relationship between independent variables and DPN. RESULTS: Sixty-nine (45.4%) fulfilled the diagnostic criteria of DPN. There was a significant association between CT + TT genotype and DPN (OR 0.35 95%CI 0.16-0.79 p = 0.01). Multivariate logistic regression showed that plasma VEGF-A level (OR = 1.003; 95% CI = 1.000-1.007; p = 0.03), diabetes duration (OR = 1.108; 95% CI = 1.045-1.175; p = 0.001), and CT+TT genotype (OR = 0.347; 95%CI = 0.148-0.817; p = 0.013) were associated with DPN. Sub-group analysis on subjects with HbA1C level ≥7% showed that VEGF-A (OR = 1.011; 95%CI = (1.004-1.017; p = 0.03), diabetes duration (OR = 1.245; 95% CI = 1.117-1.388; p < 0.001), CT + TT genotype (OR = 0.259; 95%CI = 0.074-0.911p = 0.035), with an adition of HDL (OR = 0.916; 95% CI = 0.857-0.978; p = 0.009) were significant predictors of DPN while LDL (OR = 1.017; 95% CI = 1.000-1.035; p = 0.053) acted as modifying factor. CONCLUSION: It appeared that CT + TT genotype of VEGF +936 gene might act as a protecting factor for DPN while VEGF-A, diabetes duration, HDL, and LDL acted as risk factors especially on subjects with HbA1C level ≥ 7.

Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517.

Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.

Background Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0732-2) contains supplementary material, which is available to authorized users.

Cisplatin, paclitaxel and bortezomib are effective chemotherapy drugs in cancer treatment. However, they share severe peripheral neurotoxicity (PN) as one of their major dose-limiting side effects, often impairing cancer patients' quality of life and sometimes being permanent. Even if preclinical oncology is largely based on the use of immune-deficient mice, rodent models used to study the chemotherapy-induced PN are available only in immune-competent animals. In this study we characterized for the first time the PN induced by these chemotherapies through neurophysiological, behavioral, morphological and morphometric studies in athymic nude mice, a commonly employed strain in the preclinical oncology. The animals, divided into four groups, were chronically treated with cisplatin, paclitaxel or bortezomib once or twice a week for 4 or 6. weeks or were left untreated. These schedules were tolerated, neurotoxic and in the range of antineoplastic effectiveness. Despite similarities, differences in the features of PN were evident if compared with immune-competent models under comparable regimens of treatment. The results of this study may provide a basis for future combined analysis of antineoplastic and neurotoxic effects of chemotherapy in the same animals.

The health risks and side effects of fluoroquinolone use include the risk of tendon rupture and myasthenia gravis exacerbation, and on August 15, 2013, the Food and Drug Administration updated its warning to include the risk of permanent peripheral neuropathy. We present a case of fluoroquinolone-induced peripheral neuropathy in a patient treated for clinically diagnosed urinary tract infection with ciprofloxacin antibiotic.

Skin biopsy with a 3mm disposable circular punch is easy to perform and allows, after proper processing, the visualization of epidermal, dermal, and sweat gland nerve fibers. A technique of sampling the epidermis alone by applying a suction capsule, the "blister" technique, has also been developed. It is most common to stain immunohistochemically for the pan-axonal marker protein gene product 9.5 (PGP 9.5), an ubiquitin C-terminal hydroxylase. The sections are then observed and analyzed with bright-field microscopy or with indirect immunofluorescence with or without confocal microscopy. Most studies report quantification of intraepidermal nerve fiber density displayed in bright-field microscopy. Normative values have been established, particularly from the distal part of the leg, 10cm above the external malleolus. In diabetes mellitus early degeneration of intraepidermal nerve fibers is induced and there is slower regeneration even when there is no evidence of neuropathy. Skin biopsy is of particular value in the diagnosis of small fiber neuropathy when nerve conduction studies are normal. It may also be repeated in order to study the progressive nature of the disease and also has the potential of studying regeneration of nerve fibers and thus the effects of treatment. Inflammatory demyelinating neuropathies may also involve loss of small-diameter nerve fibers and IgM deposits in dermal myelinated nerve fibers in anti-MAG neuropathy. In some cases the presence of vasculitis in skin may indicate a nonsystemic vasculitic neuropathy and in HIV neuropathy intraepidermal nerve fiber density is reduced in a length-dependent manner. In several hereditary neuropathies intraepidermal nerve fiber density may be reduced but other abnormalities can also be demonstrated in dermal myelinated fibers. Some small swellings and varicosities may be present in the distal leg skin biopsy of healthy individuals but large axonal swellings are considered as evidence of a pathological process affecting the normal structure of nerves. The indirect immunofluorescence technique with confocal microscopy provides the opportunity to study the complex structure of sensory receptors and cutaneous myelinated fibers and the innervation of sweat glands, arrector pilorum muscles, and vessels.

Background: A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice Results: We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH. Conclusions: Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

To devise a rapid, sensitive method to quantify tactile threshold of finger pads for early detection and staging of peripheral neuropathy and for use in clinical trials.Subjects were 166 healthy controls and 103 patients with, or at risk for, peripheral neuropathy. Subjects were screened by questionnaire. The test device, the Bumps, is a checkerboard-like smooth surface with 12 squares; each square encloses 5 colored circles. The subject explores the circles of each square with the index finger pad to locate the one circle containing a small bump. Bumps in different squares have different heights. Detection threshold is defined as the smallest bump height detected. In some subjects, a 3-mm skin biopsy from the tested finger pad was taken to compare density of Meissner corpuscles (MCs) to bump detection thresholds.The mean (±SEM) bump detection threshold for control subjects was 3.3 ± 0.10 μm. Threshold and test time were age related, older subjects having slightly higher thresholds and using more time. Mean detection threshold of patients with neuropathy (6.2 ± 0.35 μm) differed from controls (p0.001). A proposed threshold for identifying impaired sensation had a sensitivity of 71% and specificity of 74%. Detection threshold was higher when MC density was decreased.These preliminary studies suggest that the Bumps test is a rapid, sensitive, inexpensive method to quantify tactile sensation of finger pads. It has potential for early diagnosis of tactile deficiency in subjects suspected of having neuropathy, for staging degree of tactile deficit, and for monitoring change over time.

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way. CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made. In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison. © 2009 Elsevier Ltd. All rights reserved.

Bortezomib is a proteasome inhibitor showing strong antitumor activity against many tumors, primarily multiple myeloma. Bortezomib-induced neuropathic pain is the main side effect and the dose-limiting factor of the drug in clinical practice. In order to obtain a pre-clinical model to reproduce the characteristic pain symptoms in bortezomib-treated patients, we developed an animal model of bortezomib-induced nociceptive sensory neuropathy. In this study, bortezomib (0.15 or 0.20mg/kg) was administered to Wistar rats three times/week for 8 weeks, followed by a 4 week follow-up period. At the end of the treatment period a significant decrease in weight gain was observed in the treated groups vs. controls, and hematological and histopathological parameters were evaluated. After the treatment period, both doses of bortezomib induced a severe reduction in nerve conduction velocity and demonstrated a dose-cumulative effect of the drug. The sensory behavioral assessment showed the onset of mechanical allodynia, while no effect on thermal perception was observed. Sciatic nerves and dorsal root ganglia (DRG) were collected at the end of the 8-week treatment and at the end of the follow-up period. The pathological examination revealed a dose-dependent axonopathy of the unmyelinated fibers in nerves of treated animals. No pathological alteration in most of DRG satellite cells and neurons was observed. Therefore, this animal model may be useful for studying the neurotoxicity and pain onset mechanisms related to bortezomib treatment.

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.

The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

We have characterised for the first time the general and neurological side effects experienced when using a series of chronic non-lethal cisplatin + paclitaxel schedules in Wistar rats, selected according to our previous experience and the animals' maximum tolerated dose. At the pathological level, the use of combination schedules was definitely more toxic at the kidney and sternal bone marrow level than the single-agent schedules. At the neurophysiological examination based on the assessment of the nerve conduction velocity measurement in the tail nerve, we identified only one combination schedule that was more neurotoxic than the similar schedules based on single-agent administration. This observation was confirmed by the neuropathological examination performed on the sciatic nerve, dorsal root ganglia, ventral and dorsal roots. Our study supports the hypothesis that the general and, to a lesser extent, neurological effects of a combination of cisplatin and paclitaxel are different from those of the administration of both drugs as single agents. We believe that these models may be useful for testing neuroprotective strategies.

We investigated a series of bortezomib-treated patients and correlated the course of bortezomib-induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty-eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty-three patients had a baseline TNSr = 0–2, and 25 patients had a baseline TNSr >2 (median = 6, range 3–13). The course of bortezomib-induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib-induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.

The role of Glutamate (Glu), one of the major excitatory neurotransmitters in the central nervous system, has been thoroughly investigated in animal models and in humans in several physiologic events, such as brain development and synaptic plasticity, but also in acute and chronic neurologic diseases and psychiatric disorders. Recently, it has been demonstrated that Glu is important for sensory input transduction, particularly along the nociceptive pathway. Glu involvement in peripheral neuropathies has also been suggested on the basis of experimental studies in animals, thus widening the spectrum of possible sites of action of this neurotransmitter from the central to the peripheral nervous system. This rather unexpected observation may have important therapeutic implications, provided that a complete characterization of the glutamatergic system in the peripheral nervous system is achieved and its changes under the different pathological conditions are investigated. This review will focus on the most recent advances in the research into the role of Glu and the glutamatergic system in the pathology of the peripheral nervous system.

Peripheral neuropathy, either inherited or acquired, represents a very common disorder for which effective clinical treatments are not available yet. Observations here summarized indicate that neuroactive steroids, such as progesterone, testosterone and their reduced metabolites, might represent a promising therapeutic option. Peripheral nerves are able to synthesize and metabolize neuroactive steroids and are a target for these molecules, since they express classical and non-classical steroid receptors. Neuroactive steroids modulate the expression of key transcription factors for Schwann cell function, regulate Schwann cell proliferation and promote the expression of myelin proteins involved in the maintenance of myelin multilamellar structure, such as myelin protein zero and peripheral myelin protein 22. These actions may result in the protection and regeneration of peripheral nerves affected by different forms of pathological alterations. Indeed, neuroactive steroids are able to counteract biochemical, morphological and functional alterations of peripheral nerves in different experimental models of neuropathy, including the alterations caused by aging, diabetic neuropathy and physical injury. Therefore, neuroactive steroids, pharmacological agents able to increase their local synthesis and synthetic ligands for their receptors have a promising potential for the treatment of different forms of peripheral neuropathy. © 2007 Elsevier B.V. All rights reserved.

BACKGROUND: Antineoplastic drugs, such as cisplatin (CDDP), induce disabling peripheral neuropathies, representing a hindrance to effective cancer treatments. The exact pathogenesis of CDDP-induced neuropathy is not yet understood, and the dysregulation of gene expression has been proposed. Valproate (VPA) is an antiepileptic drug recently discovered to remodel gene expression, with hypothetically putative neuroprotective effects. MATERIALS AND METHODS: VPA was tested in both, in vitro and in vivo models of CDDP-neurotoxicity. RESULTS: VPA administered in combination with CDDP promoted dorsal root ganglia (DRG) neurons survival. Moreover, this treatment induced in Wistar rats an improvement of body weight, sensory nerve conduction velocity, and DRG morphometric analysis. In contrast, VPA was not able to rescue CDDP pre-treated rats. CONCLUSION: When used in combination with CDDP, VPA displays a protective action against neuropathy, in our models, suggesting possible future clinical applications.

This study examined the dose-dependent efficacy of erythropoietin (EPO) for preventing and/or treating cisplatin (CDDP) induced peripheral neurotoxicity (CINP), and its influence on tumour treatment and growth. Rats received eight intraperitoneal (ip) injections of 2 mg/kg CDDP twice weekly. EPO co-administered (50 or 10 microg/kg ip, three times/week) had a dose-dependent effect, partially preventing CINP, but 0.5 microg/kg ip was not effective. The neuroprotective effect lasted at least 5 weeks after the last dose of EPO and CDDP. In addition, EPO (50 microg/kg ip three times/week) after the last injection of CDDP still induced a significant recovery of CINP. In a separate experiment in rats bearing mammary carcinoma EPO treatment (50 microg/kg ip) given concurrently with CDDP (1.0 and 1.5 mg/kg twice a week for four weeks) was neuroprotective without influencing the effectiveness of the treatment or tumour growth. EPO thus appears to be an effective neuroprotectant that does not interfere with tumour treatment.

Background Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought. Objectives To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs. Search methods On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and CINAHL Plus for randomised trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related drugs among human patients. Selection criteria We included randomised controlled trials (RCTs) or quasi-RCTs in which the participants received chemotherapy with cisplatin or related compounds, with a potential chemoprotectant (acetylcysteine, amifostine, adrenocorticotrophic hormone (ACTH), BNP7787, calcium and magnesium (Ca/Mg), diethyldithiocarbamate (DDTC), glutathione, Org 2766, oxcarbazepine, or vitamin E) compared to placebo, no treatment, or other treatments. We considered trials in which participants underwent evaluation zero to six months after completing chemotherapy using quantitative sensory testing (the primary outcome) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary outcomes). Data collection and analysis Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology. Main results As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons. Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766). Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity. Authors' conclusions At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.

The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.