Framework to leverage physical therapists for the assessment and treatment of chemotherapy-induced peripheral neurotoxicity (CIPN).

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a highly prevalent, dose-limiting, costly, and tough-to-treat adverse effect of several chemotherapy agents, presenting as sensory and motor dysfunction in the distal extremities. Due to limited effective treatments, CIPN can permanently reduce patient function, independence, and quality of life. One of the most promising interventions for CIPN is physical therapy which includes exercise, stretching, balance, and manual therapy interventions. Currently, there are no physical therapy guidelines for CIPN, thus limiting its uptake and potential effectiveness. METHODS: Utilizing the authors' collective expertise spanning physical therapy, symptom management research, oncology, neurology, and treating patients with CIPN, we propose a comprehensive clinical workflow for physical therapists to assess and treat CIPN. This workflow is based on (1) physical therapy guidelines for treating neurologic symptoms like those of CIPN, (2) results of clinical research on physical therapy and exercise, and (3) physical therapy clinical judgement. RESULTS: We present detailed tables of pertinent physical therapy assessment and treatment methods that can be used in clinical settings. CIPN assessment should include detailed sensory assessment, objective strength assessments of involved extremities, and validated physical performance measures incorporating static and dynamic balance, gait, and functional mobility components. CIPN treatment should involve sensorimotor, strength, balance, and endurance-focused interventions, alongside a home-based exercise prescription that includes aerobic training. We conclude with action items for oncology teams, physical therapists, patients, and researchers to best apply this framework to address CIPN. CONCLUSIONS: Physical therapists are in a unique position to help assess, prevent, and treat CIPN given their training and prevalence, yet there are no physical therapy clinical practice guidelines for CIPN. Our preliminary suggestions for CIPN assessments and treatments can catalyze the development of guidelines to assess and treat CIPN. We urge oncology teams, physical therapists, patients, and researchers to develop, adapt, and disseminate this framework to help alleviate the burden of chemotherapy on patients with cancer.

Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with DL- and L-glufosinate.

DL-glufosinate ammonium (DL-GLF) is a registered herbicide for which a guideline Developmental Neurotoxicity (DNT) study has been conducted. Offspring effects included altered brain morphometrics, decreased body weight, and increased motor activity. Guideline DNT studies are not available for its enriched isomers L-GLF acid and L-GLF ammonium; conducting one would be time consuming, resource-intensive, and possibly redundant given the existing DL-GLF DNT. To support deciding whether to request a guideline DNT study for the L-GLF isomers, DL-GLF and the L-GLF isomers were screened using in vitro assays for network formation and neurite outgrowth. DL-GLF and L-GLF isomers were without effects in both assays. DL-GLF and L-GLF (1-100 µM) isomers increased mean firing rate of mature networks to 120-140% of baseline. In vitro toxicokinetic assessments were used to derive administered equivalent doses (AEDs) for the in vitro testing concentrations. The AED for L-GLF was ∼3X higher than the NOAEL from the DL-GLF DNT indicating that the available guideline study would be protective of potential DNT due to L-GLF exposure. Based in part on the results of these in vitro studies, EPA is not requiring L-GLF isomer guideline DNT studies, thereby providing a case study for a useful application of DNT screening assays.

Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

The preferences of women with ovarian cancer for oral versus intravenous recurrence regimens.

OBJECTIVE: To assess preferences of women with ovarian cancer regarding features of available anti-cancer regimens for platinum-resistant, biomarker-positive disease, with an emphasis on oral PARP inhibitor and standard intravenous (IV) chemotherapy regimens. METHODS: A discrete-choice-experiment preferences survey was designed, tested, and administered to women with ovarian cancer, with 11 pairs of treatment profiles defined using seven attributes (levels/ranges): regimen (oral daily, IV weekly, IV monthly); probability of progression-free (PFS) at 6 months (40%-60%); probability of PFS at 2 years (10%-20%); nausea (none, moderate); peripheral neuropathy (none, mild, moderate); memory problems (none, mild); and total out-of-pocket cost ($0 to $10,000). RESULTS: Of 123 participants, 38% had experienced recurrence, 25% were currently receiving chemotherapy, and 18% were currently taking a PARP inhibitor. Given attributes and levels, the relative importance weights (sum 100) were: 2-year PFS, 28; cost, 27; 6-month PFS, 19; neuropathy,14; memory problems, nausea, and regimen, all ≤5. To accept moderate neuropathy, participants required a 49% (versus 40%) chance of PFS at 6 months or 14% (versus 10%) chance at 2 years. Given a 3-way choice where PFS and cost were equal, 49% preferred a monthly IV regimen causing mild memory problems, 47% preferred an oral regimen causing moderate nausea, and 4% preferred a weekly IV regimen causing mild memory and mild neuropathy. CONCLUSIONS: These findings challenge the assumption that oral anti-cancer therapies are universally preferred by patients and demonstrate that there is no "one size fits all" regimen that is preferable to women with ovarian cancer when considering recurrence treatment regimens.

Associations of the Behavioral Assessment and Research System (BARS) neurobehavioral outcomes with attention problems in children living near coal ash storage sites.

Environmental exposures have been linked to childhood problems with overactivity, attention, and impulse control, and an increased risk of attention deficit hyperactivity disorder (ADHD) diagnosis. Two approaches to identify these types of exposure-related neurobehavioral problems include the use of computerized tests, such as the Behavioral Assessment and Research System (BARS), as well as the use of behavior rating scales. To assess comparability of these two types of measures, we analyzed data from 281 children aged 6 to 14 years enrolled in a 5-year research study investigating coal ash exposure and neurobehavioral health. All children lived in proximity of coal ash storage sites. We administered six computer tests from the BARS and obtained behavior measures from the parent-completed Child Behavior Checklist (CBCL) ADHD DSM oriented scale. BARS test performance was associated with age indicating that the tests could be used to evaluate neurodevelopmental changes over time or across a wide age range. Tests within the BARS including Continuous Performance (CPT) false alarm (standardized estimate 1.57, 95% confidence interval (CI) (0.67, 2.48), adjusted p = 0.006), Selective Attention (SAT) wrong count (standardized estimate 2.8, 95% CI (1.17, 4.44), adjusted p = 0.006), and SAT proportion correct (standardized estimate -2.45, 95% CI (-4.01, -0.88), adjusted p = 0.01) were associated with attention and impulse control problems on the CBCL after adjustment for multiple comparisons. Findings support that the BARS can contribute to research on environmental exposures by assessing subclinical behaviors related to ADHD such as sustained attention, impulse control, response inhibition, associative learning, and short-term memory. Future research can examine relationships of these BARS measures with biomarkers of neurotoxic exposures related to living near coal ash storage sites to better identify the potential risk for ADHD-related behaviors among children living near coal ash storage sites.

Validity and Reliability of an Assessment Tool for the Screening of Neurotoxic Effects in Agricultural Workers in Chile.

There is a substantial use of pesticides within the agricultural industry of Chile, with neurotoxic effects through mechanisms of acetylcholinesterase inhibition. These pesticides result in deterioration in health, increasing the risk of diseases such as Parkinson's and Alzheimer's in highly exposed occupational population. To date, there are no brief assessment tools to monitor cognitive impairment in agricultural workers chronically exposed to these pesticides. Method. 234 agricultural workers and 305 nonagricultural workers were assessed two times (test-retest) through a brief tool which comprised three tests (clock-drawing test (CDT); frontal assessment battery (FAB); trail making tests (TMT) A and B). The full scale of WAIS-IV was administered as a gold standard to 18% of the sample of agricultural workers. Factor analysis was used to evaluate the factor structure, and validity and test-retest reliability were assessed concurrently. Results. Cronbach's alpha values were satisfactory or above (>0.60). Test-retest correlations were all significantly correlated (p < 0.001). All the tests had a significant correlation with the full scale IQ score of WAIS-IV (p < 0.05). The Kaiser-Meyer-Olkin (KMO) measure was 0.74, and the Bartell sphericity test = p < 0.001. Three factors explaining 61.62% of the variance were extracted. Two items of the FAB test were dropped of the final factor solution. Normative data transformed into percentile scores and stratified by age and educational level were obtained for Chilean agricultural workers. Conclusion. The brief assessment tool has adequate metric properties as a screening instrument. This allows for a simple administration test (10 to 15 minutes) that can potentially be used for the rapid monitoring of cognitive deterioration in the face of occupational exposure to pesticides in agricultural workers.

Overview and critical revision of clinical assessment tools in chemotherapy-induced peripheral neurotoxicity.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major toxicity of cancer treatment, leading to dose reduction and premature treatment cessation, potentially affecting patient function, and quality of life. The development of accurate and sensitive assessment tools for CIPN is essential to enable clinical monitoring during treatment, follow-up of long-term outcomes and measurement of toxicity in clinical trials. This review examines CIPN clinical assessment scales incorporating clinician-based, composite, and patient-reported outcomes (PROs), providing a systematic review of their properties and an updated critical analysis of recommendations on current evidence for their use. This systematic review of CIPN assessment tools identified 50 papers containing 41 assessment tools, across 4 categories (common toxicity criteria; composite neurological scale; PROs; pain scale). The majority of these tools were PROs, underscoring the importance of patient-based assessment of symptoms. While there has been considerable work in the field over the past 10 years, this review highlights significant gaps, including a lack of evaluation of responsiveness and problematic neuropathic pain evaluation. There remains a need for consensus on the best available tool and the need to modify existing instruments to improve utility.

Assessment of a semi-quantitative screening method for diagnosis of ethylene glycol poisoning.

Background Ethylene glycol poisoning remains a rare but important presentation to acute toxicology units. Guidelines recommended that ethylene glycol should be available as an 'urgent' test within 4 h, but these are difficult to deliver in practice. This study assessed a semi-quantitative enzymatic spectrophotometric assay for ethylene glycol compatible with automated platforms. Methods The ethylene glycol method was assessed in 21 samples from patients with an increased anion gap and metabolic acidosis not due to ethylene glycol ingestion, and seven samples known to contain ethylene glycol. All samples were analysed in random order in a blinded manner to their origin on a laboratory spectrophotometer. Results In this study, seven samples were known to contain ethylene glycol at concentrations >100 mg/L. The method correctly identified all seven samples as containing ethylene glycol. No false-positives were observed. Thirteen samples gave clear negative results. Ethylene glycol was present at <20 mg/L in one sample, but this sample remained within the limits of the negative control. Passing-Bablock correlation of estimates of ethylene glycol concentration against results obtained when the samples had been analysed using the quantitative method on an automated analyser showed a good correlation (R = 0.84) but with an apparent under-recovery. Conclusions A semi-quantitative assay for ethylene glycol was able to discriminate well between samples containing ethylene glycol and those with other causes of acidosis. It is a practical small-scale assay for rapid identification of cases of ethylene glycol poisoning.

An assessment of the awareness of local anesthetic systemic toxicity among multi-specialty postgraduate residents.

Local anesthetics (LAs) are extensively used in clinical practice by both anesthesiologists and non-anesthesiologists and are often associated with systemic toxicity. We hypothesize that this awareness is inadequate among medical specialists and entails a risk of misdiagnosis and underreporting of such events. We therefore conducted a cross-sectional questionnaire-based study to assess the level of understanding of LA use and effective management of systemic toxicity among 200 postgraduate residents of various specialties (with the exception of anesthesiology) in a tertiary care hospital in India from October to December 2013. Among those residents who had used LAs (193/200), 27 and 25 % of responders correctly identified the toxic doses of lidocaine and of lidocaine + adrenaline, respectively. Of the responders, 70 % always performed a negative aspiration of blood before injecting the drug, 27 % sometimes aspirated and the remaining 3 % never aspirated. The majority of the responders (93 %) were unaware of the toxic dose of bupivacaine. Only 70 % of responders believed that LAs could be toxic [95 % confidence interval (CI) 65.5-74.5 %], and 81 % of these correctly identified the signs and symptoms of cardiotoxicity. Only 2 % of responders knew that lipid emulsion is a part of its treatment (95 % CI 0.6-3.4 %). Based on these results, there is a definite need to increase the awareness of detection and treatment of local anesthetic toxicity among all medical practitioners who regularly use LAs.

Chemotherapy-induced polyneuropathy: major agents and assessment by questionnaires.

Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant differences between the neuropathic pain scales, which are most commonly used for assessing CIPN.

Developmental neurotoxicity - challenges in the 21st century and in vitro opportunities.

In recent years neurodevelopmental problems in children have increased at a rate that suggests lifestyle factors and chemical exposures as likely contributors. When environmental chemicals contribute to neurodevelopmental disorders developmental neurotoxicity (DNT) becomes an enormous concern. But how can it be tackled? Current animal test- based guidelines are prohibitively expensive, at $ 1.4 million per substance, while their predictivity for human health effects may be limited, and mechanistic data that would help species extrapolation are not available. A broader screening for substances of concern requires a reliable testing strategy, applicable to larger numbers of substances, and sufficiently predictive to warrant further testing. This review discusses the evidence for possible contributions of environmental chemicals to DNT, limitations of the current test paradigm, emerging concepts and technologies pertinent to in vitro DNT testing and assay evaluation, as well as the prospect of a paradigm shift based on 21st century technologies.

Postnuclear supernatants of rat brain regions as substrates for the in vitro assessment of cadmium-induced neurotoxicity on acetylcholinesterase activity.

Acetylcholinesterase (AChE) activity is thought to be a major neurotoxicity biomarker. Considering the recently highlighted controversy over the use of AChE activity as a biomarker for the neurotoxicity induced by cadmium (Cd; a major environmental contaminant), we have evaluated the in vitro effects of different concentrations of Cd on AChE activity in postnuclear supernatants of brain regions of newborn, 21-day-old, and adult male Wistar rats. Our findings demonstrate that Cd is a consistent inhibitor of AChE activity at concentrations higher than 10(-3) M as well as that, at a concentration of 10(-2) M, Cd induces an almost absolute inhibition of this crucial enzyme in the examined postnuclear supernatants. These findings confirm previous in vitro experiments of ours, but are not in full agreement with the available in vivo findings; in fact, they underline that this in vitro approach to Cd-induced neurotoxicity does not produce the distinctive brain region-specific responses in terms of AChE activity that we have recently observed in vivo. Our study does not support the use of AChE activity as a biomarker for the assessment of Cd-induced neurotoxicity in rat brain-derived postnuclear supernatants, at least under the examined in vitro experimental conditions.

Pitfalls in clinical assessment of neurotoxic diseases: negative effects of repeated diagnostic evaluation, illustrated by a clinical case.

Exposure to different toxic substances can have acute and chronic neurological and neuropsychiatric health effects on humans. Patients often report impaired concentration and memory, irritability, fatigue, instability of affect and difficulties in impulse control. The diagnostic process for neurotoxic diseases is complex and relies heavily on the exclusion of differential diagnosis and substantiating the cognitive complaints by neuropsychological assessment. Diagnostic evaluations have the purpose to help the patient by finding an explanation for the symptoms to guide treatment strategy or prevent further deterioration. But what if the diagnostic process in itself leads to problems that can be quite persistent and difficult to manage? The iatrogenic, or sick-making, side effects of the diagnostic process are the main focus of this case study.

Cost of detecting a chronic solvent encephalopathy case by screening.

BACKGROUND: Stepwise screening of chronic solvent encephalopathy (CSE), using a postal survey followed by clinical examinations, has been shown to detect symptomatic exposed workers with an occupational disease even in industrialized countries with long-term, but relatively low dose exposure. Previous studies have suggested under-detection and late recognition of CSE, when work ability is already markedly reduced. AIMS: The aim was to estimate the cost of detecting one new CSE case by screening and diagnostics, to estimate the career extension needed to cover the cost of screening, and to study the work ability of the CSE cases. METHODS: A financial analysis of stepwise postal CSE screening followed by clinical examinations (SPC screening) was carried out, and the results were compared to those of the group of CSE cases referred to the Finnish Institute of Occupational Health (FIOH) by the existing national practice of occupational health services (OHS screening). The work ability of the SPC screened CSE cases was studied in relation to the retirement rate and the Work Ability Index (WAI). RESULTS: An analysis of the costs of detecting a new verified CSE case revealed them to be approximately 16,500 USD. Using the mean monthly wages in the fields concerned, we showed that if a worker is able to continue working for four months longer, the screening covers these costs. The cost for detecting a CSE case was twenty times higher with the existing OHS routine, when actualized according to the national guidelines. A CSE case detected at an early stage enables occupational rehabilitation or measures to decrease solvent exposure. The retirement rate of the SPC screened CSE cases was significantly lower than that of the OHS screened cases (6.7% vs. 74%). The results suggest that SPC screening detects patients at an earlier stage of the disease, when they are still capable of working. Their WAI sores were nevertheless lower than those of the general population, implying a greater risk of becoming excluded from the labor market. CONCLUSION: Stepwise screening of CSE using a postal survey followed by clinical examinations detected new CSE cases at lower costs than existing OHS screening routines. Detecting CSE at an early stage prevents early retirement.

Assessment of serum S100B and neuron specific enolase levels to evaluate the neurotoxic effects of organic solvent exposure.

OBJECTIVES: Long-term organic solvent exposure may cause toxic effects in central nervous system . Trichloroethylene (TCE) is known to be one of the neurotoxic chlorinated organic solvents. Trichloroacetic acid (TCA) is an oxidative pathway metabolite of TCE. S100B, a calcium-binding protein in glial cells, and neuron specific enolase (NSE) in neuron cytoplasma are protein markers of astrocyte and neuron damage, respectively. MATERIALS AND METHODS: Clinical and laboratory assesments were performed in 25 participants with organic solvent exposure history. Control group included 25 healthy age and sex-matched individuals. Measurements of serum S100B and NSE were performed using Roche Cobas E 601 compatible kits and elechtrochemiluminescence immunoassay. The levels of TCA in urine were measured by the headspace GC technique, after methyl esterification by methanol. RESULTS: Median value of urine TCA in solvent-exposed group was 12.30 mg/L with 10.20 mg/L and 35.00 mg/L minimum and maximum values, respectively. The difference between serum S100B levels of solvent-exposed group (0.064 µg/L) and control group (0.049 µg/L) was statistically significant (p < 0.05). Serum NSE levels of control group (15.61 ng/ml) were higher than solvent-exposed group (13.90 ng/ml) but difference was not statistically significant (p > 0.05). CONCLUSIONS: Serum S100B levels were found to be higher in solvent-exposed group when compared with control group. NSE levels were comparable between two groups. Increased Serum S100B levels in organic solvent exposure may indicate a preventive response to neuronal damage caused by reactive oxygen species (ROS) produced through oxidative metabolic pathways of organic solvents.

Decision rules for assessment of chronic solvent-induced encephalopathy: Results in 2370 patients.

For the diagnosis of patients suspected of chronic solvent-induced encephalopathy (CSE), it would be helpful if the applied cognitive tests show a characteristic profile of impairment in this disease. We investigated the existence of such a profile. In 1997-2006 two expert teams in The Netherlands systematically examined 2370 patients referred for evaluation of suspected CSE. The procedure included two selection steps: (1) intake interview, using criteria of exposure, development of symptoms and absence of non-solvent causes, and (2) seven tests of the computerized Neurobehavioural Evaluation System (NES). Patients showing negligible impairments were considered free from CSE and were not further examined. The third step comprised a neuropsychological, neurological and exposure evaluation. Explicit decision rules for the diagnosis of CSE were developed, including a minimum score for cognitive impairment summarizing 25 cognitive tests. These rules were retroactively applied to 563 patients, comprising 513 patients who had regularly completed all diagnostic steps and a sample of 50 out of the approximately 450 patients with negligible impairments on the NES, who were fully examined. The data from this sample were extrapolated to the original number of 450. In the combined population of 963 patients, a calculated 301 patients were given the diagnosis 'Solely CSE', 242 'CSE and other disease', 158 'Other Disease' and 262 'No (known) disease'. In the Solely CSE patients, the most impaired tests regarded Verbal Fluency & -Similarities, Motor Speed and Simple Attention. A profile of test results that might support the identification of patients with CSE amongst the other referred patients, was not found. The diverging results of related cognitive tests indicate that the use of a core test battery is needed to improve comparability. We consider the decision rules as a step towards a more objective assessment of CSE.

Nerve excitability assessment in chemotherapy-induced neurotoxicity.

Chemotherapy-induced neurotoxicity is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies(1,2). Chemotherapy-induced peripheral neuropathy produces symptoms of numbness and paraesthesia in the limbs and may progress to difficulties with fine motor skills and walking, leading to functional impairment. In addition to producing troubling symptoms, chemotherapy-induced neuropathy may limit treatment success leading to dose reduction or early cessation of treatment. Neuropathic symptoms may persist long-term, leaving permanent nerve damage in patients with an otherwise good prognosis(3). As chemotherapy is utilised more often as a preventative measure, and survival rates increase, the importance of long-lasting and significant neurotoxicity will increase. There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Appropriate assessment of neurotoxicity will be critical as a prognostic factor and as suitable endpoints for future trials of neuroprotective agents. Current methods to assess the severity of chemotherapy-induced neuropathy utilise clinician-based grading scales which have been demonstrated to lack sensitivity to change and inter-observer objectivity(4). Conventional nerve conduction studies provide information about compound action potential amplitude and conduction velocity, which are relatively non-specific measures and do not provide insight into ion channel function or resting membrane potential. Accordingly, prior studies have demonstrated that conventional nerve conduction studies are not sensitive to early change in chemotherapy-induced neurotoxicity(4-6). In comparison, nerve excitability studies utilize threshold tracking techniques which have been developed to enable assessment of ion channels, pumps and exchangers in vivo in large myelinated human axons(7-9). Nerve excitability techniques have been established as a tool to examine the development and severity of chemotherapy-induced neurotoxicity(10-13). Comprising a number of excitability parameters, nerve excitability studies can be used to assess acute neurotoxicity arising immediately following infusion and the development of chronic, cumulative neurotoxicity. Nerve excitability techniques are feasible in the clinical setting, with each test requiring only 5 -10 minutes to complete. Nerve excitability equipment is readily commercially available, and a portable system has been devised so that patients can be tested in situ in the infusion centre setting. In addition, these techniques can be adapted for use in multiple chemotherapies. In patients treated with the chemotherapy oxaliplatin, primarily utilised for colorectal cancer, nerve excitability techniques provide a method to identify patients at-risk for neurotoxicity prior to the onset of chronic neuropathy. Nerve excitability studies have revealed the development of an acute Na(+) channelopathy in motor and sensory axons(10-13). Importantly, patients who demonstrated changes in excitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity(11). However, across treatment, striking longitudinal changes were identified only in sensory axons which were able to predict clinical neurological outcome in 80% of patients(10). These changes demonstrated a different pattern to those seen acutely following oxaliplatin infusion, and most likely reflect the development of significant axonal damage and membrane potential change in sensory nerves which develops longitudinally during oxaliplatin treatment(10). Significant abnormalities developed during early treatment, prior to any reduction in conventional measures of nerve function, suggesting that excitability parameters may provide a sensitive biomarker.