Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS: Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS: A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION: Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.

Impact of Pain on Symptom Burden in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) affects the quality of life of cancer survivors. However, the impact of pain on symptom burden remains undefined. This study aimed to define differences in the clinical symptom profile of patients with painful and nonpainful CIPN. PATIENTS AND METHODS: A total of 579 participants (median age, 59 years [IQR, 19 years]; F=66%) were assessed cross-sectionally 6 months posttreatment. CIPN severity was graded using multiple methods, including patient-reported outcome measures, a clinically graded scale (NCI-CTCAE), and a neurologic examination score. Participants were classified into subgroups based on patient symptom report, with painful CIPN characterized by the presence of shooting/burning pain, and nonpainful CIPN characterized by the presence of numbness or tingling without shooting/burning pain. Behavioral changes were assessed via structured patient interview regarding symptom impact on sleep, exercise, and treatment-seeking. RESULTS: Among 579 participants, 24% (n=140) reported painful CIPN, 48% (n=280) reported nonpainful CIPN, and 28% (n=159) had no CIPN. Participants with painful CIPN demonstrated higher CIPN severity than those with nonpainful CIPN across multiple measures, including NCI-CTCAE, neurologic grading, and patient report (all P<.05). Participants with painful CIPN were more likely to report that their symptoms affected their ability to exercise (P=.007), produced sleep impairment, and increased treatment-seeking behavior due to their symptoms (both P<.001) compared with participants with nonpainful CIPN. CONCLUSIONS: Overall, participants with painful CIPN reported higher scores across all CIPN severity measures, including behavioral changes. This study underlines the need for accurate identification of different CIPN subgroups in hopes of informing better treatment and rehabilitation options for cancer survivors with painful CIPN.

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis.

PURPOSE OF REVIEW: Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic. RECENT FINDINGS: Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting. SUMMARY: Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.

Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia.

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity: Defining Minimal and Clinically Important Changes.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication of cancer treatment that produces functional disability. Increasingly, patient-reported outcome measures (PROMs) are used to assess CIPN, providing a broader symptom perspective than clinician-graded scales. Understanding when a reported change in CIPN symptoms meets the threshold for clinical significance is challenging. This study aimed to provide interpretation guidelines for validated CIPN PROMs, and thereby enable estimation of thresholds to identify clinically relevant symptoms. METHODS: Patients commencing neurotoxic cancer treatments were assessed at 3 timepoints: baseline, midtreatment, and end-of-treatment. Trajectory of CIPN development was assessed by means of CIPN PROMs, EORTC Quality of Life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity questionnaire (FACT/GOG-NTX). Thresholds were estimated for CIPN PROMs using the NCI CTCAE sensory neuropathy scale as the clinical anchor by midtreatment and end-of-treatment. Patients were assigned to a clinical change group according to CIPN development: either no development; grade 1 neuropathy (minimally important difference [MID]); or grade 2 neuropathy (clinically important difference). Distribution-based estimates (SD, 0.5) were also evaluated as supportive evidence. RESULTS: In total, 406 patients were recruited to the study, of whom 62% (n=199/320) developed CIPN by midtreatment and 80% (n=274/343) by end-of-treatment. Anchor-based MID estimates by midtreatment were 5.06 (95% CI, 4.26-5.86) for the QLQ-CIPN20 and 3.54 (95% CI, 2.87-4.20) for the FACT/GOG-NTX. End-of-treatment MIDs were estimated to be 7.32 (95% CI, 6.23-8.40) for the QLQ-CIPN20 and 4.84 (95% CI, 3.98-5.70) for the FACT/GOG-NTX. Distribution-based MID estimations yielded lower values than anchor-based methods, at 3.73 for the QLQ-CIPN20 and 2.64 for the FACT/GOG-NTX at midtreatment and 5.52 for the QLQ-CIPN20 and 3.64 for the FACT/GOG-NTX at end-of-treatment. CONCLUSIONS: Findings from the present series aid meaningful interpretation for commonly used validated CIPN PROMs and provide thresholds that serve as guidance on how to interpret score changes, which will be useful for design and evaluation of clinical trials and clinical practice.

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Physical activity behaviors in cancer survivors treated with neurotoxic chemotherapy.

AIM: There are many barriers to physical activity among cancer survivors. Survivors treated with neurotoxic chemotherapy may develop chemotherapy-induced peripheral neuropathy (CIPN) and experience additional barriers related to sensorimotor and mobility deficits. This study examined physical activity behaviors, including physical activity predictors, among cancer survivors treated with neurotoxic chemotherapies. METHODS: A cross-sectional study of 252 participants, 3-24 months after neurotoxic chemotherapy, was undertaken. Physical activity was self-reported (IPAQ). CIPN was self-reported (FACT/GOG-Ntx-13), clinically graded (NCI-CTCAE), and objectively measured using neurological grading scales and neurophysiological techniques (tibial and sural nerve conduction studies). Balance (Swaymeter) and fine motor skills (grooved pegboard) were assessed. Regression models were used to identify clinical, demographic and CIPN predictors of walking and moderate-vigorous physical activity. RESULTS: Forty-four percent of participants did not meet recommended physical activity guidelines (≥150 min/week). Sixty-six percent presented with CIPN. Nineteen percent of participants with CIPN reported that symptoms interfered with their ability to be physically active. A lower proportion of survivors aged ≥60, with grade ≥1 CIPN or BMI ≥30, reported meeting physical activity guidelines (all p < .05). Regression models identified older age, higher BMI, and patient-reported CIPN associated with lower walking, while higher BMI and females were associated with lower moderate-vigorous physical activity. Neurologically assessed CIPN did not associate with walking or moderate-vigorous physical activity. CONCLUSION: Cancer survivors exposed to neurotoxic chemotherapy have low physical activity levels. Further work should examine the factors causing physical activity limitations in this cohort and designing interventions to improve physical function and quality of life in survivors.

Metabolic and lifestyle risk factors for chemotherapy-induced peripheral neuropathy in taxane and platinum-treated patients: a systematic review.

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN. METHODS: Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included. RESULTS: Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk. CONCLUSIONS: Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection.

Polygenic risk of paclitaxel-induced peripheral neuropathy: a genome-wide association study.

BACKGROUND: Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. METHODS: We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. RESULTS: In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 × 10-5) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r2 = 0.53; P = 1.54 × 10-35). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10-6) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10-7). CONCLUSIONS: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.

Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients. AREAS COVERED: Individualized, or precision medicine in ALS recognizes the heterogeneous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials. EXPERT OPINION: Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research, is accelerating this process.

Association of electrochemical skin conductance with neuropathy in chemotherapy-treated patients.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse event of cancer treatment that can affect sensory, motor, or autonomic nerves. Assessment of autonomic neuropathy is challenging, with limited available tools. Accordingly, it is not routinely assessed in chemotherapy-treated patients. In this study, we aimed to examine whether electrochemical skin conductance (ESC) via Sudoscan, a potential measure of autonomic function, associates with subjective and objective measures of CIPN severity and autonomic neuropathy. METHODS: A cross-sectional assessment of patients who completed neurotoxic chemotherapy 3-24 months prior was undertaken using CIPN patient-reported outcomes (EORTC-QLQ-CIPN20), clinically graded scale (NCI-CTCAE), neurological examination score (TNSc), autonomic outcome measure (SAS), and Sudoscan. Differences in CIPN severity between participants with or without ESC dysfunction were investigated. Linear regression analyses were used to identify whether ESC values could predict CIPN severity. RESULTS: A total of 130 participants were assessed, with 93 participants classified with CIPN according to the clinically graded scale (NCI-CTCAE/grade ≥ 1), while 49% demonstrated hands or feet ESC dysfunction (n = 46). Participants with ESC dysfunction did not significantly differ from those with no dysfunction on multiple CIPN severity measures (clinical-grade, patient-report, neurological examination), and no differences on the autonomic outcome measure (SAS) (all p > 0.0063). Linear regression analyses showed that CIPN could not be predicted by ESC values. CONCLUSIONS: The inability of ESC values via Sudoscan to predict clinically-graded and patient-reported CIPN or autonomic dysfunction questions its clinical utility for chemotherapy-treated patients. The understanding of autonomic neuropathy with chemotherapy treatment remains limited and must be addressed to improve quality of life in cancer survivors.

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review.

Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes; clinico-pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP-43) pathology (12), non-TDP-43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.

NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex genetic architecture. The lengths of two short tandem repeats (STRs), at the NEK1 and STMN2 loci, were recently associated with ALS risk in cohorts of European descent. The STMN2 STR was proposed to be predictive of clinical features including the age of onset and disease duration in bulbar onset cases. We sought to investigate NEK1 and STMN2 STR lengths in a cohort of Australian sporadic ALS cases (n = 608) and neurologically healthy controls (n = 4689) of European ancestry. ExpansionHunter was used to determine NEK1 and STMN2 STR length genotypes from whole-genome sequencing data followed by PCR validation of predicted lengths. No significant association was identified between sporadic ALS risk and the length of either STR. Further, neither NEK1 nor STMN2 STR lengths were indicative of the age of onset or disease duration. We report that the NEK1 and STMN2 STRs were not associated with ALS risk or clinical features in this Australian sporadic ALS cohort.

The impact of obesity on neuropathy outcomes for paclitaxel- and oxaliplatin-treated cancer survivors.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m2) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment. METHODS: Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m2) were compared to those within the normal BMI range (< 25 kg/m2). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity. RESULTS: Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p < .001), larger waist circumference (B = .030, 95%CI = .001-.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models. CONCLUSIONS: Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment. IMPLICATIONS FOR CANCER SURVIVORS: Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions.

A Versatile Fluorescent Sensor Array for Platinum Anticancer Drug Detection in Biological Fluids.

Platinum complexes remain frontline anticancer therapies, even after 50 years of usage in clinical applications. However, there is still a lack of methodology to robustly detect and quantify these complexes in biological fluids. We report here a fluorescent sensor array comprising six sensors that demonstrates progress toward the detection of platinum levels in chemotherapy patients. Linear discriminant analysis was performed to examine each multidimensional data set, and the array was able to discriminate platinum from other biologically relevant metals and heavy metals and separately able to differentiate and identify platinum complexes with different coordination environments with 100% accuracy. Finally, the array showed sensitivity to various cisplatin and oxaliplatin concentrations in human plasma and was able to discriminate between a cohort of 27 cancer patients at different stages of platinum treatment. We envisage that our array system could lead to a better understanding of blood platinum concentrations of chemotherapy patients and could inform the modification of dosage regimes to minimize dose-limiting side effects.

Weekly Paclitaxel-Induced Neurotoxicity in Breast Cancer: Outcomes and Dose Response.

BACKGROUND: Paclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes. PATIENTS AND METHODS: Breast cancer patients receiving paclitaxel (80mg/m2 ) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients. RESULTS: Significant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT-GOG-Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT-GOG-Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT-GOG-Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT-GOG-Ntx: 45.3 ± 0.9, p < .05). CONCLUSION: Weekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose. IMPLICATIONS FOR PRACTICE: Weekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.

Hemoglobin, Body Mass Index, and Age as Risk Factors for Paclitaxel- and Oxaliplatin-Induced Peripheral Neuropathy.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development. Objective: To identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin. Design, Setting, and Participants: This cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020. Exposures: Paclitaxel or oxaliplatin chemotherapy. Main Outcomes and Measures: CIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development. Results: The study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (ß = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (ß = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (ß = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (ß = -1.08; 95% CI, -1.76 to -0.16; P = .01). Conclusions and Relevance: The results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.

Electrophysiological and phenotypic profiles of taxane-induced neuropathy.

OBJECTIVE: To comprehensively describe patient-reported, functional and neurophysiological outcomes to elucidate the phenotypic profile of taxane-induced neuropathy. METHODS: Taxane-treated patients (n = 47) completed cross-sectional bilateral clinical and sensory assessments and nerve conduction studies. Patients reported symptom severity via Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx13) questionnaire. RESULTS: Symptoms of neuropathy were reported by 81% of patients. On clinical examination, 62% had 2 or more abnormalities, with 20% indicating significant symptomatic and objective neuropathy. Nerve conduction studies were consistent with a sensory predominant axonal neuropathy. However, features more typical of entrapment neuropathy were also present in > 50%, which were not associated with overall severity of chemotherapy-induced peripheral neuropathy (CIPN) or clinical risk factors. CONCLUSIONS: There is considerable variation in CIPN phenotypes associated with taxane-treatment. Understanding their clinical associations may assist in identification of patients at risk of severe neurotoxicity. This would enable treatment modification decisions but also limit early cessation of effective anti-cancer treatment in patients with less severe neurological sequelae. SIGNIFICANCE: Understanding the CIPN phenotype may inform treatment decisions which could impact clinical and survival outcomes.

Peripheral neuropathy in hematologic malignancies - Past, present and future.

Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of hematologic malignancy. Peripheral neuropathy can be part of a paraneoplastic syndrome accompanying the disease but more commonly is a consequence of treatment with neurotoxic therapies, and produces sensory, motor, autonomic nerve dysfunction or a combination, leading to pain, loss of sensation and functional disability. This review provides an update on peripheral neuropathy in hematologic malignancy, including risk factors, mechanisms and treatment options. We examine the clinical features and risk factors for peripheral neuropathy following bortezomib, thalidomide, brentuximab vedotin and vinca alkaloid treatment, as well as related compounds. We review the current data on pharmacogenetic risk factors for the development of toxicity and highlight areas of future research.