Proton MR spectroscopy shows improved performance to segregate high-grade astrocytoma subgroups when defined with the new 2021 World Health Organization classification of central nervous system tumors.

OBJECTIVES: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors prioritizes isocitrate dehydrogenase (IDH) mutation to define tumor types in diffuse gliomas, in contrast to the 2016 classification, which prioritized histological features. Our objective was to investigate the influence of this change in the performance of proton MR spectroscopy (1H-MRS) in segregating high-grade diffuse astrocytoma subgroups. METHODS: Patients with CNS WHO grade 3 and 4 diffuse astrocytoma, known IDH mutation status, and available 1H-MRS were retrospectively retrieved and divided into 4 groups based on IDH mutation status and histological grade. Differences in 1H-MRS between groups were analyzed with the Kruskal-Wallis test. The points on the spectrum that showed the greatest differences were chosen to evaluate the performance of 1H-MRS in discriminating between grades 3 and 4 tumors (WHO 2016 defined), and between IDH-mutant and IDH-wildtype tumors (WHO 2021). ROC curves were constructed with these points, and AUC values were calculated and compared. RESULTS: The study included 223 patients with high-grade diffuse astrocytoma. Discrimination between IDH-mutant and IDH-wildtype tumors showed higher AUC values (highest AUC short TE, 0.943; long TE, 0.864) and more noticeable visual differences than the discrimination between grade 3 and 4 tumors (short TE, 0.885; long TE, 0.838). CONCLUSION: Our findings suggest that 1H-MRS is more applicable to classify high-grade astrocytomas defined with the 2021 criteria. Improved metabolomic robustness and more homogeneous groups yielded better tumor type discrimination by 1H-MRS with the new criteria. CLINICAL RELEVANCE STATEMENT: The 2021 World Health Organization classification of brain tumors empowers molecular criteria to improve tumor characterization. This derives in greater segregation of high-grade diffuse astrocytoma subgroups by MR spectroscopy and warrants further development of brain tumor classification tools with spectroscopy. KEY POINTS: • The new 2021 updated World Health Organization classification of central nervous system tumors maximizes the role of molecular diagnosis in the classification of brain tumors. • Proton MR spectroscopy performs better to segregate high-grade astrocytoma subgroups when defined with the new criteria. • The study provides additional evidence of improved metabolic characterization of brain tumor subgroups with the new criteria.

Differentiating IDH-mutant astrocytomas and 1p19q-codeleted oligodendrogliomas using DSC-PWI: high performance through cerebral blood volume and percentage of signal recovery percentiles.

OBJECTIVE: Presurgical differentiation between astrocytomas and oligodendrogliomas remains an unresolved challenge in neuro-oncology. This research aims to provide a comprehensive understanding of each tumor's DSC-PWI signatures, evaluate the discriminative capacity of cerebral blood volume (CBV) and percentage of signal recovery (PSR) percentile values, and explore the synergy of CBV and PSR combination for pre-surgical differentiation. METHODS: Patients diagnosed with grade 2 and 3 IDH-mutant astrocytomas and IDH-mutant 1p19q-codeleted oligodendrogliomas were retrospectively retrieved (2010-2022). 3D segmentations of each tumor were conducted, and voxel-level CBV and PSR were extracted to compute mean, minimum, maximum, and percentile values. Statistical comparisons were performed using the Mann-Whitney U test and the area under the receiver operating characteristic curve (AUC-ROC). Lastly, the five most discriminative variables were combined for classification with internal cross-validation. RESULTS: The study enrolled 52 patients (mean age 45-year-old, 28 men): 28 astrocytomas and 24 oligodendrogliomas. Oligodendrogliomas exhibited higher CBV and lower PSR than astrocytomas across all metrics (e.g., mean CBV = 2.05 and 1.55, PSR = 0.68 and 0.81 respectively). The highest AUC-ROCs and the smallest p values originated from CBV and PSR percentiles (e.g., PSRp70 AUC-ROC = 0.84 and p value = 0.0005, CBVp75 AUC-ROC = 0.8 and p value = 0.0006). The mean, minimum, and maximum values yielded lower results. Combining the best five variables (PSRp65, CBVp70, PSRp60, CBVp75, and PSRp40) achieved a mean AUC-ROC of 0.87 for differentiation. CONCLUSIONS: Oligodendrogliomas exhibit higher CBV and lower PSR than astrocytomas, traits that are emphasized when considering percentiles rather than mean or extreme values. The combination of CBV and PSR percentiles results in promising classification outcomes. CLINICAL RELEVANCE STATEMENT: The combination of histogram-derived percentile values of cerebral blood volume and percentage of signal recovery from DSC-PWI enhances the presurgical differentiation between astrocytomas and oligodendrogliomas, suggesting that incorporating these metrics into clinical practice could be beneficial. KEY POINTS: • The unsupervised selection of percentile values for cerebral blood volume and percentage of signal recovery enhances presurgical differentiation of astrocytomas and oligodendrogliomas. • Oligodendrogliomas exhibit higher cerebral blood volume and lower percentage of signal recovery than astrocytomas. • Cerebral blood volume and percentage of signal recovery combined provide a broader perspective on tumor vasculature and yield promising results for this preoperative classification.

Plasma neurofilament light chain levels in chemotherapy-induced peripheral neurotoxicity according to type of anticancer drug.

BACKGROUND AND PURPOSE: A real-time biomarker in chemotherapy-induced peripheral neurotoxicity (CIPN) would be useful for clinical decision-making during treatment. Neurofilament light chain (NfL) can be detected in blood in the case of neuroaxonal damage. The aim of the study was to compare the levels of plasma NfL (pNfL) according to the type of chemotherapeutic agent and the severity of CIPN. METHODS: This single-center prospective observational longitudinal study included patients treated with paclitaxel (TX; n = 34), brentuximab vedotin (BV; n = 29), or oxaliplatin (PT; n = 19). All patients were assessed using the Total Neuropathy Score-clinical version and Common Terminology Criteria for Adverse Events before, during, and up to 6-12 months after the end of treatment. Nerve conduction studies (NCS) were performed before and after chemotherapy discontinuation. Consecutive plasma samples were analyzed for NfL levels using a Simoa® analyzer. Changes in pNfL were compared between groups and were eventually correlated with clinical and NCS data. Clinically relevant (CR) CIPN was considered to be grade ≥ 2. RESULTS: Eighty-two patients, mostly women (59.8%), were included. One third of the patients who received TX (29.4%), BV (31%), or PT (36.8%) developed CR-CIPN, respectively, without differences among them (p = 0.854). Although pNfL significantly increased during treatment and decreased throughout the recovery period in all three groups, patients receiving TX showed significantly greater and earlier changes in pNfL levels compared to the other agents (p < 0.001). CONCLUSIONS: A variable change in pNfL is observed depending on the type of agent and mechanism of neurotoxicity with comparable CIPN severity, strongly implying the need to identify different cutoff values for each agent.

Incidence and risk factors for developing chemotherapy-induced neuropathic pain in 500 cancer patients: A file-based observational study.

OBJECTIVE: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP). METHODS: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN. RESULTS: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001). CONCLUSION: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Voxel-level analysis of normalized DSC-PWI time-intensity curves: a potential generalizable approach and its proof of concept in discriminating glioblastoma and metastasis.

OBJECTIVE: Standard DSC-PWI analyses are based on concrete parameters and values, but an approach that contemplates all points in the time-intensity curves and all voxels in the region-of-interest may provide improved information, and more generalizable models. Therefore, a method of DSC-PWI analysis by means of normalized time-intensity curves point-by-point and voxel-by-voxel is constructed, and its feasibility and performance are tested in presurgical discrimination of glioblastoma and metastasis. METHODS: In this retrospective study, patients with histologically confirmed glioblastoma or solitary-brain-metastases and presurgical-MR with DSC-PWI (August 2007-March 2020) were retrieved. The enhancing tumor and immediate peritumoral region were segmented on CE-T1wi and coregistered to DSC-PWI. Time-intensity curves of the segmentations were normalized to normal-appearing white matter. For each participant, average and all-voxel-matrix of normalized-curves were obtained. The 10 best discriminatory time-points between each type of tumor were selected. Then, an intensity-histogram analysis on each of these 10 time-points allowed the selection of the best discriminatory voxel-percentile for each. Separate classifier models were trained for enhancing tumor and peritumoral region using binary logistic regressions. RESULTS: A total of 428 patients (321 glioblastomas, 107 metastases) fulfilled the inclusion criteria (256 men; mean age, 60 years; range, 20-86 years). Satisfactory results were obtained to segregate glioblastoma and metastases in training and test sets with AUCs 0.71-0.83, independent accuracies 65-79%, and combined accuracies up to 81-88%. CONCLUSION: This proof-of-concept study presents a different perspective on brain MR DSC-PWI evaluation by the inclusion of all time-points of the curves and all voxels of segmentations to generate robust diagnostic models of special interest in heterogeneous diseases and populations. The method allows satisfactory presurgical segregation of glioblastoma and metastases. KEY POINTS: • An original approach to brain MR DSC-PWI analysis, based on a point-by-point and voxel-by-voxel assessment of normalized time-intensity curves, is presented. • The method intends to extract optimized information from MR DSC-PWI sequences by impeding the potential loss of information that may represent the standard evaluation of single concrete perfusion parameters (cerebral blood volume, percentage of signal recovery, or peak height) and values (mean, maximum, or minimum). • The presented approach may be of special interest in technically heterogeneous samples, and intrinsically heterogeneous diseases. Its application enables satisfactory presurgical differentiation of GB and metastases, a usual but difficult diagnostic challenge for neuroradiologist with vital implications in patient management.

Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients.

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel-induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12-weekly paclitaxel-based regimen. Patients were clinically examined by means of the Total Neuropathy Score-clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0-1 and 26 (44%) grade 2-3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week-12 was determined, whereas patients with TNSc grade 2-3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0-1. receiver-operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2-3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2-3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro-axonal injury in PIPN. An early increase of this biomarker after a 3-weekly chemotherapy course can be a predictive marker of final PIPN severity.

Serum neurofilament light chain levels as biomarker of paclitaxel-induced cognitive impairment in patients with breast cancer: a prospective study.

OBJECTIVE: To prospectively assess the utility of serum neurofilament light chain (sNfL) levels in identifying the risk to develop chemotherapy-induced cognitive impairment (CICI) in cancer patients. We also examined if sNfL can be identified as an early biomarker of CICI development. METHODS: We longitudinally measured sNfL levels in 20 female patients with breast cancer, scheduled to receive the 12 weekly paclitaxel-based regimen. An equal number of age-matched female heathy subjects was incuded as control group. CICI was graded by means of the Montreal Cognitive Assessment scale (MOCA); peripheral neurotoxicity (PN) was graded using the neurosensory Common Criteria for Adverse Events (CTCAE)v5.0, while sNfL levels were quantified using a high-sensitive technique (Quanterix, Simoa) before the administration of chemotherapy (T0), after 3 courses (T1), and at the end of chemotherapy (T2). RESULTS: Pre-treatment sNfL levels were comparable in patients and controls (p = 0.103). At T2, 5/20 patients (mean age 61.4 ± 5.0 years) developed CICI. These 5 patients also had clinically-significant PN. Patients with and without CICI had comparable sNfL values at T2 (p = 0.1). In addition, at T2, sNfL levels did not correlate significantly with MOCA score in CICI patients (p = 0.604). The difference of sNfL levels between T1 and T0 failed to predict independently the occurrence of CICI at T2. CONCLUSION: Our findings do not support the utility of measuring sNfL levels as a biomarker of CICI. Grade 2-3 PN most strongly confounded our outcomes. Considering the small sample size, which might have prevented the results from being extrapolated, further testing in larger studies is warranted.

Neuromuscular complications of cancer therapy.

PURPOSE OF REVIEW: The neuromuscular complications of cancer therapy include chemotherapy-induced peripheral neurotoxicity (CIPN), immune-related neuromuscular complications to immune checkpoint inhibitors and radiation-induced neuropathy/plexopathy. With a wider focus on CIPN, we will discuss new pathogenetic insights, recent predictive biomarkers and emerging therapies for neuromuscular complications of cancer therapy. RECENT FINDINGS: Findings from recent preclinical studies have improved our knowledge on new CIPN pathogenetic pathways, including the activation of senescence-like processes in neurons, axonal degeneration and neuroinflammation. Metabolomics and serum neurofilament light chain levels appear the most promising biomarkers to predict CIPN development and severity. There is some recent evidence of promising pharmacological compounds to prevent or treat CIPN, and new drugs are in early development and testing. SUMMARY: A multimodal assessment, with neurophysiological, imaging and patient-reported outcome measures, coupled with the use of reliable blood or genetic biomarkers, may offer pathogenetic grounds for future preventive and symptomatic strategies for the multidisciplinary treatment of neuromuscular complications of cancer therapy.

Duloxetine against symptomatic chemotherapy-induced peripheral neurotoxicity in cancer survivors: a real world, open-label experience.

The objective of this observational study was to evaluate the efficacy and safety of duloxetine in a cohort of 100 cancer survivors with chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN was graded employing the TNSc and the NCI-CTCv4. The Patient Global Impression of Change (PGIC) scale measured the efficacy of duloxetine (1: no benefit; to 7: excellent response). A clinically meaningful response was considered a PGIC > 4. Median age was 62 (29-81) years and 42% were male. CIPN was graded as grades 1, 2 and 3 in 20, 66, and 14% of patients, respectively. Median time to duloxetine initiation was 6 (1-63) months after chemotherapy. Fifty-seven patients early dropped out from duloxetine, due to lack of efficacy (20%) or side effects (37%). Male patients more frequently discontinued duloxetine due to lack of efficacy (35.7 vs. 8.6% P = 0.001). PGIC scores were higher in female patients (4 vs. 1, P = 0.001), taxane-treated patients (4 vs. 1, P = 0.042) and with short-lasting (<6 months) CIPN (4 vs. 1, P = 0.008). Patients with long-lasting CIPN had a higher rate of adverse events (47 vs. 27%, P = 0.038) and discontinuation (54.8 vs. 45.1%, P = 0.023). In the multivariate analysis, female gender and short-lasting CIPN were independently associated with a favorable response to duloxetine. Low tolerability, male gender, and long-lasting CIPN significantly limited duloxetine use in daily practice setting. A minority of cancer survivors with CIPN treated with duloxetine had a meaningful CIPN improvement, and tolerability was overall low. Female gender and short-term CIPN were independently associated with a favorable response to duloxetine.

Plasticity in bilateral hippocampi after a 3-month physical activity programme in lung cancer patients.

BACKGROUND AND PURPOSE: Cancer treatments have deleterious effects on both brain structure and the cognition of lung cancer patients. Physical activity (PA) has beneficial effects on the cognition of healthy adults by eliciting brain plasticity, especially on the medial temporal lobe (hippocampus). Therefore, the aim was to study the neuroprotective effects of a 3-month PA programme (PAP) on the brain structure and cognitive performance of lung cancer patients. METHODS: Twelve patients (seven non-small-cell lung cancer [NSCLC] patients following chemotherapy, five small-cell lung cancer [SCLC] patients following chemotherapy and prophylactic cranial irradiation) agreed to complete the PAP and underwent baseline and 3-month (post-PAP) brain magnetic resonance imaging and neuropsychological evaluations (PAP group). Twelve lung cancer patients (seven NSCLC, five SCLC; non-PAP group) and 12 healthy sex-, age- and education-matched controls were recruited and completed two evaluations separated by the same amount of time. A region of interest voxel-based morphometry analysis focused on bilateral hippocampi was performed. RESULTS: Physical activity programme patients presented greater grey matter volume (GMV) across time in both hippocampi. Moreover, it was observed that SCLC patients in both the PAP and non-PAP groups presented a time-dependent GMV loss in bilateral hippocampi that was not significant in NSCLC patients. Importantly, the PA intervention decreased the magnitude of that GMV loss, becoming thus especially beneficial at the brain structural level for SCLC patients. CONCLUSIONS: Our study demonstrates, using a neuroimaging approach for the first time, that PA is able to stop the deleterious effects of systemic chemotherapy and brain radiation on brain structures of the lung cancer population, especially in SCLC patients.

Real world, open label experience with lacosamide against acute painful oxaliplatin-induced peripheral neurotoxicity.

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.

Incidence and characteristics of neurotoxicity in immune checkpoint inhibitors with focus on neuromuscular events: Experience beyond the clinical trials.

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.

Assessing risk factors of falls in cancer patients with chemotherapy-induced peripheral neurotoxicity.

AIM: To identify the risk factors of falls in a well-characterized cohort of cancer patients with chemotherapy-induced peripheral neurotoxicity (CIPN). PATIENTS AND METHODS: We studied 122 cancer patients experiencing any grade of CIPN, following completion of different chemotherapeutic regimens for various non-hematological malignancies. The results of the clinical examination were summarized by means of the Total Neuropathy Score-clinical version (TNSc®). A neurophysiological examination was also carried out. RESULTS: Among 122 patients, 21 (17.2%) of them reported falls. These were 7 males and 14 females with a mean age of 57.3 ± 8.1 years. All of them (21; 100%) had grade 3 CIPN, according to TNSc® with a median value of 15. Univariate analysis showed that the following variables were strongly associated with falls: TNSc® score of > 14 corresponding to grade 3 CIPN, evidence of motor impairment, evidence of sensory ataxia with positive Romberg sign, and decrease of sural a-SAP > 50% from the baseline value. Multivariate regression analysis failed to define independent predictors of falls. However, ROC analysis demonstrated that a discriminative TNSc® cutoff value of > 14 predicted falls with a sensitivity of 100% and specificity of 87%, whereas sensory ataxia predicted falls with a sensitivity of 95% and specificity of 83%. CONCLUSION: Grade 3 CIPN, as assessed with TNSc®, and evidence of sensory ataxia with a positive Romberg sign were strongly associated with an increased risk of falls. Although our results need further validation, the TNSc® scale appears to be a practical and easy tool for identifying patients at higher risk of falling.

Immune-Driven Pathogenesis of Neurotoxicity after Exposure of Cancer Patients to Immune Checkpoint Inhibitors.

Over the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancer types. ICIs work through the blockage of immune inhibitory signals, while increasing the T-cell specific immune antitumoral response. However, due to the fact that ICIs' mechanism of action is not tissue antigen-specific and not limited to the tumor microenvironment, the use of cancer immunotherapy can produce a broad range of immune-related adverse events (irAEs). Neurological immune-related adverse events (NirAEs) are rare (the overall incidence varies between 1% to 6%), and these adverse events mainly concern the peripheral nervous system, rather than the central nervous system. Due to their potential severity, which could cause interruptions to cancer treatment, NirAEs are of particular clinical importance. Currently, the pathogenesis of these complications is not completely understood, although T-cells seem to play a principal role. Nevertheless, the development of NirAEs is likely to be a multifactorial and complex process. This conclusion can be extracted from the wide range of neurological auto-inflammatory and autoimmune disorders triggered or exacerbated by ICIs, and the extensive variability of the limited histological findings reported. The aim of this review is to summarize the potential immune-driven pathological mechanisms of NirAEs.

Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications. CIPN may involve multiple areas of the peripheral nervous system from the autonomic and dorsal root ganglia (DRG) to the axon and any peripheral nerve fibre type. Large diameter sensory myelinated (Aß) fibres are more frequently involved, but motor, small myelinated (Aδ), unmyelinated (C) or autonomic fibres may also be affected. Here, we review the current evidence on techniques for the CIPN assessment in the clinical and experimental settings. Nerve conduction studies (NCS) may be used at the subclinical and early CIPN stage, to assess the extent of large nerve fibre damage and to monitor long-term outcomes, with the sural or dorsal sural nerve as the most informative. The quantitative sensory neurological examination provides valuable data alongside NCS. Quantitative sensory testing and nerve excitability studies add information regarding pathophysiology. Nerve MRI and ultrasound may provide information on enlarged nerve, increased nerve signal intensity and DRG or spinal cord changes. Skin biopsy, corneal confocal microscopy, laser-evoked potentials, contact heat-related potentials and microneurography may reveal the extent of damage to small unmyelinated nerve fibres that go undetected by NCS. The information on the role of these latter techniques is preliminary. Hence, the use of multimodal testing is recommended as the optimal CIPN assessment strategy, employing objective NCS and other specialised techniques together with subjective patient-reported outcome measures.

Contrast-enhancement in supratentorial low-grade gliomas: a classic prognostic factor in the molecular age.

BACKGROUND: Contrast enhancement (CE) is found in 10-60% of low-grade gliomas. Its prognostic significance is controversial, and its correlation with IDH mutations and 1p/19q codeletion is elusive. The aim of this study is to investigate whether CE is associated with molecular characteristics of low-grade gliomas and uncover its prognostic value. MATERIALS AND METHODS: All confirmed histological cases of low-grade gliomas diagnosed at our institution between years 2000-2016 were reviewed (n = 102). Spinal and brainstem localization, only-biopsied tumours with ring-like enhancement and incomplete medical records were excluded. RESULTS: Mean age was 42 years ( ± 13.9 years), and 63.6% were male. The median follow-up time was 79.8 months. CE was present on 25% of preoperative MRI, and 25% of patients were considered high-risk according to Pignatti score. Most were astrocytomas (67%) and 87.2% were surgically removed. IDH mutation was found in 64.6% of tumour samples, and 18.8% had a 1p/19q codeletion. No subgroup differences were observed according to CE except for presurgical performance status and postoperative chemotherapy. IDH status and 1p/19q codeletion were evenly distributed. On univariate analysis, age, size > 6 cm, CE, extent of resection, Pignatti score, IDH mutation and 1p/19q codeletion were significantly associated to OS. On multivariate analysis, only CE and IDH status were independently associated to OS. CE remained a significant prognostic factor in IDH-mutant non-codeleted tumours when analysed by tumour subtype. CONCLUSION: CE in low-grade gliomas provides prognostic information in IDH-mutant non-codeleted tumours, although its meaning remains uncertain in IDH-wildtype gliomas.

Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: From pathogenesis to treatment.

Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length-dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre-existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs-induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.

Immune checkpoint inhibitors-induced neuromuscular toxicity: From pathogenesis to treatment.

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment, and include myositis, myasthenia gravis, and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment. Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multi-disciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange, and other immune-modulating treatments should be considered in more severe cases. Consideration of re-challenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs.

Liability of the voltage-gated potassium channel KCNN3 repeat polymorphism to acute oxaliplatin-induced peripheral neurotoxicity.

Thus far, there are conflicting results on the causal role of K+ channels in the pathogenesis of acute oxaliplatin-induced peripheral neurotoxicity (OXAIPN). As such, we tested the hypothesis that the voltage-gated K+ channel KCNN3 repeat polymorphism confers liability to acute OXAIPN. DNA from 151 oxaliplatin-treated patients for colorectal cancer was extracted and genotyped. The incidence of acute OXIPN was measured by the OXA-neuropathy questionnaire, while the severity of acute OXAIPN was scored basing on the number of symptoms reported by the patients at each clinical assessment. The increased number of acute symptoms was considered as being suggestive of an increased severity of acute OXAIPN. A total of 130/151 (86.1%) patients developed any grade of acute OXAIPN. Grade I acute neurotoxicity was revealed in 43 (28.5%) patients; grade II in 34 (22.5%); and grade III in 53 (53.1%) patients. Genotyping revealed alleles carrying 11 to 20 CAG repeats. The majority of patients were heterozygous (131; 89.4%). The most common numbers of CAG repeats were 15 (n = 46), 16 (n = 53), and 17 (n = 95). Patients carrying alleles with either 15 to 17 CAG repeats (P = .601) did not experience a higher incidence of grade III (treatment-emergent) acute OXAIPN. Likewise, no increased incidence of acute treatment-emergent OXAIPN was noted in heterozygous patients carrying either two short alleles (<19 CAG repeats) or one short and one long (≥19 CAG repeats) allele (P = .701). Our results do not support a causal relationship between the KCNN3CAG repeat polymorphism and acute OXΑIPN.