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.

Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes.

Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. Early diagnosis and initiation of immunosuppressive therapy are likely to be crucial in preventing the accumulation of neurological disability. Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.

Neurological adverse events related to immune-checkpoint inhibitors in Spain: a retrospective cohort study.

BACKGROUND: Neurological immune-related adverse events associated with immune checkpoint inhibitors can have several clinical manifestations, but the syndromes and prognostic factors are still not well known. We aimed to characterise and group the clinical features, with a special focus in patients presenting with encephalopathy, and to identify predictors of response to therapy and survival. METHODS: This retrospective observational study included patients with neurological immune-related adverse events from 20 hospitals in Spain whose clinical information, serum samples, and CSF samples were studied at Hospital Clinic de Barcelona, Barcelona, Spain. Patients with pre-existing paraneoplastic syndromes or evidence of alternative causes for their neurological symptoms were excluded. We reviewed the clinical information, classified their clinical features, and determined the presence of neural antibodies. Neurological status was assessed by the treating physician one month after adverse event onset (as improvement vs no improvement) and at the last evaluation (complete recovery or modified Rankin Scale score decrease of at least 2 points, indicating good outcome, vs all other modified Rankin Scale scores, indicating poor outcome); if the participant had died, the date and cause of death were recorded. We used Fisher's exact tests and Mann-Whitney U tests to analyse clinical features, and multivariable logistic regression to analyse prognostic factors. FINDINGS: From Jan 1, 2018, until Feb 1, 2023, 83 patients with suspected neurological immune-related adverse events after use of immune checkpoint inhibitors were identified, of whom 64 patients were included. These patients had a median age of 67 years (IQR 59-74); 42 (66%) were male and 22 (34%) were female. The predominant tumours were lung cancer (30 [47%] patients), melanoma (13 [21%] patients), and renal cell carcinoma (seven [11%] patients). Neural antibodies were detected in 14 (22%) patients; 52 (81%) patients had CNS involvement and 12 (19%) had peripheral nervous system involvement. Encephalopathy occurred in 45 (70%) patients, 12 (27%) of whom had antibodies or well defined syndromes consistent with definite paraneoplastic or autoimmune encephalitis, 24 (53%) of whom had encephalitis without antibodies or clinical features characteristic of a defined syndrome, and nine (20%) of whom had encephalopathy without antibodies or inflammatory changes in CSF or brain MRI. Nine (14%) of 64 patients had combined myasthenia and myositis, five of them with myocarditis. Even though 58 (91%) of 64 patients received steroids and 31 (48%) of 64 received additional therapies, 18 (28%) did not improve during the first month after adverse event onset, and 11 of these 18 people died. At the last follow-up for the 53 remaining patients (median 6 months, IQR 3-13), 20 (38%) had a poor outcome (16 deaths, one related to a neurological immune-related adverse event). Mortality risk was increased in patients with lung cancer (vs those with other cancers: HR 2·5, 95% CI 1·1-6·0) and in patients with encephalopathy without evidence of CNS inflammation or combined myocarditis, myasthenia, and myositis (vs those with the remaining syndromes: HR 5·0, 1·4-17·8 and HR 6·6, 1·4-31·0, respectively). INTERPRETATION: Most neurological immune-related adverse events involved the CNS and were antibody negative. The presence of myocarditis, myasthenia, and myositis, of encephalopathy without inflammatory changes, or of lung cancer were independent predictors of death. Most deaths occurred during the first month of symptom onset. If our findings are replicated in additional cohorts, they could confirm that these patients need early and intensive treatment. FUNDING: The Instituto de Salud Carlos III and the European Union.

CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern?

Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity-initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)-is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered per se as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.

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.

TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients.

Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson's disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800-0.935) showed that detection of 24.1% cells with cytoplasmic TDP-43 positivity in the dermis had 85% sensitivity and 80% specificity for detecting ALS. We have identified significantly increased TDP-43 levels in epidermis and in the cytoplasm of dermal cells of ALS patients. Our findings provide support for the use of TDP-43 in skin biopsies as a potential biomarker.

Optimal outcome measures for assessing exercise and rehabilitation approaches in chemotherapy-induced peripheral-neurotoxicity: Systematic review and consensus expert opinion.

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: We systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the gap in the identification of effective rehabilitation and treatment options for CIPN.

Myasthenia Gravis Induced by Immune Checkpoint Inhibitors: An Emerging Neurotoxicity in Neuro-Oncology Practice: Case Series.

Immunotherapy with immune checkpoint inhibitors (ICIs) have been reported to induce de novo or exacerbate pre-existing Myasthenia Gravis (MG). We present a single center case series of patients who developed an immune-related myasthenia gravis (irMG) related with ICIs. We performed a retrospective chart review of the electronic medical records between 1 September 2017 and 2022. We report the clinical features, presentation forms, diagnostic workflows, general management and outcomes of six patients who received ICIs for different solid organ malignancies and developed an irMG frequently overlapping with immune-related myocarditis and/or myositis. The aim of the article is to describe the clinical features, treatment and outcomes of this challenging and potentially life-threating syndrome, comparing our data with those described in the literature. Differences between irMG and classic MG are highlighted.

Brentuximab-Induced Peripheral Neurotoxicity: A Multidisciplinary Approach to Manage an Emerging Challenge in Hodgkin Lymphoma Therapy.

Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate approved to treat classical Hodgkin lymphoma (HL). BV-induced peripheral neurotoxicity (BVIN) is one of the greatest concerns for haematologists treating HL for several reasons. First, BVIN is highly frequent. Most patients receiving BV will experience some degree of BVIN, resulting in the primary reason for dose modification or discontinuation of HL therapy. Second, BV produces sensory, motor, and/or autonomic peripheral nerve dysfunction, which can present as severe, disabling forms of BVIN-predominantly motor-in some patients. Third, although largely reversible, BVIN may persist months or years after treatment and thereby become a major issue in HL survivorship. BVIN may, therefore, negatively affect the quality of life and work-life of often young patients with HL, in whom long-term survival is expected. Currently, the only strategy for BVIN includes dose adjustments and treatment discontinuation; however, this could interfere with LH therapy efficacy. In this setting, early recognition and adequate management of BVIN are critical in improving clinical outcomes. Careful neurologic monitoring may allow accurate diagnoses and gradation of ongoing forms of BVIN presentation. This review analysed current, available data on epidemiology, pathophysiology, patient- and treatment-related risk factors, clinical and neurophysiologic phenotypes, and management in patients with HL. Furthermore, this review specifically addresses limitations posed by BVIN assessments in clinical practice and provides skills and tools to improve neurologic assessments in these patients. Integrating this neurotoxic drug in clinical practice requires a multidisciplinary approach to avoid or minimise neurotoxicity burden in survivors of HL.

Predictive Biomarkers of Oxaliplatin-Induced Peripheral Neurotoxicity.

Oxaliplatin (OXA) is a platinum compound primarily used in the treatment of gastrointestinal cancer. OXA-induced peripheral neurotoxicity (OXAIPN) is the major non-hematological dose-limiting toxicity of OXA-based chemotherapy and includes acute transient neurotoxic effects that appear soon after OXA infusion, and chronic non-length dependent sensory neuronopathy symmetrically affecting both upper and lower limbs in a stocking-and-glove distribution. No effective strategy has been established to reverse or treat OXAIPN. Thus, it is necessary to early predict the occurrence of OXAIPN during treatment and possibly modify the OXA-based regimen in patients at high risk as an early diagnosis and intervention may slow down neuropathy progression. However, identifying which patients are more likely to develop OXAIPN is clinically challenging. Several objective and measurable early biomarkers for OXAIPN prediction have been described in recent years, becoming useful for informing clinical decisions about treatment. The purpose of this review is to critically review data on currently available or promising predictors of OXAIPN. Neurological monitoring, according to predictive factors for increased risk of OXAIPN, would allow clinicians to personalize treatment, by monitoring at-risk patients more closely and guide clinicians towards better counseling of patients about neurotoxicity effects of OXA.

Prospective Evaluation of Health Care Provider and Patient Assessments in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND AND OBJECTIVE: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. METHODS: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. RESULTS: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. CONCLUSIONS: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.

Late effects of cancer treatment: consequences for long-term brain cancer survivors.

Late adverse effects of cancer treatments represent a significant source of morbidity and also financial hardship among brain tumor patients. These effects can be produced by direct neurologic damage of the tumor and its removal, and/or by complementary treatments such as chemotherapy and radiotherapy, either alone or combined. Notably, young adults are the critical population that faces major consequences because the early onset of the disease may affect their development and socioeconomic status. The spectrum of these late adverse effects is large and involves multiple domains. In this review we classify the main long-term adverse effects into 4 sections: CNS complications, peripheral nervous system complications, secondary neoplasms, and Economic impact. In addition, CNS main complications are divided into nonfocal and focal symptoms. Owing to all the secondary effects mentioned, it is essential for physicians to have a high level of clinical suspicion to prevent and provide early intervention to minimize their impact.

Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review.

Importance: Encephalitis is a severe immune-related adverse event secondary to treatment with immune checkpoint inhibitors (ICIs). The spectrum of ICI-induced encephalitis (ICI-iE) ranges from disease that resolves fully to lethal forms. Moreover, ICIs may unmask a paraneoplastic encephalitis. To our knowledge, the factors associated with ICI-iE prognosis are unknown. Objectives: To evaluate the presentation of ICI-iE and to identify features helpful in assessing outcomes. Evidence Review: This systematic review pooled case series from the published literature (n = 77) and medical records from 1 center (n = 5) to assess the association between the form of ICI-iE presentation and its prognosis. Eligibility criteria included references identified by searches of PubMed and Web of Knowledge databases in the English literature from June 2000 (first patient dose of ipilimumab) to April 17, 2020, that examined patients with encephalitis with presumed autoimmune etiologic features induced by ICIs. Information regarding clinical, cerebrospinal fluid, and neuroimaging (magnetic resonance imaging) features, as well as treatment given, were extracted. Findings: A total of 82 patients (52 men [63%]; median age, 61.0 years [interquartile range, 52.5-70.0 years]) were included. Most patients presented with focal syndromes (39 [48%]) or meningoencephalitis (36 [44%]). Seven patients (9%) had nonclassifiable ICI-iE. Neuronal autoantibodies were detected in 23 patients with focal syndromes and 1 patient with nonclassifiable ICI-iE. Most autoantibodies were onconeuronal (17 of 24 [71%]), targeting intracellular antigens. Patients without a focal syndrome or with a negative-antibody focal syndrome had a good prognosis (49 of 55 [89%]). Among patients with autoantibodies, those with anti-glutamic acid decarboxylase or anticell surface responded to treatment and had a favorable prognosis (100%). However, patients with other autoantibodies had poor outcomes (17 of 24 [71%]). Antineuronal autoantibodies (13 of 24 [54%] vs 5 of 41 [12%]; P < .001), focal syndrome (16 of 39 [41%] vs 4 of 43 [9%]; P = .001), and abnormal magnetic resonance imaging findings (14 of 39 [36%] vs 4 of 32 [13%]; P = .02) were associated with poor outcomes. Conversely, fever (21 of 23 [91%] vs 41 of 59 [70%]; P = .04) and more inflammatory changes in cerebrospinal fluid (30 of 31 [97%] vs 21 of 33 [64%]; P = .001) were associated with a better prognosis. Conclusions and Relevance: Immune checkpoint inhibitors may induce mainly 2 different encephalitic syndromes: a focal limbic or extralimbic encephalitis and a meningoencephalitis. Immune checkpoint inhibitor-induced encephalitis is associated with an overall favorable outcome, with a low rate of fatal events. An undetected preexisting paraneoplastic encephalitic syndrome may be triggered by ICIs, and this type of syndrome has the worst outcome among all the different types of ICI-induced encephalitis syndromes. Clinical presentation and systematic measurement of autoantibodies will be a helpful guide for the therapeutic strategy and for counseling regarding prognosis.

Liquid biopsy for disease monitoring after anti-CD19 chimeric antigen receptor T cell in diffuse large B-cell lymphoma.

Objectives: Chimeric antigen receptor T cells (CARTs) against CD19 antigen represent an effective therapy for relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL). There is no diagnostic test able to predict which patients with residual disease will relapse from those that will reach a delayed complete response. Positron emission tomography/computed tomography scan (PET-CT) is characterized by a significant number of false positive results after immunotherapy. Circulating tumor DNA (ctDNA) may be a good-useful tool to quantify minimal residual disease and for monitoring disease response. Methods: We present a patient with DLBCL treated with CART cells in which we tested the combined use of ctDNA and PET-CT scan. Results: Disease reassessment with PET-CT scan showed a partial remission (3 weeks) and a very good partial remission (2 months). A clinical progression at 3 months was confirmed with PET-CT scan. Levels of ctDNA progressively decreased and became undetectable. An initial increase in KMT2D p.E4385G variant allele frequency confirmed disease progression. Conclusions: Our case shows how the complementary use of ctDNA and PET-CT scan could be a helpful tool in the clinical management of these patients.

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.

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.