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.

Oxygen matters: Unraveling the role of oxygen in the neuronal response to cisplatin.

BACKGROUND AND AIMS: Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions, including oxygen levels, is crucial for achieving meaningful results. Nevertheless, oxygen culture conditions are often overlooked, particularly in the context of chemotherapy-induced neurotoxicity. METHODS: In this study, we investigated the role of oxygen levels in primary neuronal cultures by comparing neuronal performance under cisplatin exposure (1 µg/mL) in supraphysiological normoxia (representing atmospheric conditions in a standard incubator; 18.5% O2) and physioxia (representing physiologic oxygen conditions in nervous tissue; 5% O2). Experiments were also conducted to assess survival, neurite development, senescence marker expression, and proinflammatory cytokine secretion. RESULTS: Under control conditions, both oxygen concentration conditions exhibited similar behaviors. However, after cisplatin administration, sensory neurons cultured under supraphysiological normoxic conditions show higher mortality, exhibit an evolutionarily proinflammatory cytokine profile over time, and activate apoptotic-regulated neuron death markers. In contrast, under physiological conditions, neurons treated with cisplatin exhibited senescence marker expression and an attenuated inflammatory secretome. INTERPRETATION: These results underscore the critical role of oxygen in neuronal culture, particularly in studying compounds where neuronal damage is mechanistically linked to oxidative stress. Even at identical doses of evaluated neurotoxic drugs, distinct cellular phenotypic fates can emerge, impacting translatability to the in vivo setting.

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.

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.

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.

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.

Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.

Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.

Perilesional edema in brain metastases as predictive factor of response to systemic therapy in non-small cell lung cancer patients: a preliminary study.

BACKGROUND: The significance of upfront systemic therapies as an alternative to whole brain radiotherapy (WBRT) for multiple brain metastases (BM) is debatable. Our purpose is to investigate if peritumoral edema could predict the intracranial response to systemic chemotherapy (chemo) in patients with advanced non-squamous non-small cell lung cancer (non-SQ-NSCLC) and synchronous multiple BM. METHODS: In this observational cohort study, we evaluated the outcome of 28 patients with multiple BM (≥3) treated with chemo based on cisplatin/carboplatin plus pemetrexed (chemo, group A, n=17) or WBRT plus subsequent chemo (group B, n=11). The intracranial response, assessed by the response assessment neuro-oncology (RANO) BM criteria, was correlated with the degree of BM-associated edema estimated by the maximum diameter ratio among fluid attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1WI (T1Gd) per each BM at the baseline brain magnetic resonance imaging (MRI). RESULTS: No differences were observed in baseline characteristics between both groups, except for the number of patients under steroid treatment that was clearly superior in group B (P=0.007). Median OS was similar between groups. Regarding FLAIR/T1Gd ratio (F/Gd), patients treated with chemo alone exhibited significantly higher values (P=0.001) in those who developed intracranial progression disease (PD) (2.80±0.32 mm), compared with those who achieved partial response (PR) (1.30±0.11 mm) or stable disease (SD) (1.35±0.09 mm). In patients treated with WBRT, F/Gd ratio was not predictive of response. CONCLUSIONS: Peritumoral edema estimated by F/Gd ratio appears a promising predictive tool to identify oligosymptomatic patients with multiple BM in whom WBRT can be postponed.

Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells.

Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol- and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible.

Defining a Standardized Information Model for Multi-Source Representation of Breast Cancer Data.

This work aims to define a standardized information model for representation of multiple data sources in breast cancer. A set of data elements has been identified using ICHOM Breast Cancer as the minimum data set and adapting it to the needs of Hospital Universitario 12 de Octubre. With this, an information model has been defined according to ISO 13606 and SNOMED CT standards.