Vincristine-induced Neuropathy Research Articles

Efficacy and Toxicity of Vincristine and CYP3A5 Genetic Polymorphism in Rhabdomyosarcoma Pediatric Egyptian Patients.

Rhabdomyosarcoma (RMS) is a rare cancer that develops in soft tissue, particularly skeletal muscle tissue and occasionally hollow organs like the bladder or uterus. Vincristine (VCR) is the main therapy used in treatment of RMS, it is an alkaloid produced from vinca and it is one of the most commonly prescribed drugs in pediatric oncology for the treatment of a number of tumors. The CYP3A5 enzyme is responsible for vincristine metabolism. The effect of CYP3A5 genetic polymorphism on the efficacy and toxicity of VCR on RMS patients still needs further research. Genotyping for CYP3A5 SNPs rs776746, rs10264272 and rs41303343 was performed using Taqman Real-Time PCR assays in a retrospective cohort study of 150 RMS pediatric patients treated with vincristine. The relationship between these genotypes and RMS survival was then examined. We found that patients with CYP3A5*3/*3 had the highest incidence of vincristine-induced neuropathy reaching 61.3%. Patients with CYP3A5*1/*3, CYP3A5*3/*6 and the normal metabolizers with CYP3A5*1/*1 had frequencies of 22%, 10.7%, and 4.7%. patients with the lowest frequency of 1.3% were those with the CYP3A5*1/*6 genotype. There was no correlation between the genotypes of CYP3A5*3, CYP3A5*6, CYP3A5*7, and RMS survival. Initial risk, metastasis, response, convulsions, unsteady gait and hepatotoxicity grade had a significant effect on overall survival with p<0.05. CYP3A5*1/*1 have less severe vincristine-induced neuropathy than CYP3A5 *1/*3, CYP3A5 *1/*6 and CYP3A5 *3/*3, CYP3A5 *3/*6. There is a significant influence of CYP3A5 mutation on neuropathy grade and assist of ADL as a part of neurotoxicity.

The Assessment of Ferulic Acid in Rats with Vincristine-Induced Neuropathy

The Assessment of Ferulic Acid in Rats with Vincristine-Induced Neuropathy

Compression therapy using surgical gloves is ineffective for the prevention of vincristine-induced neuropathy in patients with malignant lymphoma.

Vincristine (VCR) often induces peripheral neuropathy (PN) as an adverse event. Currently, there is no consensus on the prevention of vincristine-induced PN (VIPN). In this study, we aimed to investigate the efficacy of compression therapy using surgical gloves for preventing VIPN. Patients with malignant lymphoma (vincristine-naïve) who were receiving chemotherapy with cyclophosphamide, doxorubicin, VCR, and prednisolone, with or without rituximab, every 3weeks for six cycles were eligible. For every VCR infusion, each patient wore two one-size-smaller gloves on one hand (study hand) for 90min. The other hand was left bare (control hand). PN was assessed at each treatment using the Common Terminology Criteria for Adverse Events ver. 4.0. Fifty-one patients with malignant lymphoma were enrolled and 44 were evaluated. At 1month after treatment, the occurrence rates of grade ≥ 2 sensory PN were 13.6 and 13.6% in the study and control hands, respectively (p = 1.0), and those of grade ≥ 2 motor PN were 15.9 and 15.9% in the study and control hands, respectively (p = 1.0). Compression therapy using surgical gloves showed no significant effect for the prevention of VIPN. November 1, 2018, National University Hospital Council of Japan (UMIN 000034145).

EXPLORING THE POTENTIAL PHARMACOLOGICAL EFFECT OF THYMOQUINONE IN AMELIORATING THE ACQUISITION AND EXPRESSION OF VINCRISTINE INDUCED NEUROPATHIC PAIN IN MICE

Background: Chemotherapy-induced neuropathy (CIPN) is the most severe consequence, causing both sensory and motor impairment with an incidence of between 19% and over 85%. Leukaemia, lymphoma, and sarcoma are just a few of the cancers that are treated using vincristine (VCR), a typical anticancer treatment used in chemotherapy. Peripheral neuropathy caused by vincristine is the primary impediment to the efficacy of ongoing anti-cancer treatment and continued use. Objectives: The current study's goal was to contemplate the significance of thymoquinone on the development and expression of vincristine-induced neuropathy. Methodology: All groups except normal saline were administered vincristine 0.1mg/kg i.p for 14 days. In selected groups Gabapentin (75mg/kg) and thymoquinone were administered at 10, 20, and 30 mg/kg/day for 14 days orally along with vincristine (acquisition) and once at day 14 (expression). Thermal hyperalgesia and mechanical allodynia were quantified on days 1, 6, and 14 after 30, 60, 90, and 120 minutes. The data were processed using the Students’t-test and post hoc Dunnett's test. Results: The acquisition and expression of thermal hyperalgesia as well as mechanical allodynia was significantly improved by thymoquinone at all the tested doses at days 6 and 14 as well as after 30, 60, 90, and 120 minutes significant improvement was observed. Conclusion: It is manifested that TQ can be an impending candidate for the management of vincristine-induced neuropathy.

Title: Risk Factors and Natural History of Vincristine Induced Neuropathy on UKALL 2011: A Randomised Controlled Trial of the Effect of Omitting Vincristine Pulses

Introduction UKALL 2011 is a randomised study recruiting children and young adults (up to 25) with Acute Lymphoblastic Leukaemia (ALL) or Lymphoblastic Lymphoma (LBL). One of the aims of the trial was to reduce maintenance morbidity by randomising to Vincristine (VCR)/dexamethasone pulses or not. Results of this randomisation were presented at ASH 2022. In a sub-study, we also aimed to determine the natural history of vincristine induced neuropathy (VIN), including patients randomised to vincristine in maintenance or not and to determine pharmacogenomic risk factors for VIN. Methods Children and adolescents, aged 5-18yrs, were recruited from 5 centres in the UK. Patients were stratified by NCI risk, cytogenetics and end of induction MRD to receive Regimens A (NCI standard risk, MRD low risk), B (NCI high risk, MRD low risk) or C (Cytogenetic poor risk or MRD intermediate risk regardless of NCI risk). The maximum total number of vincristine doses was dependent on regimen and gender: females - Regimen A/B 33, Regimen C 42; males Regimen A/B 46, Regimen C 55. VIN was assessed at 7 time points (diagnosis, end of induction, delayed intensification, maintenance cycles 1,3 &amp; 5 and end of treatment) using the Paediatric TNSr-Vincristine. The Paediatric TNSr-Vincristine assessed proximal extension of numbness, vibration, temperature sensation, muscle strength, tendon reflexes, constipation and hoarseness with each item scored from 0-4, with higher scores indicating more severe neuropathy (n=67). To assess how walking was affected, gait assessment was completed using the GAITRite® walkway-a mat embedded with several thousand electronic pressure sensors activated by mechanical pressure that captured key walking outcomes (velocity, cadence and step length) (n=46). The gait parameters were analysed and compared with age and gender matched controls enabling Z-scores comparison to normal controls. Nine candidate SNPs associated with VIN were genotyped (n=58) and were analysed against highest TNS score at any timepoint and TNS scores above and below the mean. 39 children were randomised to vincristine or not (20 vincristine vs. 19 no vincristine). We fitted linear mixed-effects regression. Predictive factors included genetics; treatment time point; post induction regime (C vs A/B). For the randomised cohort the effect of pulsed vincristine was explored. All tests were two-sided, with significance determined as p&amp;lt;0.05. We adjusted the effects in the model to accommodate effect of age and gender on the total neuropathy score for paediatrics. Analyses were performed using R version 4.3.1. Results Compared to diagnosis, the likelihood of VIN increased between end of induction and intensification, and then reduced over subsequent visits, but remained significantly abnormal at end of treatment (TNS incident rate ratio (IRR) 6.2 (end of induction/intensification vs diagnosis); 4.1 (end of treatment vs diagnosis); p&amp;lt;0.001) (Fig 1). Older children were more likely to have a higher TNS score (IRR 2.4 (p=0.003). Velocity, cadence and step length data were significantly affected compared to normal standards ( p&amp;lt;0.001; Figure 2). Regimen C led to a reduction in step length Z-score of a third ((L) p=0.05; (R) p=0.03)). The likelihood of a higher VIN score in patients randomised to pulsed vincristine in maintenance compared to no vincristine was borderline significant (TNS score (IRR) 1.31 with a confidence interval of 1.00-1.71 (p=0.05)).When analysed by ABCB1 haplotype, TTT/TTT carrier status (loci rs1045642, rs1128503 and rs2032582) was significantly associated with lower TNS scores (p=0.04), whilst the CEP72 TT genotype was significantly associated with TNS scores below the mean (p=0.03) in contrast to previous literature and the ABCB1 rs2032582 G allele was associated with significantly higher mean TNS scores (p=0.04) Conclusion VIN increases with intensity of vincristine treatment and does not normalise at the end of treatment. VIN led to a slower gait and shorter steps whilst removing vincristine in maintenance was associated with reduced likelihood of VIN. VIN was not strongly influenced by any single genotype in this cohort. Conflicting pharmacogenomics results could be explained by differences in ethnicity, protocol design and relatively small numbers in this analysis. Gait analysis represents a novel functional method of assessing VIN enabling comparison to normal age matched peers.

Vincristine-Induced Neuropathy in Patients Diagnosed with Solid and Hematological Malignancies: The Role of Dose Rounding.

Vincristine is a vital constituent of chemotherapeutic regimens. Vincristine-induced neuropathy is a challenging adverse effect that impacts quality of life and treatment course. The dose rounding of chemotherapies is a strategy that is commonly used in clinical practice. Nevertheless, the frequency of developed neuropathy in vincristine first-time users and the potential association with dose rounding remains elusive. A retrospective analysis was conducted on patients administered vincristine for the first time between 2016 and 2022 using the King Saud University Medical City (KSUMC) database. Patients were stratified into pediatric and adult groups. Neuropathy frequency, its association with demographic and clinical parameters, and the Impact of dose rounding were assessed using SPSS software version 28. Approximately 34.6% of patients were diagnosed with neuropathy after vincristine administration. Autonomic neuropathy was common among affected adults and pediatric patients (55.1% and 56.1%, respectively), while cranial neuropathy was more frequent in pediatric patients. Higher BSA (p = 0.038) and Scr (p = 0.044) in the pediatric group, the presence of respiratory comorbidities (p = 0.044), and the use of azole antifungals (p < 0.001) in the adult group were significantly associated with neuropathy episodes. The rounding-up of vincristine doses was significantly associated with increased neuropathy occurrence (p < 0.001), while dose rounding-down was significantly associated with a decrease in neuropathy in both groups of patients (p < 0.001). Our findings demonstrate that autonomic neuropathy is the most common vincristine-related neuropathy, regardless of the patient's age. Dose rounding is a significant determinant of vincristine-induced neuropathy in both groups. Further studies are needed to evaluate the variables that exacerbate or prevent neuropathy associated with the first-time use of vincristine.

Neuroprotective mechanism of Ajugarin-I against Vincristine-Induced neuropathic pain via regulation of Nrf2/NF-κB and Bcl2 signalling.

Vincristine (VCR) is a well-known chemotherapeutic agent that frequently triggers neuropathic pain. Ajugarin-I (Aju-I) isolated from Ajuga bracteosa exerts antioxidant, anti-inflammatory, and neuroprotective properties. The present study was designed to investigate the ameliorative potential of Aju-I against VCR-induced neuropathic pain and explored the underlying mechanism involved. The neuroprotective potential of Aju-I was first confirmed against hydrogen peroxide (H2O2)-induced cytotoxicity and oxidative stress in PC12 cells. For neuropathic pain induction, vincristine was given intraperitoneally (i.p.) into adult male albino mice (BALB/c) of the same age (8-12weeks old) for 10days (days 1-10). Aju-I (1 and 5mg/kg) doses were administered from day 11 to 21 intraperitoneally (i.p.) after the neuropathic induction. Initially, behavioral tests such as thermal hyperalgesia, mechanical allodynia, and cold allodynia were performed to investigate the antinociceptive potential of Ajugarin-I (1 and 5mg/kg, b.w). The nuclear factor-erythroid factor 2-related factor 2(Nrf2), nuclear factor-κB (NF-κB), BCL2-associated×protein (Bax), and B-cell-lymphoma-2 (Bcl-2) signaling proteins were determined by immunohistochemistry and western blot. Additionally, inflammatory cytokines, antioxidant, and oxidative stress parameters were also measured in the spinal cord and sciatic nerve. The behavioral results demonstrated that Aju-I (5mg/kg) markedly alleviated VCR-induced neuropathic pain behaviors including hyperalgesia and allodynia. It reversed the histological alterations caused by VCR in the sciatic nerve, spinal cord, and brain. It significantly alleviated oxidative stress and inflammation by regulating the immunoreactivity of Nrf2/NF-κB signaling. It suppressed apoptosis by regulating the immunoreactivity of Bcl-2/Bax and Caspase-3. The flow cytometry and comet analysis also confirmed its anti-apoptotic potential. It considerably improved the antioxidant status and mitigated VCR-induced inflammatory cytokines. High-performance liquid chromatography (HPLC) analysis indicated that Aju-I crosses the blood-brain barrier (BBB) and penetrated the brain tissue. These findings suggest that Aju-I treatment inhibited vincristine-induced neuropathy via regulation of Nrf2/NF-κB and Bcl2 signaling.

Through Its Powerful Antioxidative Properties, L-Theanine Ameliorates Vincristine-Induced Neuropathy in Rats.

L-theanine (LT), which is a major amino acid found in green tea, was shown to alleviate Vincristine (VCR)-induced peripheral neuropathy and associated neuronal functional changes in rats. To induce peripheral neuropathy, rats were administered VCR at a dose of 100 mg/kg/day intraperitoneally on days 1-5 and 8-12, while control rats received LT at doses of 30, 100, and 300 mg/kg/day intraperitoneally for 21 days or saline solution. Electrophysiological measurements were taken to evaluate the nerve functional loss and recovery through motor and sensory nerve conduction velocities. The sciatic nerve was examined for several biomarkers, including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total calcium, IL-6, IL-10, MPO, and caspase-3. The results showed that VCR caused significant hyperalgesia and allodynia in rats; decreased nerve conduction velocity; increased NO and MDA levels; and decreased GSH, SOD, CAT, and IL-10 levels. LT was found to significantly reduce VCR-induced nociceptive pain thresholds, decrease oxidative stress levels (NO, MDA), increase antioxidative strength (GSH, SOD, CAT), and reduce neuroinflammatory activity and apoptosis markers (caspase-3). LT's antioxidant, calcium homeostasis, anti-inflammatory, anti-apoptotic, and neuroprotective properties make it a potential adjuvant to conventional treatment in VCR-induced neuropathy in rats.

The Ameliorative Effect of Thymoquinone on Vincristine-Induced Peripheral Neuropathy in Mice by Modulating Cellular Oxidative Stress and Cytokine.

Thymoquinone (TQ), an active constituent of Nigella sativa, has been reported to exert a broad spectrum of pharmacological effects, including neuroprotective, anticancer, anti-inflammatory, antidiabetic, antiepileptic, antioxidant, and other modulatory roles in inflammation in experimental studies. The present study aims to evaluate the potential effects of TQ on vincristine-induced neuropathy in mice, as well as the possible role of oxidative stress, and pro- and anti-inflammatory cytokine in neuropathy development. A Swiss strain of male albino mice were randomly divided into seven groups, comprising of five animals each. Vincristine sulfate (0.1 mg/kg, i.p.) was administered for 10 consecutive days for the induction of peripheral neuropathy. The animals received their respective treatment of TQ (2.5, 5, and 10 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) concurrently with vincristine for 10 days followed by 4 days post treatment. The animals were assessed for pain and related behavior on day 7 and 14 using hot and cold plates, and a rotarod test. TQ preventive treatment attenuated vincristine induced neuropathy in a dose dependent manner evidenced as a significant (p &lt; 0.001) increase in reaction time on the hot plate and the cold plate, and a fall off time on the rotarod test. Further, TQ preventive treatment resulted in a significant (p &lt; 0.001) reduction in the number of flinches and duration of paw elevation in a formalin test. Preventative treatment with TQ abolished the vincristine-induced rise in malondialdehyde and glutathione depletion in sciatic nerve tissue, as well as the blood IL-6 levels. In conclusion, TQ at 2.5, 5, and 10 mg/kg dose produced significant attenuation of neuropathic pain induced by vincristine which may be due to its antinociceptive, antioxidant, and anti-proinflammatory activity.

Blockade of Cholecystokinin Type 2 Receptors Prevents the Onset of Vincristine-Induced Neuropathy in Mice.

Vincristine (VCR) is responsible for the onset of the VCR-induced peripheral neuropathy (VIPN), associated with neuropathic pain. Several reports have strongly linked the cholecystokinin type 2 receptor (CCK2R) to nociceptive modulation. Thus, our aim was to evaluate the effect of CCK2R blockade on the onset of VIPN, as well as its interaction on VCR anticancer efficacy. VCR was administrated in mice for 8 days (100 µg/kg/d, i.p.). Transcriptomic analysis of the dorsal root ganglia (DRG) was performed at day 7 in VCR and control mice. Proglumide (30 mg/kg/d), a CCK1R and CCK2R antagonist, and Ly225910 (1 mg/kg/d), a selective CCK2R antagonist, were administrated one day before and during VCR treatment. Tactile sensitivity was assessed during treatments. Immunofluorescence and morphological analyses were performed on the skin, DRG and sciatic nerve at day 7. The cytotoxicity of VCR in combination with proglumide/Ly225910 was evaluated in human cancer cell lines. Cck2r was highly upregulated in the DRG of VCR mice. Proglumide accelerated the recovery of normal sensitivity, while Ly225910 totally prevented the onset of allodynia and nerve injuries induced by VCR. Proglumide or Ly225910 in combination with VCR did not affect the cytotoxicity of VCR. Targeting CCK2R could therefore be an effective strategy to prevent the onset of VIPN.

Detection of vincristine-induced neuropathy in patients with oligodendroglioma.

Detection of vincristine-induced neuropathy in patients with oligodendroglioma.

MiR-30d Participates in Vincristine-Induced Neuropathic Pain by Down-Regulating GAD67.

Vincristine is a common chemotherapeutic agent in cancer treatment, while it often causes chemotherapy-inducedperipheralneuropathy(CIPN), which brings patients a great disease burden and associated economic pressure. The mechanism under CIPN remains mostly unknown. The previous study has shown that cell-type-specific spinal synaptic plasticity in the dorsal horn plays a pivotal role in neuropathic pain. Downregulation of GABA transmission, which mainly acts as an inhibitory pathway, has been reported in the growing number of research. Our present study found that GAD67, responsible for > 90% of basal GABA synthesis, is down-regulated, while its relative mRNA remains unchanged in vincristine-induced neuropathy. Considering microRNAs (miRNAs) as a post-transcription modifier by degrading targeted mRNA or repressing mRNA translation, we performed genome-wide miRNA screening and revealed that miR-30d might contribute to GAD67 down-regulation. Further investigation confirmed that miR-30d could affect the fluorescence activity of GAD67 by binding to the 3 'UTR of the GAD67 gene, and intrathecal injection of miR-30d antagomir increased the expression of GAD67, partially rescued vincristine-induced thermal hyperalgesia and mechanical allodynia. In summary, our study revealed the molecule interactions of GAD67 and miR-30d in CIPN, which has not previously been discussed in theliterature. The results give more profound insight into understanding the CIPN mechanism and hopefully helps pain control.

Prospective cohort study of Kaposi sarcoma treated under real-world conditions in Malawi.

11569 Background: Kaposi sarcoma (KS) is the leading cancer in Malawi (34% of cancers). Outside of clinical trials, prospective KS studies from sub-Saharan Africa (SSA) are few and limited by loss to follow up. We conducted a prospective KS cohort study of standard of care bleomycin/vincristine (BV) at Lighthouse HIV clinic, in Lilongwe, Malawi. Methods: We enrolled pathologically confirmed, newly diagnosed, HIV+ KS patients from Feb 2017 to Jun 2019. We collected clinical and treatment characteristics, toxicity, and outcomes of KS with follow-up censored Jun 2020. Patients were treated with bleomycin (25 mg/m2) and vincristine (0.4 mg/m2) every 14 days for a planned maximum of 16 cycles. STATA v13.0 was used to calculate descriptive statistics and Kaplan Meier survival analysis. Toxicity was graded using NCI CTCAE v5.0. Results: We enrolled 138 participants, median age 36 (IQR 32-44) and 110 (80%) male. By ACTG staging, 107 (78%) were T1 (tumour severity), 46 (33%) were S1 (illness severity) and 46 (33%) had Karnofsky performance status ≤70. Presenting symptoms included edema in 69 (53%), visceral disease in 9 (7%), and oral involvement in 43 (33%). Prior to KS diagnosis, 70 (51%) participants were aware of being HIV+ for median 17 months (IQR 6-60) and had been on ART for median 16 months (IQR 6-60). Median CD4 count was 197 (IQR 99-339), median HIV-viral load was 2.6 log copies/mL (IQR 1.6 – 4.8) and 57% were HIV-suppressed ( &lt; 1000 HIV copies/ml). The median number of cycles was 16 (IQR 7-16). 62 (45%) participants missed at least one dose due to stock out. Amongst patients with missed doses, the median number was 3 (IQR 2-4) for bleomycin and 2 (IQR 1-3) for vincristine. 14 (10%) participants experienced at least one reduced dose due to toxicity. 5 (4%) participants suffered grade ≥3 anaemia, 13 (9%) grade ≥3 neutropenia, and one participant had grade 4 bleomycin-induced dermatitis. There was no reported grade ≥3 bleomycin lung toxicity or vincristine-induced neuropathy. Of 115 evaluable participants, responses at the end of therapy were: complete response in 52 (45%), partial response in 27 (23%) stable disease in 5 (4%), and progressive disease in 31 (28%). Median duration of follow-up was 20 months. At censoring, 69 (50%) were alive, 36 (26%) dead, and 33 (24%) lost to follow-up. Overall survival is shown Table as crude and worst-case scenario; worst-case assumes all participants lost to follow up died. Conclusions: Here, we present one of the most complete characterizations of KS presentation and treatment from SSA. As in other studies from the region, the majority of patients presented with advanced disease, chemotherapy stock-outs and loss to follow up were common, and mortality was high. Studies are planned to understand the virologic characteristics, improve therapies, and better implement existing therapies.[Table: see text]

Immune-mediated vincristine-induced neuropathy: Unlocking therapies.

Vincristine-induced peripheral neuropathy (VIPN) is a prevalent and painful complication in cancer patients that lacks effective treatments. In this issue of JEM, Starobova et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201452) report that VIPN is driven by innate immune system activation, a discovery that unlocks immunotherapies as potential treatments.

Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release.

Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.

Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy

BackgroundA combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology.MethodsIn this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables.ResultsFive-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes.ConclusionReplacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation.

Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity. Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2days, over 2weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting RESULTS: Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats. In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation.

Sodium channel Nav1.6 in sensory neurons contributes to vincristine-induced allodynia.

Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.

Isolated central nervous system leukemiarelapse presenting as Guillain-Barré-like syndrome: A case report

We report the clinical picture, management and outcome of a 14-year-old boy treated for acute lymphoblastic leukemia (ALL) in whom isolated central nervous system relapse manifested by a Guillain-Barré-like syndrome (GBS). While on maintenance chemotherapy for his first CNS-relapse, he developed acute progressive lower motor neuron right facial palsy and marked hypotonia and areflexia of both lower limbs with otherwise no systemic manifestations. Vincristine-induced neuropathy (VIN) was suspected but his electrophysiological evaluation revealed a proximal demyelinating polyradiculoneuropathy pattern suggestive of GBS, but his cerebrospinal fluid analysis showed increased protein and infiltration by 95% leukemic blast cells. Immunoglobulins and chemotherapy were initiated. Although GBS in children with ALL is very rare, differentiating it from VIN by electrophysiological studies and excluding CNS relapse is crucial to determine the proper treatment and ensure a better clinical outcome.

Centrosomal protein72 rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

Aim:We examined the utility of the rs924607 TT genotype of the centrosomal protein 72 (CEP72) as a potential biomarker for predilection toward vincristine-induced peripheral neuropathy in children treated for acute lymphoblastic leukemia.Materials & methods:We conducted a random-effects meta-analysis of data from four studies comprising 817 patients. We tested for an association using a recessive model where a one-sided p-value < 0.05 was considered statistically significant.Results & conclusion:We were unable to confirm the association between the rs924607 TT genotype and neurotoxicity (odds ratio: 1.99; p = 0.16; 95% CI: 0.76–5.25) in our global meta-analysis. Analysis of the continuation phase (following induction) studies showed significantly higher odds for neuropathy in CEP72 rs924607 TT homozygotes (odds ratio: 2.28; p = 0.02; 95% CI: 1.16–6.87).