Vincristine-induced Peripheral Neuropathy Research Articles

Pharmacological potential of 4-dimethylamino chalcone against acute and neuropathic pain in mice.

This work investigated the acute antinociceptive effect of a synthetic chalcone, 4-dimethylamino chalcone (DMAC), as well as its effects on vincristine-induced peripheral neuropathy (VIPN) in mice. The inhibitory activity of myeloperoxidase was assessed by measuring HOCl formation. Formalin and hot plate tests were used to study the acute antinociceptive effect of DMAC. VIPN was induced through the administration of vincristine sulphate (0.1mg/kg, i.p., 14 days). Then, DMSO, DMAC (10 or 30mg/kg; i.p.), or pregabalin (10mg/kg, i.p.) were administered for 14 consecutive days. Thermal hyperalgesia and mechanical allodynia were evaluated before and after VIPN induction and on days 1, 3, 7, and 14 of treatment. Neurodegeneration and neuroinflammation were assessed through immunohistochemistry for NF200, iNOS, and arginase-1 within the sciatic nerve. DMAC inhibited myeloperoxidase activity in vitro and presented an acute antinociceptive effect in both formalin and hot plate tests, with the involvement of muscarinic and opioid receptors. Treatment with 30mg/kg of DMAC significantly attenuated thermal hyperalgesia and mechanical allodynia and prevented macrophage proinflammatory polarisation in VIPN mice. Our results show that DMAC, acting through different mechanisms, effectively attenuates VIPN.

Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes.

Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann-Whitney U tests for non-parametric data. The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7weeks post mid-treatment). By 3months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life.

Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia.

Vincristine-induced peripheral neuropathy (VIPN) is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine induced pain. Our previous studies have shown that the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel NaV1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) NaV1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in V1/2 of activation of NaV1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from NaV1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel NaV1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia.

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).

Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice.

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy.

Chemotherapy-related toxicities follow a typical pattern in children treated for acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) therapy has been associated with a significant burden of toxicities. The aim of this study was to describe the full spectrum of toxic effects associated with childhood ALL. Toxicity-related data were collected from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 toxicity registry, in which data on 19 clinically relevant toxicities were registered during ALL treatment, and from patient medical records. All patients treated according to the NOPHO ALL-2008 protocol in Oulu University Hospital between 2008 and 2020 were included in the study. The cohort consisted of 73 patients, 38 of whom were male. Mean age at diagnosis was 6.6 ± 4.2 (range 1.4-16.0) years. All but one of the patients developed at least one treatment-related toxicity and more than half had multiple toxicities. Female sex and older age were associated with a higher tendency towards toxicity. The most common toxicity was vincristine-induced peripheral neuropathy, which was observed in 70 patients. Most toxicities were moderate or severe, but even mild toxicities often affected leukaemia treatment. Moderate and severe treatment-related toxicities are common, and most toxicities occur in a typical pattern in relation to the treatment phases.

Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis.

Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1-5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP)3A5 genotype distribution. A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine.

Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice.

Previous studies have suggested that the incidence of vincristine-induced peripheral neuropathy (VIPN) is potentially linked with cytochrome P450 (CYP)3A5, a polymorphic enzyme that metabolizes vincristine in vitro, and with concurrent use of azole antifungals such as ketoconazole. The assumed mechanism for these interactions is through modulation of CYP3A-mediated metabolism, leading to decreased vincristine clearance and increased susceptibility to VIPN. Given the controversy surrounding the contribution of these mechanisms, we directly tested these hypotheses in genetically engineered mouse models with a deficiency of the entire murine Cyp3a locus [Cyp3a(-/-) mice] and in humanized transgenic animals with hepatic expression of functional and nonfunctional human CYP3A5 variants. Compared with wild-type mice, the systemic exposure to vincristine was increased by only 1.15-fold (95% confidence interval, 0.84-1.58) in Cyp3a(-/-) mice, suggesting that the clearance of vincristine in mice is largely independent of hepatic Cyp3a function. In line with these observations, we found that Cyp3a deficiency or pretreatment with the CYP3A inhibitors ketoconazole or nilotinib did not influence the severity and time course of VIPN and that exposure to vincristine was not substantially altered in humanized CYP3A5*3 mice or humanized CYP3A5*1 mice compared with Cyp3a(-/-) mice. Our study suggests that the contribution of CYP3A5-mediated metabolism to vincristine elimination and the associated drug-drug interaction potential is limited and that plasma levels of vincristine are unlikely to be strongly predictive of VIPN. SIGNIFICANCE STATEMENT: The current study suggests that CYP3A5 genotype status does not substantially influence vincristine disposition and neurotoxicity in translationally relevant murine models. These findings raise concerns about the causality of previously reported relationships between variant CYP3A5 genotypes or concomitant azole use with the incidence of vincristine neurotoxicity.

Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

Vincristine-Induced Peripheral Neuropathy in Children With Malignancy and the Effect of Missed Doses on Treatment Success.

Recognizing the symptoms of vincristine-induced peripheral neuropathy (VIPN) earlier is crucial to preventing the persistent neurological sequelae. The treatment of neuropathy is to discontinue the drug, and the effect of a missed dose of vincristine on treatment success is unclear. This study aims to evaluate VIPN in children with malignancy and the effect of skipping vincristine doses on the treatment success of patients at a single center, retrospectively. Medical records of the children with cancer who received vincristine in our institution between 2013 and 2020 were analyzed retrospectively. Vincristine neuropathy was found in 42 (7%) of 598 pediatric patients who received at least one dose of vincristine during the study period. Neuropathy developed at a statistically significantly lower cumulative dose in patients younger than seven years of age (p=0.04). The mean neuropathy duration of the cases was 8.5 months, and the findings of 40 (95.2%) cases improved. The mean cumulative dose was higher in patients with diffuse nerve involvement. The missed dose of vincristine was lower in the cases in complete remission compared to the other cases and higher doses of vincristine were missed in the stable disease group than in the remission group (p=0.03). VIPN can be encountered in less cumulative doses, mainly in the younger age group. Missed doses of vincristine may affect treatment success, and more comprehensive studies are needed to show this effect more clearly.

Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis).

Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). VIPN was measured 1-7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed. Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33-0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. 1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.

Prospective assessment of vincristine-induced peripheral neuropathy in paediatric acute lymphoblastic leukemia

ObjectiveVincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL. MethodsChildren diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory. ResultsThirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline. ConclusionsClinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up. SignificanceVIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.

A cohort study of vincristine-induced peripheral neuropathy in children

To study the characteristics of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL) and the factors influencing the development of VIPN. The children with ALL, aged 1-18 years, who were treated with CCCG-ALL2015 or CCCG-ALL2020 regimen in the Affiliated Hospital of Guizhou Medical University from January 2018 to February 2022 were enrolled as subjects. According to the influence of age on risk, the children were divided into 1-10 years group with 91 children and >10 years group with 29 children. VIPN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (5th edition), and the incidence rate, severity, and type of VIPN were compared between different groups. A total of 120 children were enrolled in this study, among whom 56 (46.7%) developed VIPN. The >10 years group had a significantly higher incidence rate of VIPN than the 1-10 years group (69% vs 40%, P<0.05). Among the 56 children with VIPN, 12 (21%) had grade 3 VIPN or above, and 44 (79%) had grade 2 VIPN. There were 77 cases of autonomic nerve symptoms (59.7%), 42 cases of peripheral nerve injury (32.5%), and 10 cases of cranial nerve injury (7.8%). There were no significant differences in the severity and type of VIPN between the groups with different ages, sexes, degrees of risk, or treatment regimens (P>0.05). The results of binary logistic regression analysis showed that age is the influencing factor for the occurrence of VIPN (P>0.05). There is a relatively high incidence rate of VIPN in children with ALL, with the highest incidence rate of autonomic nervous symptoms. The incidence of VIP in children over 10 years old is relatively high.

Vincristine induced peripheral neuropathy in children undergoing chemotherapy for acute lymphoblastic leukaemia during induction

Background: Vincristine is an anticancer agent administered to all children with acute lymphoblastic leukemia (ALL), and peripheral neuropathy is the major dose-limiting toxicity of this therapy. As cure rates of childhood ALL exceeds 80%, therefore treatment-related toxicities need to be reduced. Thus, the aim of this study was to determine the prevalence and risk factors of vincristine-induced peripheral neuropathy (VIPN) in children with ALL undergoing induction chemotherapy. Methods: A case-control study was conducted from September 2017 to August 2018 in the Department of Paediatric Haematology and Oncology at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Eighty newly diagnosed ALL and 35 acute myeloid leukemia (AML) cases aged 5 to 17 years with no pre-existing neurological abnormality were recruited. To assess the peripheral neuropathy, we used pediatric-modified total neuropathy score and National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version-04 grade. Results: Among ALL patients, 29.2% developed peripheral neuropathy compared to 10% in AML control group (P=0.04). Higher proportion (57.1%) of peripheral neuropathy was found in age below 10 years (P&lt;0.001). There was no significant association of peripheral neuropathy with sex and body mass index of the patients. Conclusion: Almost 3 in 10 patients developed VIPN during the induction therapy which is significantly higher in age below 10 years compared to ≥ 10 years. Bangabandhu Sheikh Mujib Medical University Journal 2023;16(1): 02-07

Evaluation of vincristine-induced peripheral neuropathy in children with cancer: Turkish validity and reliability study

BackgroundThe evaluation of peripheral neuropathy in children receiving Vincristine treatment is challenging. This study examined the Turkish validity and reliability of the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) measurement tool, which can measure Vincristine-induced peripheral neuropathy symptoms in children with cancer. MethodsA total of 53 children aged 5–17 years who received Vincristine treatment in two pediatric hematology-oncology centers participated in the study. Data was collected using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the Common Terminology Criteria for Adverse Events (CTCAE), the Wong-Baker FACES Pain Scale, and the Adolescent Pediatric Pain Tool (APPT). The correlation between the TNS-PV total score and other scales and the inter-rater reliability coefficient was evaluated. FindingsOf the children, 81.1% were diagnosed with ALL and 13.2% with Ewing Sarcoma. Cronbach's alpha values of form A and B of the TNS-PV scale were 0.628 and 0.639, respectively. As the cumulative Vincristine dose increased, the children's scores on TNS-PV were higher. A moderate and significant positive correlation was found between the TNS-PV form A total score and the worst subjective symptoms a, b (A), strength, tendon reflexes, and autonomic / constipation (r = 0.441, r = 0.545, r = 0.472, r = 0.536, p < 0.01). DiscussionThe TNS-PV form B total score was found to have a moderate level, significant correlation with CTCAE sensory neuropathy score and Wong-Baker FACES Pain Scale, and a high level, significant positive correlation with CTCAE motor neuropathy score. Application to practiceThe TNS-PV is valid and reliable for measuring Vincristine-induced peripheral neuropathy in practice in Turkish children 5 years and older.

The Battlefield of Chemotherapy in Pediatric Cancers

The survival rate for pediatric cancers has remarkably improved in recent years. Conventional chemotherapy plays a crucial role in treating pediatric cancers, especially in low- and middle-income countries where access to advanced treatments may be limited. The Food and Drug Administration (FDA) approved chemotherapy drugs that can be used in children have expanded, but patients still face numerous side effects from the treatment. In addition, multidrug resistance (MDR) continues to pose a major challenge in improving the survival rates for a significant number of patients. This review focuses on the severe side effects of pediatric chemotherapy, including doxorubicin-induced cardiotoxicity (DIC) and vincristine-induced peripheral neuropathy (VIPN). We also delve into the mechanisms of MDR in chemotherapy to the improve survival and reduce the toxicity of treatment. Additionally, the review focuses on various drug transporters found in common types of pediatric tumors, which could offer different therapeutic options.

Correction: van de Velde et al. Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology: A Randomized Controlled Trial Comparing Push Injections with One-Hour Infusions (The VINCA Trial). Cancers 2020, 12, 3745

In the original publication, there was a mistake in Table 1 as published [...].

Vitamin D3 Promotes Structural and Functional Recovery After Vincristine-Induced Peripheral Neuropathy in Rats: An Experimental Study.

Background Vincristine-induced peripheral neuropathy (VIPN) is a distal axonopathy characterized by the loss of distal myelinated axons. This study aimed to assess the potential neuroregenerative roles of vitamin D3 using functional and electron microscopic analyses in a rat model of VIPN. Methodology A total of 40female Wistar rats were randomly divided into four main groups: Group 1 (control, n = 10), Group 2 (vincristine, n =10), Group 3 (vincristine + vitamin D3, n = 10), and Group 4 (vincristine + vehicle, n = 10). Vincristine was administered intraperitoneally at a dose of 0.15 mg/kg, for two weeks, to induce peripheral neuropathy. Following successful induction, vitamin D3 (500 IU/kg/day) and vehicle treatments were applied weekly over four weeks. Structural (electron microscopic analysis) and functional analysis (von Frey test, pinch test, and electrophysiological analysis) were performed to assess functional recovery after peripheral nerve impairment. Results Withdrawal responses to mechanical allodynia and pinch tests were significantly higher in the vitamin D3-treated group (P< 0.05). The electrophysiological analysis also supported these results. Electron microscopic evaluation revealed that the remyelinated nerve fibers in the vitamin D3-treated group (Group 3) had thick myelin sheaths and normal axonal morphology. Conclusions Our study demonstrated that vitamin D3 could promote functional and structural recovery in a rat model of VIPN. Further studies should be conducted to elucidate the underlying mechanisms by which vitamin D3 exerts its regenerative effects in VIPN, using alternative administration protocols.

Electrophysiologic Patterns of Symptomatic Vincristine-Induced Peripheral Neuropathy in Children with Acute Lymphocytic Leukemia.

Acute lymphocytic leukemia is one of the most common cancers in children. Multi-drug chemotherapy is used for treatment, and the representative drug is vincristine. Although various side effects may occur due to vincristine, the association with peripheral neuropathy is high compared to that of other drugs. This study focused on children under the age of 18 years of age with ALL who received chemotherapy containing vincristine. We retrospectively analyzed the results of a nerve conduction study and a cumulative dose of vincristine in 30 children diagnosed with peripheral neuropathy. The average cumulative dose until diagnosis of vincristine-induced peripheral neuropathy was 14.99 ± 1.21 mg/m2, and motor nerves were predominantly involved. Additionally, a marked decrease in average amplitude was also observed in motor nerves. In addition, when the relationship between the incidence of peripheral neuropathy and the cumulative dose was analyzed through the survival curve, about 50% of children developed peripheral neuropathy at a dose of 15.5 ± 1.77 mg/m2. Based on the electrophysiological characteristics of pediatric vincristine-induced peripheral neuropathy, as well as the relationship between the incidence rate and the cumulative dose, it is possible to observe more closely the vincristine-induced peripheral neuropathy occurrence in children with ALL at an appropriate time.

Total Neuropathy Scale Pediatric Vincristine to detect vincristine induced peripheral neuropathy in children with Acute Lymphoblastic Leukemia

Objective: To analyze the Total Neuropathy Scale Pediatric Vincristine (TNS-PV) score as a vincristine induced peripheral neuropathy (VIPN) diagnostic tool. Methodology: This observational analytic study was conducted in Outpatient Pediatric Hematology Oncology Dr. Soetomo Hospital. The inclusion criteria were Acute Lymphoblastic Leukemia (ALL) children aged 4-18 years that had undergone chemotherapy treatment, received a cumulative dose of vincristine &gt;12 mg/m2, had no muscle weakness and signed informed consent. The TNS-PV instrument were used to assess VIPN and nerve conduction studies (NCS) was used as the gold standard. Results: A total of 54 children were enrolled, two refused to sign the informed consent. About 60% were male children, 76.9% aged &lt;10 years old, and 94% were ALL-L1. The TNS-PV had an area under the curve (AUC) of 0.638 (95% CI 0.531-0.834) with cut off value of 3.5. It had a sensitivity 87.9%; specificity 42.1%, positive predictive value 72.5%; negative predictive value (NPV) 66.6% and OR (Odds ratio) 5,273. Conclusion: TNS-PV score cannot replace NCS as the gold standard, but TNS-PV can be an alternative tool for diagnosing VIPN.