Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect. METHODS: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action. RESULTS: Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxel-induced peripheral neuropathy is PPARγ dependent. CONCLUSIONS: Taken together, the present study suggests ursolic acid has potential as a new PPARγ agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Electroacupuncture use for treatment of taxane-induced peripheral neuropathy in patients with breast cancer: protocol for a pilot, randomised, blinded, sham-controlled trial (EA for CIPN).

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of neurotoxic chemotherapy. Acute symptoms of CIPN during treatment can lead to dose reduction and cessation. Trials using electroacupuncture (EA) to treat established CIPN postchemotherapy have shown some efficacy. The current trial aims to assess the feasibility and preliminary efficacy of using EA to treat CIPN during chemotherapy. METHODS AND ANALYSIS: The current study is a single-centre, 1:1 randomised, sham-controlled pilot study set in a tertiary cancer hospital in Sydney, Australia, and will recruit 40 adult patients with early breast cancer undergoing adjuvant or neoadjuvant paclitaxel chemotherapy. Patients who develop CIPN within the first 6 weeks of chemotherapy will receive either true EA or sham-EA once a week for 10 weeks. The coprimary endpoints are recruitment and adherence rate, successful blinding of patients and compliance with the follow-up period. Secondary endpoints are mean change of CIPN symptoms from randomisation to end of treatment, sustained change in CIPN symptoms at 8-week and 24-week follow-up postchemotherapy, proportion of subjects attaining completion of 12 weeks of chemotherapy without dose reduction or cessation, change in acupuncture expectancy response pretreatment, during treatment and posttreatment. The primary assessment tool for the secondary endpoints will be a validated patient-reported outcome measure (European Organisation for Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy) captured weekly from randomisation to week 12 of chemotherapy. ETHICS AND DISSEMINATION: The study protocol (2021/ETH12123) has been approved by the institutional Human Research Ethics Committee at St Vincent's Hospital Sydney and Chris O'Brien Lifehouse. Informed consent will be obtained prior to starting study-related procedures. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000081718.

Complementary and alternative medicine in relation to chemotherapy-induced peripheral neuropathy: A narrative review.

PURPOSE: To summarizes the available evidence on the effectiveness, safety, and feasibility of complementary and alternative medicine (CAM) in the management of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: We searched for systematic reviews, and meta-analyzes published up to April 2023 in the Pubmed and Web of Science databases. The latest original research on related topics was also reviewed. The search was restricted to English-language papers. Two independent reviewers performed a quality assessment of the identified literature. RESULTS: The results of 35 systematic reviews and meta-analyzes were included in this study. Preliminary evidence suggests that CAM, including acupuncture, physical activity (PA), herbal and nutritional supplements, mind-body therapies, touch therapy, and non-invasive neuromodulation techniques, have shown tremendous potential for the prevention and treatment of CIPN. Of these, there is strong evidence supporting acupuncture, PA, and herbal medicine. However, existing clinical studies are also limited by the heterogeneity of study methods, insufficient sample size, and poor study design. Further studies are needed to validate the efficacy of CAM in patients with CIPN and to elucidate potential therapeutic mechanisms. CONCLUSIONS: Current research has reached a preliminary conclusion suggesting the potential efficacy of certain CAMs in the management of CIPN. Future clinical trials should incorporate more robust study design protocols and larger sample sizes to enhance the validity of findings.

Evaluation of Chemotherapy Induced Peripheral Neuropathy, Sarcopenia and Fatigue in Children with Acute Lymphoblastic Leukaemia and Lymphoma in Tertiary Care Hospital, Dakshina Kannada.

Objectives: The study aims to assess the proportion and magnitude of chemotherapy-induced peripheral neuropathy (CIPN) and other common complications reported in children with acute lymphoblastic leukaemia (ALL)/ acute lymphoblastic lymphoma (LBL) undergoing chemotherapy. Material and Methods: The study included children between 5 and 18 years old with ALL/LBL undergoing chemotherapy in Tertiary Care Hospitals, Mangalore. The study was conducted using various instruments, including paediatric-modified total neuropathy scale for CIPN, handheld dynamometer for muscle strength, bioimpedance analyser for muscle mass, timed up-and-go test for physical performance, and national comprehensive cancer network (NCCN) guidelines for scoring cancer-related fatigue at 3-time points. The collected data were analysed by IBM Statistical Package for the Social Sciences version 29 using Z-scores with standard deviation for distinct ALL/LBL types. In addition, the Paired t-test compared the baseline outcome to the 3rd and 6th time points. Results: The study evaluated 25 children with ALL undergoing chemotherapy based on the UKALL 2003 protocol during their maintenance phase. The study found that 25 children experienced CIPN, with changes in sensory and pin sensibility scores at 3 and 6 months. The study found a significant change in handgrip strength, body mass index, and muscle mass at 3 months, with no significant change in physical performance over time. Fatigue scores increased from baseline to 3 months, with significant changes observed for the 7-12 years age group at 3 months but not for the 5-6 years age group at 6 months. Conclusion: Children with ALL/LBL undergoing chemotherapy experience CIPN and other side effects such as sarcopenia and fatigue. The study highlights the potential benefits of physiotherapy interventions and supportive care strategies aimed at managing the adverse effects of chemotherapy in children with ALL/LBL.

Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221.

BACKGROUND: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor. METHODS: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet. RESULTS: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05). CONCLUSIONS: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

The association of clinical and patient factors with chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer: secondary analysis of the SCOT trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of oxaliplatin. CIPN can impair long-term quality of life and limit the dose of chemotherapy. We investigated the association of CIPN over time with age, sex, body mass index, baseline neuropathy, and chemotherapy regimen in people treated with adjuvant oxaliplatin-containing chemotherapy for colorectal cancer. PATIENTS AND METHODS: We carried out secondary analysis of data from the SCOT randomised controlled trial. SCOT compared 3 months to 6 months of oxaliplatin-containing adjuvant chemotherapy in 6088 people with colorectal cancer recruited between March 2008 and November 2013. Two different chemotherapy regimens were used: capecitabine with oxaliplatin (CAPOX) or fluorouracil with oxaliplatin (FOLFOX). CIPN was recorded with the Functional Assessment of Cancer Therapy/Gynaecologic Oncology Group-Neurotoxicity 4 tool in 2871 participants from baseline (randomisation) for up to 8 years. Longitudinal trends in CIPN [averages with 95% confidence intervals (CIs)] were plotted stratified by the investigated factors. Analysis of covariance (ANCOVA) was used to analyse the association of factors with CIPN adjusting for the SCOT randomisation arm and oxaliplatin dose. P < 0.01 was adopted as cut-off for statistical significance to account for multiple testing. RESULTS: Patients receiving CAPOX had lower CIPN scores than those receiving FOLFOX. Chemotherapy regimen was associated with CIPN from 6 months (P < 0.001) to 2 years (P = 0.001). The adjusted ANCOVA coefficient for CAPOX at 6 months was -1.6 (95% CIs -2.2 to -0.9) and at 2 years it was -1.6 (95% CIs -2.5 to -0.7). People with baseline neuropathy scores ≥1 experienced higher CIPN than people with baseline neuropathy scores of 0 (P < 0.01 for all timepoints apart from 18 months). Age, sex, and body mass index did not link with CIPN. CONCLUSIONS: A neuropathy assessment before treatment with oxaliplatin can help identify people with an increased risk of CIPN. More research is needed to understand the CIPN-inducing effect of different chemotherapy regimens.

A pilot randomized, placebo-controlled, double-blind study of omega-3 fatty acids to prevent paclitaxel-associated acute pain syndrome in breast cancer patients: Alliance A22_Pilot2.

PURPOSE: Paclitaxel is associated with an acute pain syndrome (P-APS- and chronic chemotherapy-induced peripheral neuropathy (CIPN). P-APS is associated with higher risk of CIPN. Omega-3 fatty acids have well-established anti-inflammatory and neuroprotective properties. The primary purpose of this pilot study was to assess whether omega-3 fatty acids could decrease P-APS and thus CIPN. METHODS: Patients scheduled to receive weekly paclitaxel for breast cancer were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior and continued until paclitaxel was stopped. Patients completed acute pain questionnaires at baseline, daily after each treatment, and 1 month after completion of therapy. RESULTS: Sixty patients (49 evaluable) were randomized to treatment versus placebo. Seventeen (68.0%) patients receiving the omega-3 fatty acids intervention experienced P-APS, compared to 15 (62.5%) of those receiving placebo during the first week of treatment (p = 0.77). Over the full 12-week study, 21 (84.0%) patients receiving the omega-3 fatty acid intervention experienced P-APS, compared to 21 (87.5%) of those receiving placebo (p = 1.0). Secondary outcomes suggested that those in the intervention arm used more over-the-counter analgesics (OR: 1.65, 95% CI: 0.72-3.78, p = 0.23), used more opiates (OR: 2.06, 95% CI: 0.55-7.75, p = 0.28), and experienced higher levels of CIPN (12.8, 95% CI: 7.6-19.4 vs. 8.4, 95% CI: 4.6-13.2, p = 0.21). CONCLUSIONS: The results of this pilot study do not support further study of the use of omega-3 fatty acids for the prevention of the P-APS and CIPN. TRIAL REGISTRATION: Number: NCT01821833.

Neurological Outcomes of Chemotherapy-Induced Peripheral Neuropathy in Patients With Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis aimed to determine whether chemotherapy-induced peripheral neuropathy (CIPN) affects the risk of falls and physical function in patients with cancer. METHODS: A literature search was conducted in the CINAHL, Scopus, and PubMed databases for articles published from January 1950 to April 2022. Seven review authors retrieved studies using predetermined eligibility criteria, extracted the data, and evaluated the quality. RESULTS: Nine studies were included in the analysis. Patients with CIPN had a significantly higher risk of falls than those without CIPN (risk ratio = 1.38, 95% confidence interval [CI] =1.18-1.62). Patients with CIPN had lower grip strength (standardized mean difference [SMD] =-0.42, 95% CIs = -0.70 to -0.14, P = .003), longer chair stand time (SMD = 0.56, 95% CIs = -0.01 to 1.17, P = .05), worse timed up and go test time (SMD = 0.79, 95% CIs = 0.41 to 1.17, P < .0001), and lower mean Fullerton Advanced Balance scale score (SMD = -0.81, 95% CIs = -1.27 to -0.36, P = .005) than patients without CIPN. There were no significant differences in gait speed (P = .38) or Activities-specific Balance Confidence Scale score (P = .09) between patients with and without CIPN. CONCLUSIONS: This systematic review and meta-analysis demonstrated that patients with CIPN are prone to falls and impaired balance function and muscle strength.

An umbrella review of the evidence to guide decision-making in acupuncture therapies for chemotherapy-induced peripheral neuropathy.

BACKGROUND: Acupuncture therapy is believed to have therapeutic potential for patients suffering from chemotherapy-induced peripheral neuropathy (CIPN). This umbrella review aims to summarize and evaluate the evidence from current systematic reviews/meta-analyses (SRs/MAs) on the effectiveness of acupuncture treatment for CIPN. METHODS: We conducted a comprehensive search in eight electronic databases for SRs/MAs that included RCTs on acupuncture treatment for CIPN. Two separate researchers independently evaluated the methodological quality, reporting quality, and evidence quality of the SRs/MAs that were included in the study. Additionally, we examined the extent of overlap among the included RCTs by calculating the corrected covered area (CCA). Furthermore, we assessed the dependability of the effect sizes by conducting excess significance tests. We conducted a quantitative synthesis of all RCTs included in the SRs/MAs to obtain objective and updated conclusions. Furthermore, we also conducted an analysis of the acupuncture points used in RCTs. RESULTS: This umbrella review includes 9 SRs/MAs, and their methodological quality, risk of bias, reporting quality, and evidence quality were all deemed unsatisfactory. Out of the 9 SRs/MAs, 28 RCTs were included, with a total CCA of 25.4%, indicating a high degree of overlap. The test of super-significance did not yield any significant results. Our updated meta-analysis suggests that CIPN patients can benefit from acupuncture therapy, as indicated by effectiveness in measures including BPI-SF, VAS, FACT-NTX, NRS, SCV, and NCI-CTCAE. Egger's test and sensitivity analysis demonstrate the reliability and stability of this conclusion. The commonly used acupuncture points in the current RCTs include ST36, LI11, LI4, LR3, and SP6. CONCLUSION: Based on the existing evidence, acupuncture is effective and safe for patients with CIPN, as it can significantly improve effective rate, pain symptoms, quality of life, and nerve conduction velocity. However, given the low quality of current evidence, we should be cautious in interpreting this conclusion.

Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

OBJECTIVE: Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice. METHODS: To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF). RESULTS: Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area. CONCLUSIONS: LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Wellbeing and Complementary Therapies in Breast Cancer Peripheral Neuropathy Care: A Scoping Review Focused on Foot Health.

BACKGROUND: Chemotherapy-induced peripheral neuropathy is a multidimensional health problem. Up to now, little evidence has been found concerning its impact on quality of life and foot health. Evaluation tools and prevention and treatment strategies must be reported. This study aimed to map the literature on the impact of this side effect on the wellbeing and foot health of people with breast cancer and to describe their main assessment strategies and complementary therapies. METHODS: A scoping review was carried out while following the PRISMA-ScR and Arksey and O'Malley guidelines. Different databases (Cochrane Plus, Scopus, Web of Science, and Pubmed) were used. A total of 221 results were identified. Sixteen articles were included. RESULTS: The thematic analysis obtained the following categories: the impact of peripheral neuropathy on quality of life and foot health, complementary therapies as a path for new strategies, and the need for clinicians and researchers to get involved in researching this side effect. CONCLUSIONS: Peripheral neuropathy has a negative impact on people's quality of life. Implications for foot health and maintaining an active and healthy lifestyle have not been previously reported. Complementary therapies are recommended by scientific evidence, highlighting exercise. However, there is a need to develop more research that will help to incorporate them into evidence-based practice.

Hyperbaric Oxygen Therapy Alleviates Paclitaxel-Induced Peripheral Neuropathy Involving Suppressing TLR4-MyD88-NF-κB Signaling Pathway.

Paclitaxel (PAC) results in long-term chemotherapy-induced peripheral neuropathy (CIPN). The coexpression of transient receptor potential vanilloid 1 (TRPV1) and Toll-like receptor 4 (TLR4) in the nervous system plays an essential role in mediating CIPN. In this study, we used a TLR4 agonist (lipopolysaccharide, LPS) and a TLR4 antagonist (TAK-242) in the CIPN rat model to investigate the role of TLR4-MyD88 signaling in the antinociceptive effects of hyper-baric oxygen therapy (HBOT). All rats, except a control group, received PAC to induce CIPN. Aside from the PAC group, four residual groups were treated with either LPS or TAK-242, and two of them received an additional one-week HBOT (PAC/LPS/HBOT and PAC/TAK-242/HBOT group). Mechanical allodynia and thermal hyperalgesia were then assessed. The expressions of TRPV1, TLR4 and its downstream signaling molecule, MyD88, were investigated. The mechanical and thermal tests revealed that HBOT and TAK-242 alleviated behavioral signs of CIPN. Immunofluorescence in the spinal cord dorsal horn and dorsal root ganglion revealed that TLR4 overexpression in PAC- and PAC/LPS-treated rats was significantly downregulated after HBOT and TAK-242. Additionally, Western blots showed a significant reduction in TLR4, TRPV1, MyD88 and NF-κB. Therefore, we suggest that HBOT may alleviate CIPN by modulating the TLR4-MyD88-NF-κB pathway.

Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy (CIPN) with Non-Pharmacological Interventions: Clinical Recommendations from a Systematic Scoping Review and an Expert Consensus Process.

Background: Most individuals affected by cancer who are treated with certain chemotherapies suffer of CIPN. Therefore, there is a high patient and provider interest in complementary non-pharmacological therapies, but its evidence base has not yet been clearly pointed out in the context of CIPN. Methods: The results of a scoping review overviewing the published clinical evidence on the application of complementary therapies for improving the complex CIPN symptomatology are synthesized with the recommendations of an expert consensus process aiming to draw attention to supportive strategies for CIPN. The scoping review, registered at PROSPERO 2020 (CRD 42020165851), followed the PRISMA-ScR and JBI guidelines. Relevant studies published in Pubmed/MEDLINE, PsycINFO, PEDro, Cochrane CENTRAL, and CINAHL between 2000 and 2021 were included. CASP was used to evaluate the methodologic quality of the studies. Results: Seventy-five studies with mixed study quality met the inclusion criteria. Manipulative therapies (including massage, reflexology, therapeutic touch), rhythmical embrocations, movement and mind-body therapies, acupuncture/acupressure, and TENS/Scrambler therapy were the most frequently analyzed in research and may be effective treatment options for CIPN. The expert panel approved 17 supportive interventions, most of them were phytotherapeutic interventions including external applications and cryotherapy, hydrotherapy, and tactile stimulation. More than two-thirds of the consented interventions were rated with moderate to high perceived clinical effectiveness in therapeutic use. Conclusions: The evidence of both the review and the expert panel supports a variety of complementary procedures regarding the supportive treatment of CIPN; however, the application on patients should be individually weighed in each case. Based on this meta-synthesis, interprofessional healthcare teams may open up a dialogue with patients interested in non-pharmacological treatment options to tailor complementary counselling and treatments to their needs.

The effect of hand therapy on alleviating chemotherapy-induced peripheral neuropathy in a model mouse.

The use of neurotoxic chemotherapeutic agents induces numbness in the limbs through chemotherapy-induced peripheral neuropathy (CIPN). Recently, we found that hand therapy involving finger massage improved mild to moderate numbness in CIPN patients. In this study, we behaviorally, physiologically, pathologically, and histologically investigated the mechanisms underlying hand therapy-induced numbness improvement in a CIPN model mouse. Hand therapy was performed for 21 days after the disease induction. Its effects were evaluated using mechanical and thermal thresholds and blood flow in the bilateral hind paw. Moreover, 14 days after the hand therapy was administered, we assessed the blood flow and conduction velocity in the sciatic nerve, the level of serum galectin-3, and the histological myelin and epidermis-related changes in the hindfoot tissue. Hand therapy significantly improved allodynia, hyperalgesia, blood flow, conduction velocity, serum galectin-3, and epidermal thickness in the CIPN model mouse. Furthermore, we observed the images of repairs of the myelin degeneration. Thus, we found that hand therapy could improve numbness in the CIPN model mouse and that it could help to repair peripheral nerves by promoting blood circulation in the limbs.

Efficacy of electroacupuncture in the treatment of peripheral neuropathy caused by Utidelone: Study protocol for a randomized controlled trial.

Introduction: Utidelone (UTD1) is a new chemotherapeutic drug for recurrent or metastatic breast cancer. However, it usually leads to severe peripheral neuropathy (PN) and causes numbness of the hands and feet and significant pain in patients' life. Electroacupuncture (EA) is considered beneficial in improving PN and relieving numbness of the hands and feet. This trial aims to evaluate the therapeutic effect of EA on PN caused by UTD1 in patients with advanced breast cancer. Methods and analysis: This study is a prospective randomized controlled trial. A total of 70 patients with PN caused by UTD1 will be randomly assigned to the EA treatment group and the control group in a ratio of 1:1. The patients in the EA treatment group will receive 2 Hz EA three times a week for 4 weeks. The patients in the control group will take mecobalamin (MeCbl) tablets orally, one tablet each, three times a day for 4 weeks. The main outcome measures will be the evaluation scale of peripheral neurotoxicity of chemotherapeutic drugs according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item (EORTC QLQ-CIPN20) and the peripheral neurotoxicity assessment rating according to NCI CTCAE version 5.0. Secondary outcomes will be the quality of life scale according to the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). The results will be evaluated at baseline, post-treatment phase, and follow-up. All major analyses will be based on the intention-to-treat principle. Ethics and dissemination: This protocol was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital on 26 July 2022. The license number is IRB-2022-425. This study will provide clinical efficacy data on EA in the treatment of PN caused by UTD1 and will help to prove whether EA is an effective and safe therapy. The study results will be shared with healthcare professionals through the publication of manuscripts and conference reports. Trial registration number: ChiCTR2200062741.

Evaluation of 8% Capsaicin Patches in Chemotherapy-Induced Peripheral Neuropathy: A Retrospective Study in a Comprehensive Cancer Center.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is often painful and can arise during or after the end of oncological treatments. They are mostly induced by platinum salts, taxanes, and immunotherapies. Their incidence is estimated between 19 and 85%. They can require a chemotherapy dose reduction or early termination. The European Society for Medical Oncology (ESMO) recommends high-concentration capsaicin patch (HCCP) in second line for the treatment of painful CIPN. This treatment induces a significative pain relief but only shown by low-powered studies. The objective of this study was to evaluate efficacy and tolerability of HCCP applications in CIPN. Methods: This monocentric observational retrospective real-world-data study of the CERCAN cohort took place in the Western Cancer Institute's Anaesthesiology and Pain Department at Angers, France. Independent pain physicians completed the CGIC (Clinician Global Impression of Change) for each patient who benefited from HCCP applications for painful CIPN starting from 1 January 2014 to 22 December 2021, based on the collected data after every patch application. Results: A total of 57 patients (80.7% women) was treated with HCCP for painful CIPN, and 184 applications were realized, consisting of 296 sessions. CGIC found an important or complete pain relief for 61 applications (33.2%, corresponding to 43.9% patients). We found less efficacy for platinum-salts-induced CIPN compared to others (p = 0.0238). The efficacy was significatively higher for repeated applications when HCCP was used in second line compared to third line (p = 0.018). The efficacy of HCCP was significatively higher starting the third application (p = 0.0334). HCCPs were mainly responsible for local adverse events found in 66.6% patients (65.1% burning or painful sensation, 21.1% erythema). Conclusion: HCCP applications in painful CIPN induce an important pain relief with a global satisfying tolerability.

Impact of Baseline Expectancy on Outcome Prediction of Real and Sham Acupuncture for Persistent Chemotherapy-Induced Peripheral Neuropathy Pain in Solid Tumor Survivors: A Secondary Analysis of a Randomized Clinical Trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) pain significantly worsens cancer survivors' quality of life. Expectancy may play an important role in acupuncture response. We sought to explore whether expectancy predicts pain outcome in real acupuncture (RA) and sham acupuncture (SA) in cancer survivors. METHODS: We analyzed data from a randomized clinical trial that evaluated the effect of RA on CIPN symptoms compared to SA and wait list control (WLC) in 75 cancer survivors. This secondary analysis was limited to CIPN pain measured by the Numeric Rating Scale (NRS), graded from 0 to 10. Interventions were delivered over 8 weeks. SA was implemented using a combination of non-acupuncture points and a non-insertion procedure. Patient expectancy was measured by the Acupuncture Expectancy Scale (AES) 3 times during the study. We used a linear regression model to evaluate if the NRS score was associated with the baseline AES score at the end of treatment (week 8), adjusting for baseline NRS score. RESULTS: AES was similar among 3 groups at baseline (RA: 11.8 ± 2.7; SA: 12.1 ± 3.8.; WLC: 14.6 ± 4.2; P = .062). Baseline AES was not found to be significantly associated with the week 8 NRS score among patients in all RA, SA, and WLC groups (all P > .05). However, we found a trend that higher baseline AES predicted lower NRS score at week 8 in the SA group: a one-point higher score on baseline expectancy was associated with a 0.3-point reduction in NRS pain score (P = .059) at week 8. CONCLUSIONS: The association of baseline expectancy and acupuncture response was similar between RA and SA. However, SA seemed to rely more on expectancy than RA. Further studies with larger sample sizes are needed to confirm this finding.

Investigation of effects of quercetin and low-level laser therapy in cisplatin-induced in vitro peripheral neuropathy model.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-dependent side effects of cisplatin. The loss of sensory neurons is observed in CIPN. There are many methods to minimalize CIPN symptoms such as pharmacological agents and photobiostimulation but the mechanisms of these methods are unclear. Our study is aimed at determining the effects of quercetin and low-level laser therapy (LLLT) in undifferentiated and nerve growth factor-differentiated PC12 cells in cisplatin-induced peripheral neuropathy. PC12 cells with cisplatin were co-treated with quercetin and LLLT (diode pumped all-solid-state laser, 670 nm, output 500 mW, and the laser beam surface area was 1.96 cm2). The effects of quercetin and LLLT on GAP-43 and Synapsin I expressions were analyzed by real-time PCR, cell viability was assessed by MTT assay, Annexin and dead assay measured the induction of apoptosis, the alterations in mitopotential were assessed by mitopotential assay, and lactate dehydrogenase activity in cells was analyzed. All experiment data were analyzed by the Tukey test and applied as a post hoc test, and statistical evaluation was made. Our results indicated that cisplatin increased apoptosis (24,210 ± 2189, 46,504 ± 8246) cells, mitochondrial dysfunction (44,312 ± 0.751, 68,788 ± 1271), and LDH activity (62,821 ± 8245, 87,838 ± 8116). Furthermore, it decreased cell viability (42,447 ± 1780, 36,140 ± 3682) and inhibited GAP-43 and Synapsin I genes in undifferentiated and differentiated PC12 cells. However, apoptosis, the alterations in mitopotential, and lactate dehydrogenase activity decreased by applications of quercetin and LLLT. It has been recommended that quercetin and low-level laser therapy roles on cisplatin-induced peripheral neuropathy should be investigated in vivo, and the relationship between quercetin and low-level laser therapy should be molecular.

Data mining analysis reveals key acupoints and meridians for the treatment of chemotherapy-induced peripheral neuropathy.

OBJECTIVE: To explore effective acupoints and combinations for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) METHODS: Clinical controlled trials and randomized controlled trials of acupuncture for CIPN were sourced from PubMed, Embase, Web of Science, and Chinese databases, including the Wanfang database, VIP Journals database, and China National Knowledge Infrastructure database. The quality of eligible research was evaluated based on CONSORT and STRICTA statements. The common acupoints, meridians, and acupoint combinations were determined from acupuncture prescriptions reporting positive effects and were analyzed using SPSS 23.0 and SPSS Modeler 14.1. Finally, a complex network was constructed using Cytoscape 3.8.2 to explore the core acupoints. RESULTS: The quality of 24 clinical trials was evaluated, and 20 acupuncture prescriptions that reported positive outcomes were included in subsequent data mining analysis. The most frequently used acupoints are ST36, LI11, LI4, LR3, and SP6. Meanwhile, they are also the core acupoints in acupuncture prescriptions according to the complex network with 28 nodes and 177 edges. The most commonly used meridians were the large intestine, stomach, and spleen. Acupoint combinations of LI11 and ST36, SP6 and ST36 were frequently used. CONCLUSION: Our study provides a reference for the selection of effective acupoints for CIPN treatment and a basis for the effective use of this form of traditional Chinese medicine. Furthermore, we found limitations in the design and implementation of the available clinical research, which should be minimized in future studies.