Search Results (63)

Background/Objectives: Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 85% of patients receiving neurotoxic regimens, often leading to dose reduction and impaired quality of life, yet effective preventive or therapeutic options remain scarce. Emerging evidence implicates chemotherapy-induced gut microbiota dysbiosis in CIPN pathogenesis via a gut–nerve axis. Concurrently, rectal ozone insufflation (ROI) has been shown to modulate the gut microbiota and reduce inflammation in preclinical models. This article critically examines the evidence on the role of gut dysbiosis in CIPN, evaluates the microbiota-modulating capacity of rectal ozone therapy (OT), and assesses the biological plausibility of ozone as a microbiota-targeting intervention for CIPN, while explicitly distinguishing between established evidence and hypothetical mechanisms. Evidence synthesis: Neurotoxic agents induce dysbiosis marked by reduced microbial diversity, loss of short-chain fatty acid-producing bacteria, and expansion of pro-inflammatory taxa. Preclinical models demonstrate a causal role for specific microbial communities in CIPN, with microbiota depletion or fecal transplantation modulating neuropathic phenotypes. In human cohorts, dysbiosis severity correlates with CIPN symptoms. Preclinical studies show that ROI restores microbial balance, enhances short-chain fatty acid levels, and strengthens intestinal barrier function via Nrf2/HO-1 and SIRT1 pathways. Preliminary retrospective data from small case series (n = 7 and n = 15) report sustained symptom improvement in CIPN patients receiving OT. However, no human study has directly linked ozone-induced microbiota changes to clinical outcomes, and the clinical evidence for OT in CIPN remains limited to uncontrolled observations. Conclusions: Convergent preclinical evidence supports a biological rationale for investigating ROI as a microbiota-targeting intervention in CIPN. However, this rationale remains largely hypothetical in the clinical setting. High-quality randomized controlled trials with longitudinal microbiome profiling are urgently needed to establish mechanistic causality and to determine whether the promising preclinical findings translate into clinically meaningful benefits. Until such evidence is available, the framework presented here should be regarded as hypothesis-generating rather than as a basis for clinical practice. Full article

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of neurotoxic chemotherapy that can affect functioning and quality of life. Currently, duloxetine is the only recommended agent to treat painful CIPN; however, no effective pharmacological treatments have been approved for the prevention or cure of CIPN, highlighting the need to understand non-pharmacological strategies such as exercise. Given significant heterogeneity in the CIPN outcome measures chosen across studies, this scoping review aimed to identify the outcome measures used to evaluate the effectiveness of exercise interventions as a potential countermeasure for CIPN. Following the Arksey and O’Malley framework refined by Levac and colleagues, and the PRISMA-ScR guidelines, four databases were searched, and 20 studies were included in the review. Data were abstracted on study characteristics, cancer and chemotherapy factors, exercise prescription, outcome measures, and CIPN-related findings. Outcome measures varied widely across studies, encompassing various patient-reported, clinical, and functional measures. The most common patient-reported, clinical, and functional measures were the EORTC QLQ-CIPN20, vibration sensation, and maximal isometric strength, respectively. No study satisfied the components of the core outcome measure set proposed by Park and colleagues, limiting cross-study comparisons. These findings underscore the need for standardized CIPN outcome measures in future exercise studies to strengthen evidence synthesis and inform clinical practice. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting 30–40% of patients treated with neurotoxic chemotherapy. Sensory symptoms arise from injury to dorsal root ganglion (DRG) neurons and their axons; yet, the underlying mechanisms remain incompletely understood. While human induced pluripotent stem cell (iPSC)-derived sensory neuron (iSN) monolayers have provided mechanistic insight, they lack the three-dimensional architecture and cellular heterogeneity of native DRG tissue. Here, we generated human iPSC-derived DRG organoids (iDRGOs) containing mixed neuronal and peripheral glial populations and established a quantitative neurite outgrowth assay to model chemotherapy-induced neurotoxicity in a 3D context. iDRGOs from three healthy donors were exposed to bortezomib, vincristine, or paclitaxel. All three drugs caused dose-dependent neurite outgrowth impairment without significant short-term changes in organoid size, consistent with early axonal injury. Vincristine reduced MAP2 levels when normalized to total protein, whereas bortezomib and paclitaxel showed divergent microtubule-associated responses compared to monolayer cultures. The developmental stage significantly influenced the baseline neurite outgrowth, highlighting the need for age standardization. These results establish iDRGOs as a physiologically relevant human platform that complements monolayer models for mechanistic studies and therapeutic screening in CIPN. Full article

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity affecting many patients treated with neurotoxic agents, leading to persistent pain and impaired quality of life. Methods: In our trial, Trial ID: NCT06091553, 160 patients met the eligibility criteria and were randomized into three groups. First, Arm D (duloxetine). Second, Arm (D + A): duloxetine is augmented with amitriptyline. Third, Arm (D + G): duloxetine is augmented with gabapentin. The primary outcome is the difference in Pain Inventory—Short Form (BPI-SF) measured during the final follow-up week (Week 4 and Week 8) between the treatments. Results: All groups showed significant within-group reductions in pain scores from baseline to Weeks 4 and 8. Meanwhile, all groups exhibited numerical improvements for the average pain by Week 8. No statistically significant differences were found between groups at either Week 4 (p = 0.161) or Week 8 (p = 0.868). Similarly, the proportion of responders was comparable across treatment arms at both time points, with 74.5–82.8% achieving a clinically meaningful reduction in pain by Week 8 (p = 0.566). Conclusions: These findings support duloxetine as an evidence-based first-line therapy for painful CIPN, while combination regimens may be reserved for individualized use in patients with inadequate response, pending confirmation in larger multicenter trials. Full article

Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer progression but also to chemotherapy-induced side effects such as peripheral neuropathy. Chemokines, particularly CCL3, appear to be key players in this bidirectional communication. This literature review aims to critically examine the role of CCL3 in CRC and chemotherapy-induced peripheral neuropathy (CIPN), with a focus on identifying potential mechanistic overlaps. Specifically, we evaluate whether CCL3 may serve as a molecular link between cancer progression and the development of neuropathic pain. In CRC, CCL3 is frequently upregulated, promoting tumor proliferation, invasion, and immune remodeling through CCR5- and MAPK-dependent pathways. Elevated CCL3 expression correlates with advanced stage, nerve infiltration, and worse prognosis, while select studies suggest it may also enhance antitumor immunity via dendritic cell recruitment. In parallel, CCL3 is also upregulated in the nervous system during CIPN, where it contributes to chronic pain through activation of glial cells, sensitization of nociceptive pathways (e.g., TRPV1, P2X7), and desensitization of opioid receptors. Notably, MAPK signaling is a shared downstream pathway in both contexts, suggesting a potential mechanistic bridge between tumor biology and neurotoxicity. In conclusion, CCL3 emerges as a central molecule at the intersection of CRC and CIPN. Understanding its context-dependent roles may offer new opportunities for risk prediction, biomarker development, and therapeutic intervention—contributing to the broader goals of cancer neuroscience in improving both oncologic and neurologic outcomes. Full article

Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. Female C57BL/6 mice received PTX vehicle (VEH) or PTX (70 mg/kg intravenously, once per week for four weeks), and the remaining four groups received PTX with co-treatment of either ricolinostat (50 mg/kg orally, daily) or ITF6475 (1, 6, or 12.5 mg/kg orally, daily). Neurophysiological assessments at the end of treatment showed a significant reduction in caudal sensory nerve action potential amplitude across all PTX-treated groups compared to the VEH group. At the same time, PTX treatment led to the development of mechanical allodynia. However, co-treatment with the HDAC6 inhibitor prevented significant differences compared to the VEH group. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model. Full article

Background: Chemotherapy-induced peripheral neuropathy is a common and debilitating side effect of cancer treatment. While exercise has shown promise in alleviating this burden, it remains underutilised in clinical practice due to the lack of accessible, clinician-friendly guidance. Aim: This review aimed to synthesise current evidence on exercise interventions for managing chemotherapy-induced peripheral neuropathy and provide practical insights to support clinicians in integrating these approaches into patient care. Methods: A search was conducted across MEDLINE, CINAHL, and SPORTDiscus using keywords related to exercise and CIPN. Studies were included if they involved adults receiving neurotoxic chemotherapy and exercise-based interventions. Two authors independently screened studies and resolved conflicts with a third author. Study quality was assessed using the JBI Critical Appraisal Tools, and only studies meeting a minimum quality standard were included. A balanced sampling approach was employed. Data on study design, participant characteristics, interventions, and outcomes were extracted. Results: Eleven studies were included, covering various exercise modalities: multimodal (n = 5), yoga (n = 2), aerobic (n = 1), resistance (n = 1), balance (n = 1), and sensorimotor (n = 1). Exercise interventions, particularly multimodal exercise, significantly improved symptom severity, functionality, and quality of life (p < 0.05). The studies had high methodological quality, with randomised controlled trials scoring between 9/13 and 11/13, and quasi-experimental studies scoring 8/9 on JBI tools. Conclusions: This review highlights the significant benefits of exercise, especially multimodal exercise, for managing CIPN and provides guidance for integrating these strategies into clinical practice. Future research is needed to refine exercise prescriptions and develop standardised guidelines. Full article

This study investigates the role of p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion (DRG) neurons in the development and progression of chemotherapy-induced peripheral neuropathy (CIPN). This research evaluates whether inhibiting activation of p38 MAPK could reduce neuropathic outcomes in a transgenic breast cancer mouse model (C3TAg) and wild-type mice (FVB/N) treated with cisplatin. Cisplatin treatment stimulated p38 MAPK phosphorylation and nuclear translocation in DRG neurons. Neflamapimod, a specific inhibitor of p38 MAPK alpha (p38α), proven to be safe in clinical trials, inhibited neuronal cisplatin-induced p38 MAPK phosphorylation in vitro and in vivo. Neflamapimod also reduced cisplatin-induced oxidative stress, mitochondrial dysfunction, and cleaved caspase-3 expression in DRG neurons in vitro, protecting neuronal integrity and preventing axonal damage. Functionally, neflamapimod improved mechanical and musculoskeletal hyperalgesia, and cold sensitivity in cisplatin-treated mice, reversing neuropathic pain and neurotoxicity. This study identifies p38 MAPK activation as a critical driver of CIPN and highlights its potential as a therapeutic target for CIPN. Targeting p38 MAPK activation with neflamapimod offers a promising strategy to mitigate neurotoxicity and hyperalgesia without exacerbating cancer progression, positioning it as a novel intervention for CIPN. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) affects 20–85% of individuals exposed to neurotoxic chemotherapeutic agents. Perineural electrical dry needling (PEDN) and neural mobilization (NM) interventions may be beneficial in the management of chronic neurogenic pain; however, there is a paucity of research on the efficacy of both interventions for CIPN. Methods: Three patients were referred to an outpatient physical therapy clinic with chronic neuropathic pain associated with CIPN. Each underwent PEDN and NM twice weekly until goals were met or progress stalled. The primary outcome measure was the Numeric Pain Rating Scale (NPRS). Secondary outcomes included the Global Rating of Change (GROC) and the Lower Extremity Functional Scale (LEFS). All outcome measures were assessed at evaluation and discharge. Results: At discharge, patients A and B exceeded the minimum clinically important difference (MCID) for the primary and secondary outcome measures, indicating decreased neuropathic pain and improved lower extremity function. Patient C improved in all outcome measures but only experienced clinically meaningful changes in the NPRS and LEFS, not the GROC. Conclusions: Following 4–8 sessions of PEDN and NM, three patients with CIPN demonstrated clinically meaningful improvements in chronic lower extremity neuropathic pain and function. PEDN and NM may be beneficial in the management of patients presenting with chronic neuropathic pain secondary to CIPN. Full article

Objectives: Neurotoxic effects causing peripheral nerve damage have been reported for several chemotherapy agents. There is no established and standardized method to assess the presence of chemotherapy-induced peripheral neuropathy (CIPN). We compared patient-reported CIPN symptoms to neurophysiological findings and neurological assessments in patients receiving taxane-based chemotherapy. Methods: Patients scheduled to receive taxane-based chemotherapy for the treatment of gynecologic cancer were included and prospectively followed for up to 9 months after chemotherapy discontinuation, between May 2020 and January 2023. Patient-reported symptoms, using the EORTC-QLQ-CIPN20 questionnaire, and nerve conduction studies (NCSs) were performed at baseline, halfway through the treatment cycle, at the end of the treatment, 3 months after treatment, and 6–9 months after treatment. Results: A total of 149 patients were included. Overall, 47.0% of patients reported symptoms compatible with CIPN at any of the follow-ups. Subjective symptoms did not correlate with nerve conduction studies. SNAP amplitudes at baseline were lower in patients who developed CIPN compared to the group without CIPN. Conclusions: The overall diagnostic accuracy of electrophysiological parameters as a marker for CIPN was low. Full article

Although the literature on patient-reported outcomes (PROMs) continues to expand, challenges persist in selecting reliable and valid instruments for assessing peripheral neuropathy (PN) in patients with cancer. This systematic review aimed to identify all validated self-report PN scales and critically appraise their measurement properties. This review was conducted using the COSMIN methodology for PROMs and the PRISMA statement. Five databases were searched from inception to August 2024, identifying 46 eligible studies and 16 PROMs. Evidence quality ranged from “very low” to “moderate”, with notable inconsistencies in the content and structural validity phases of most instruments. Instruments such as the Chemotherapy-induced peripheral neuropathy assessment tool and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity demonstrated moderate quality and potential utility in clinical practice, while others, including the Location-based assessment of sensory symptoms in cancer and the Measure of Ovarian Symptoms and Treatment, had insufficient evidence to support their use. Importantly, all PROMs focused on chemotherapy-induced peripheral neuropathy, highlighting a significant gap in instruments addressing other PN causes, such as radiotherapy or tumor-related nerve damage. Further research should prioritize developing and validating instruments for distinct cancer populations, ensuring robust psychometric properties and clinical applicability. Full article

A microphysiological system (MPS) is an in vitro culture technology that reproduces the physiological microenvironment and functionality of humans and is expected to be applied for drug screening. In this study, we developed an MPS for the structured culture of human iPSC-derived sensory neurons and then predicted drug-induced neurotoxicity by morphological deep learning. Using human iPSC-derived sensory neurons, after the administration of representative anti-cancer drugs, the toxic effects on soma and axons were evaluated by an AI model with neurite images. Significant toxicity was detected in positive drugs and could be classified by different effects on soma or axons, suggesting that the current method provides an effective evaluation of chemotherapy-induced peripheral neuropathy. The results of neurofilament light chain expression changes in the MPS device also agreed with clinical reports. Therefore, the present MPS combined with morphological deep learning is a useful platform for in vitro peripheral neurotoxicity assessment. Full article

Previous data regarding chemotherapy-induced olfactory and gustatory dysfunction (CIOGD) are heterogeneous due to inconsistent study designs and small numbers of patients. To provide consistent, reliable data, we conducted a cohort study using standardized testing. Patients diagnosed with lymphoma, leukemia, or gastrointestinal malignancies were examined up to five times (T1 to T5), beginning prior to chemotherapy. We examined patients receiving temporary treatment up to 12 months post-therapy. Clinical assessment included extensive questionnaires, psychophysical tests of olfactory and gustatory function, and measurement of peripheral neuropathy. Statistical analysis included non-parametric tests to evaluate the longitudinal development of CIOGD. Our data (n = 108) showed a significant decline in olfactory and gustatory testing during chemotherapy (p-values < 0.001). CIOGD appeared stronger among patients above 60 years, while sex did not matter significantly. However, we identified distinct associations between CIOGD and reported anorexia as well as with higher neuropathy scores. Self-assessment appeared less sensitive to chemosensory dysfunction than psychophysical testing. Post-therapy, olfactory and gustatory function regenerated, though baseline levels were not attained within 6 to 12 months. In conclusion, our data highlight the wide prevalence and slow recovery of CIOGD. Understanding CIOGD as a potential neurotoxic effect may disclose new therapeutic prospects. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of chemotherapy, and effective treatments for CIPN are still lacking. For this reason, there is a growing interest in complementary and alternative medicine as a potential source of nonsurgical treatments for CIPN symptoms alongside pregabalin. One such option being explored is Chuna manual therapy (CMT), a traditional Korean manual therapy. Methods: This study compares the effectiveness and safety of using only pregabalin (PG) as a conventional method of treating breast and colorectal cancer patients with CIPN symptoms with a combination of both PG and electroacupuncture (EA) or CMT, while also assessing the feasibility of future large-scale clinical studies. Due to the COVID-19 pandemic, only 74 CIPN patients were recruited to this study. Twenty-five were assigned to the PG group, 26 to the PG + EA group, and 22 to the PG + CMT group for a five-week treatment and a four-week follow-up study. Results: For the primary outcome, we evaluated the mean differences in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) compared to the baseline at week 5 (visit 4). Although we found that the PG + CMT group showed the biggest difference (−16.64 [95% CI: −25.16, −8.11]) compared to the PG group (−8.60 [95% CI: −14.93, −2.27]) and the PG + EA group (−6.73 [95% CI: −12.34, −1.13]), this finding lacked statistical significance (p = 0.2075). In terms of safety, two patients in the PG + CMT group reported side effects: one bruise and one headache. Conclusions: The low attrition and high adherence rates of all the groups, and the similar rates of side effects among them, support the feasibility of larger-scale follow-up studies. Full article