Chemotherapy-induced Peripheral Neuropathies Research Articles

Conservative non-pharmacological treatments for chemotherapy-induced peripheral neuropathies in women treated for breast cancer: a systematic review.

Over the last few decades, the use of neo/adjuvant therapies has significantly increased the number of breast cancer survivors who experience chemotherapy-induced peripheral neuropathy (CIPN). To date, few, low-efficacy, pharmacological remedies exist to manage this side effect. For this reason, alternative treatments are increasingly being investigated as possible strategies to prevent or promote faster recovery from CIPN. In this review we aimed to provide an overview of the literature evidence regarding all the non-pharmacological and rehabilitative interventions for patients affected by CIPN secondary to breast cancer care. A comprehensive literature search was conducted on PubMed, Scopus and Web of Science and included a total of 1895 patients (1528 with breast cancer) with a wide range of CIPN (motor, sensory and autonomic neuropathies) and chemotherapy treatments (e.g., Taxanes, Platins, Vinca alkaloids or monoclonal antibody drugs). Of the initial 1108 hits, only 25 studies - describing different treatment modalities for peripheral neuropathies - were finally included in the qualitative synthesis. Most studies focused on acupuncture, physiotherapy, cryotherapy, and yoga. There is still controversial evidence on conservative non-pharmacological interventions for the management of CIPN symptoms. We believe however that moderate exercise, as well as all types of stress reducing activities like sport, yoga and mindfulness, should be encouraged in cancer patients for their positive effect on global physical and psychological health. Further studies of higher methodological quality are needed to determine the best conservative approach to CIPN.

Exploring the Role of Mesenchymal Stem Cell-Derived Exosomes in Diabetic and Chemotherapy-Induced Peripheral Neuropathy.

Diabetic and chemotherapy-induced peripheral neuropathies are known for long-term complications that are associated with uncontrolled hyperglycemia and cancer treatment, respectively. Peripheral neuropathy often requires long-term therapy and could persist after treatment provoking detrimental effects on the patient's quality of life. Despite continuous drug discoveries, development of efficient therapies is still needed for the significant management of diabetic and chemotherapy-induced peripheral neuropathy. Exosomes are nanosized extracellular vesicles that show great promise recently in tissue regeneration and injury repair compared to their parent stem cells. Herein, we provided a summary for the use of mesenchymal stem cell-derived exosomes in diabetic and chemotherapy-induced peripheral neuropathy in addition to recent advancements and ways proposed for the enhancement of their efficacy in these diseases.

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain.

Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

Antinociceptive effect of plant-based natural products in chemotherapy-induced peripheral neuropathies: A systematic review.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and difficult-to-treat symptoms in cancer patients. For this reason, the explore for unused helpful choices able of filling these impediments is essential. Natural products from plants stand out as a valuable source of therapeutic agents, being options for the treatment of this growing public health problem. Therefore, the objective of this study was to report the effects of natural products from plants and the mechanisms of action involved in the reduction of neuropathy caused by chemotherapy. The search was performed in PubMed, Scopus and Web of Science in March/2021. Two reviewers independently selected the articles and extracted data on characteristics, methods, study results and methodological quality (SYRCLE). Twenty-two studies were selected, describing the potential effect of 22 different phytochemicals in the treatment of CIPN, with emphasis on terpenes, flavonoids and alkaloids. The effect of these compounds was demonstrated in different experimental protocols, with several action targets being proposed, such as modulation of inflammatory mediators and reduction of oxidative stress. The studies demonstrated a predominance of the risk of uncertain bias for randomization, baseline characteristics and concealment of the experimental groups. Our findings suggest a potential antinociceptive effect of natural products from plants on CIPN, probably acting in several places of action, being strategic for the development of new therapeutic options for this multifactorial condition.

Effect of cryotherapy on paclitaxel-induced peripheral neuropathy of the hand in female breast cancer patients: A prospective self-controlled study.

The purpose of this study was to examine the efficacy of cryotherapy with frozen gloves for the prevention of the chemotherapy-induced peripheral neuropathy of the hand. Most breast cancer patients receive chemotherapy; consequently, patients frequently experience adverse effects of chemotherapy-induced peripheral neuropathy. A quasi-experimental and prospective self-controlled study was conducted. Breast cancer patients wore frozen glove on the dominant hand for 90 min during their weekly treatment with paclitaxel (80 mg/m2 ). Treatment of the dominant hand, the intervention group, was continued for 12 weeks. The non-dominant hand was considered the control group. A total of 22 patients participated in this study, and only one patient did not reach the cumulative dose (960 mg/m2 ). Findings show that the incidences of sensory and motor symptoms of chemotherapy-induced peripheral neuropathies at the following times (Time 1 to Time 4) were significantly lower in the intervention group than in the control group. However, although the incidences of motor symptoms were lower in the experimental group than in the control group, a significant difference was shown only at Time 4. Additionally, both groups of patients reported that their incidence of sensory symptoms were higher than those of motor symptoms. Cryotherapy with frozen gloves is useful in reducing both the sensory and motor symptoms of the chemotherapy-induced peripheral neuropathy of the hands.

Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

Axonal degeneration is an active process that differs from neuronal death, and it is the hallmark of many disorders affecting the central and peripheral nervous system. Starting from the analyses of Wallerian degeneration, the simplest experimental model, here we describe how the long projecting neuronal populations affected in Parkinson’s disease and chemotherapy-induced peripheral neuropathies share commonalities in the mechanisms and molecular players driving the earliest phase of axon degeneration. Indeed, both dopaminergic and sensory neurons are particularly susceptible to alterations of microtubules and axonal transport as well as to dysfunctions of the ubiquitin proteasome system and protein quality control. Finally, we report an updated review on current knowledge of key molecules able to modulate these targets, blocking the on-going axonal degeneration and inducing neuronal regeneration. These molecules might represent good candidates for disease-modifying treatment, which might expand the window of intervention improving patients’ quality of life.

Corneal and Epidermal Nerve Quantification in Chemotherapy Induced Peripheral Neuropathy.

Chemotherapy-induced neurotoxicity is an increasingly recognized clinical issue in oncology. in vivo confocal microscopy (IVCM) of corneal nerves has been successfully used to diagnose peripheral neuropathies, including diabetic neuropathy. The purpose of this study was to test if the combination of corneal nerve density and morphology assessed by IVCM is useful to monitor the neurotoxic effects of chemotherapy compared to epidermal nerve quantification. Overall, 95 adult patients with different cancer types were recruited from the oncology and hematology departments of the San Raffaele Hospital. Neurological examination, including clinical Total Neuropathy Score, and in vivo corneal confocal microscopy (IVCM), were performed before and after chemotherapy. In a group of 14 patients, skin biopsy was performed at the first and last visit. In the group of 14 patients who underwent both skin biopsy and corneal nerve imaging, clinical worsening (+69%, p = 0.0018) was paralleled by corneal nerve fiber (CNF) density reduction (−22%, p = 0.0457). Clinical Total neuropathy score significantly worsened from the first to the last visit (+62%, p < 0.0001). CNF length was not significantly reduced overall. However, CNF density/tortuosity ratio significantly decreased after therapy. Correlation analysis showed that the CNF density/tortuosity ratio was also correlated with the number of chemotherapy cycles (r = −0.04790, P = 0.0009). Our data confirm that in vivo corneal confocal microscopy is a helpful, non-invasive tool which shows promise for the diagnosis of chemotherapy-induced peripheral neuropathies. IVCM could allow a rapid, reproducible and non-invasive quantification of peripheral nerve pathology in chemotherapy-associated neuropathy.

Programmed axon degeneration: from mouse to mechanism to medicine.

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (WldS) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.

Enolate-forming compounds provide protection from platinum neurotoxicity

Cisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs (e.g., carboplatin, oxaliplatin) are highly effective and widely used in the treatment of solid tumors in both pediatric and adult patients. Although considered to be life-saving as a cancer treatment, Pt-based drugs frequently result in dose-limiting toxicities such as chemotherapy-induced peripheral neuropathies (CIPN). Specifically, irreversible damage to outer hair cells and injury of sensory neurons are linked to profound sensorineural hearing loss (ototoxicity), which complicates tumor management and can lead to a poor clinical prognosis. Given the severity of CIPN, substantial effort has been devoted to the development of neuroprotective compounds, regardless clinical results have been underwhelming. It is noteworthy that Pt is a highly reactive electrophile (electron deficient) that causes toxicity by forming adducts with nucleophilic (electron rich) targets on macromolecules. In this regard, we have discovered a series of carbon-based enol nucleophiles; e.g., N-(4-acetyl-3,5-dihydroxyphenyl)-2-oxocytclopentane-1-carboxamide (Gavinol), that can prevent neurotoxicity by scavenging the platinum ion. The chemistry of enol compounds is well understood and mechanistic research has demonstrated the role of this chemistry in cytoprotection. Our cell-derived data were corroborated by calculations of hard and soft, acids and bases (HSAB) parameters that describe the electronic character of interacting electrophiles and nucleophiles. Together, these observations indicate that the respective mechanisms of Pt neurotoxicity and antitumor activity are separable and can therefore be affected independently.

Additive Duloxetine for Cancer-Related Neuropathic Pain Nonresponsive or Intolerant to Opioid-Pregabalin Therapy: A Randomized Controlled Trial (JORTC-PAL08)

ContextAlthough opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails. ObjectivesWe investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy. MethodsA multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]–Item 5) ≥ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases. ResultsSeventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P = 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 0.002). ConclusionAdding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine.

Tapentadol for neuropathic pain: a review of clinical studies.

Neuropathic pain (NP) is an enormous burden for patients, caregivers and society. NP is a pain state that may develop after injury of the peripheral or central nervous system because of a wide range of diseases and traumas. A NP symptom component can be found also in several types of chronic pain. Many NP patients are substantially disabled for years. Due to its chronicity, severity and unpredictability, NP is difficult to treat. Tapentadol is a central-acting oral analgesic with combined opioid and noradrenergic properties, which make it potentially suitable for a wide range of pain conditions, particularly whenever a NP component is present or cannot be excluded. In randomized controlled trials, tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain. In observational studies, tapentadol reduced NP in chemotherapy-induced peripheral neuropathies, blood and solid cancers, and the NP component in neck pain and Parkinson’s disease. This narrative review aims to provide clinicians with a broad overview of tapentadol effects on NP.

Axonal Degeneration Is Mediated by Necroptosis Activation

Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.SIGNIFICANCE STATEMENT We show that axonal degeneration triggered by diverse stimuli is mediated by the activation of the necroptotic programmed cell-death program by a cell-autonomous mechanism. This work represents a critical advance for the field since it identifies a defined degenerative pathway involved in axonal degeneration in both the peripheral nervous system and the CNS, a process that has been proposed as an early event in several neurodegenerative conditions and a major contributor to neuronal death. The identification of necroptosis as a key mechanism for axonal degeneration is an important step toward the development of novel therapeutic strategies for nervous-system disorders, particularly those related to chemotherapy-induced peripheral neuropathies or CNS diseases in which axonal degeneration is a common factor.

Evaluation by Oncologists of Strategies for the Prevention and Treatment of Chemotherapy-induced Peripheral Neuropathies

Evaluation by Oncologists of Strategies for the Prevention and Treatment of Chemotherapy-induced Peripheral Neuropathies

Peripheral Neuropathy Research Registry: A prospective cohort.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus-, and chemotherapy-induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi-center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease-altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted-omics methodologies.

Uncoupling neurotrophic function from nociception of nerve growth factor: what can be learned from a rare human disease?

Nerve growth factor (NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V (HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100th position of mature NGF resulting in a change of residue from arginine to tryptophan (R100W). Although those HSAN V patients associated with the NGFR100W mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGFR100W mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGFR100W provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGFR100W no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGFR100W mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGFR100W mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review.

A cross-sectional, comparative, syndromic description of oncological mixed pain in Medical Oncology units in Spain.

The reason cancer pain remains prevalent and hard to classify may be partially explained by the failure to identify neuropathic mechanisms. The objective of this research was to identify the syndromes of cancer pain that may be particularly hard to manage due to their mixed pathophysiology. A series of 384 patients who had cancer of any type, at any stage, and suffered from chronic pain (symptom onset > 3months) were assessed during a routine return visit in Spain. Medical oncologists indicated the presence and pathophysiology of 33 predefined pain syndromes on a per-patient basis. This information was then measured against clinical, psychosocial, and health care-related data to determine which syndromes pose particular challenges. The mean (standard deviation) age of patients was 61.6 (12.6)years, 49.7% were women. Most (82%) had advanced metastatic disease, 68.7% were on second-line or palliative therapies. The worst syndrome was nociceptive, pure neuropathic, and mixed in 34.6, 26.9, and 38.6% of patients, respectively. Any syndrome could be of mixed pathophysiology. Only 10 syndromes were common (≥ 5% of patients). Syndromes related to malignant bone pain and involvement of chest wall structures were the most frequent. Certain syndromes (including tumor-related bone pain, chemotherapy-induced peripheral neuropathies, paraneoplastic pain syndromes, and malignant neuralgias or injury to cranial nerves) can be particularly challenging when they have a mixed pathophysiology, because the neuropathic component is rarely or unevenly considered. Virtually all cancer pain syndromes can present mixed pathophysiology. Certain syndromes can include neuropathic components that are frequently overlooked.

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

Ultrasound analysis of a novel therapeutic intervention for neuropathy: intraneural facilitation acute effects on idiopathic and chemotherapy induced peripheral neuropathy

Intraneural Facilitation (INF) is a novel therapy for the treatment of various neuropathic pathologies. INF is an evidence‐based approach which utilizes physical‐therapy‐based “holds” to stretch and relax peripheral associated nerve areas and thus potentially allows for re‐establishment of blood supply (oxygen and nutrients) to damaged nerves.The acute efficacy of INF therapy to treat idiopathic or chemotherapy‐induced neuropathy remains undetermined. Therefore, in a pilot feasibility study, we examined the effects of acute changes by ultrasound assessment of the arterial pulsatility index and volume flow with pre‐ and post‐Intraneural Facilitation Treatment in patients with chemotherapy‐induced neuropathy and idiopathic peripheral neuropathy.PurposeTo determine the acute effect of a novel therapeutic intervention called intraneural facilitation on patients with idiopathic (IPN) and chemotherapy‐induced (CIN) peripheral neuropathies.MethodsThis is a prospective pre‐ and posttest, single group clinical pilot study in an outpatient physical therapy clinic. Participants are patients with peripheral idiopathic or chemotherapy‐induced neuropathy. Outcome measures were assessed with ultrasound measures 1) pulsatility index (PI), which is a measure of the variability of blood velocity in a vessel, equal to the difference between the peak systolic and minimum diastolic velocities divided by the mean velocity during the cardiac cycle, and 2) volume flow (VF), a measure of a cross‐sectional blood vessel area in a time‐averaged velocity.ResultsThere were 38 arterial ultrasound measurements in 13 patients diagnosed with either CIN or IDN for this pilot study. The PI showed significant improvement from pre‐ to post‐treatment in both neuropathy categories, CIN and IDN respectively (p &lt; 0.05). The average total percent change in the 38 arterial measurements of PI was +1.32% and VF was −2.59%. The percent change in PI and VF in patients with IDN was +1.25% and −8.26% and CIN was +1.36% and +0.12%, respectively. Ultrasound measurements of the left radial artery showed a treatment efficacy with a significant change in PI (p = 0.0463).ConclusionThese preliminary pilot outcome results, using ultrasound assessment parameters PI and VF are clinically promising. Intraneural facilitation treatment improves objective PI and VF “markers” in patients with CIN and IDN. Overall, the average percent change of PI showed that there was a significant acute improvement in patients with both CIN and IDN. Greater frequency and chronicity of INF treatment is suggestive to be potentially efficacious in the resolution of the respective neuropathies. These promising pilot patient data suggests the need for further expansive prospective studies to expand a more comprehensive clinical understanding of this new novel treatment called, Intraneural Facilitation Treatment. These studies are currently in progress.Support or Funding InformationDepartmentalThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth

As cancer is becoming more and more a chronic disease, a large proportion of patients is confronted with devastating side effects of certain anti-cancer drugs. The most common neurological complications are painful peripheral neuropathies. Chemotherapeutics that interfere with microtubules, including plant-derived vinca-alkaloids such as vincristine, can cause these chemotherapy-induced peripheral neuropathies (CIPN). Available treatments focus on symptom alleviation and pain reduction rather than prevention of the neuropathy. The aim of this study was to investigate the potential of specific histone deacetylase 6 (HDAC6) inhibitors as a preventive therapy for CIPN using multiple rodent models for vincristine-induced peripheral neuropathies (VIPN). HDAC6 inhibition increased the levels of acetylated α-tubulin in tissues of rodents undergoing vincristine-based chemotherapy, which correlates to a reduced severity of the neurological symptoms, both at the electrophysiological and the behavioral level. Mechanistically, disturbances in axonal transport of mitochondria is considered as an important contributing factor in the pathophysiology of VIPN. As vincristine interferes with the polymerization of microtubules, we investigated whether disturbances in axonal transport could contribute to VIPN. We observed that increasing α-tubulin acetylation through HDAC6 inhibition restores vincristine-induced defects of axonal transport in cultured dorsal root ganglion neurons. Finally, we assured that HDAC6-inhibition offers neuroprotection without interfering with the anti-cancer efficacy of vincristine using a mouse model for acute lymphoblastic leukemia. Taken together, our results emphasize the therapeutic potential of HDAC6 inhibitors with beneficial effects both on vincristine-induced neurotoxicity, as well as on tumor proliferation.

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review.

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.