Drug-induced Neuropathy Research Articles

Immune cells mediate the effects of gut microbiota on neuropathic pain: a Mendelian randomization study

BackgroundThe gut microbiota may be involved in neuropathic pain. However, the causal association between gut microbiota and neuropathic pain remains unclear. Whether immune cells and inflammatory factors mediate the pathway from gut microbiota to neuropathic pain has not been elucidated.MethodsWe obtained the summary data of 412 gut microbiota, 731 immune cells, 91 inflammatory factors, and five types of neuropathic pain (drug-induced neuropathy, postherpetic neuralgia, sciatica, trigeminal neuralgia, and unspecified neuralgia) from large-scale genome-wide association study (GWAS) datasets and the FinnGen database. We used bidirectional Mendelian randomization (MR) analysis to explore the causal association between gut microbiota and neuropathic pain. Additionally, we conducted a mediation analysis to identify whether immune cells and inflammatory factors act as mediators within these causal relationships.ResultsOur study revealed 30 causal relationships between 26 gut bacterial taxa and five types of neuropathic pain, including four associated with drug-induced neuropathy, six with postherpetic neuralgia, five with sciatica, eight with trigeminal neuralgia, and seven with unspecified neuralgia. Moreover, we identified 35 gut bacterial pathway abundances causally involved in neuropathic pain. The reverse MR analysis showed no evidence of reverse causality from gut microbiota to neuropathic pain. Mediation analysis demonstrated that the immune cell phenotype “HLA-DR++ monocyte % leukocyte” mediated the causal relationship between p_Proteobacteria and sciatica with a mediation proportion of 36.15% (P = 0.038), whereas “CD11c on CD62L+ myeloid dendritic cell” mediated the causal pathway from assimilatory sulfate reduction to trigeminal neuralgia with a mediation proportion of 27.90% (P = 0.041).ConclusionThis study identified the causal relationships between several specific gut microbiota and various neuropathic pain subtypes. Additionally, two immune cells may act as potential mediators in the pathways from gut microbiota to neuropathic pain.

Exploring causal correlations between plasma proteins and peripheral neuropathy: a Mendelian randomization.

Peripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies. To identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN. Through MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN. Mendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

Role of High Dose B12 in Curing Hypoglycaemic Drug-induced Neuropathy

Role of High Dose B12 in Curing Hypoglycaemic Drug-induced Neuropathy

DRUG INDUCED NEUROPATHY

Neuropathy is a painful condition and originates from a variety of etiologies. Many drugs can cause neuropathy, which is known as Drug-Induced Neuropathy (DIN), which is included in iatrogenic cases. These drugs are chemotherapy agents, antimicrobials, cardiovascular drugs, psychotropics, anticonvulsants, etc. Not all neuropathies require pharmacological therapy, but simply stop therapy, and the complaints will improve (reversible). However, there are quite a few DINs with a “coasting" response neuropathy when DIN is stopped. This review synthesizes current clinical concepts regarding mechanisms, drug-induced neuropathy, and treatment options for drug-induced peripheral neuropathy.

Patterns of facial and blink reflex abnormalities in type 2 diabetes mellitus patients with short disease duration: a clue to subclinical cranial neuropathy

Abstract Background Cranial neuropathies occur in 3 to 14% of diabetic patients. Motor conduction study of the facial nerve and blink reflex study are electrophysiologic techniques used to assess the facio-trigeminal pathway in diabetic patients. The patterns of facial and blink reflex abnormalities are inconsistent among studies. This study aimed to assess the subclinical facial nerve and blink reflex abnormalities patterns in short-duration type 2 diabetes mellitus patients. This cross-sectional study included 30 type 2 diabetic patients with disease duration ≤ 5 years. We included only patients with the Toronto clinical neuropathy score ≤ 5. We enrolled 30 age- and sex-matched healthy subjects as a control group. We performed facial nerve motor conduction and blink reflex studies. Patients with prior history of cranial nerve lesions, stroke, or any other disease-causing polyneuropathy or drug-induced neuropathy were excluded from the study. Results Thirty diabetic patients were included, 20 females (66.7%) and ten males (33.3%). Their mean age was 52.63 ± 8.94 years. None of the patients had clinical evidence of neuropathy. There were significant differences between patients and controls in the distal latencies and amplitudes of facial nerve compound muscle action potentials and contralateral R2 late response latencies of the blink reflex. We detected subclinical cranial abnormalities in 6 diabetic patients (20%). One of them (3.3%) had facial nerve conduction abnormalities, four of them (13.4%) had blink reflex abnormalities, and one of them (3.3%) had both facial nerve and blink reflex abnormalities. Conclusion Subclinical cranial neuropathy can occur in short-duration type 2 diabetes mellitus patients. We detected different blink reflex patterns and facial conduction study abnormalities. We recommend blink reflex and facial nerve conduction studies as simple tests for the early evaluation of neurological subclinical affection in patients with short disease duration of T2DM as they may appear in the absence of peripheral neuropathy.

Otic Organoids Containing Spiral Ganglion Neuron-like Cells Derived from Human-induced Pluripotent Stem Cells as a Model of Drug-induced Neuropathy.

The spiral ganglion of the cochlea is essential for hearing and contains primary bipolar neurons that relay action potentials generated by mechanosensory hair cells. Injury to spiral ganglion neurons (SGNs) causes permanent hearing loss because these cells have limited regenerative capacity. Establishment of human cell-derived inner ear tissue in vitro could facilitate the development of treatments for hearing loss. Here, we report a stepwise protocol for differentiating human-induced pluripotent stem cells (hiPSCs) into otic organoids that contain SGN-like cells and demonstrate that otic organoids have potential for use as an experimental model of drug-induced neuropathy. Otic progenitor cells (OPCs) were created by 2D culture of hiPSCs for 9 days. Otic spheroids were formed after 2D culture of OPCs for 2 days in a hypoxic environment. Otic organoids were generated by 3D culture of otic spheroids under hypoxic conditions for 5 days and normoxic conditions for a further 30 days or more. The protein expression profile, morphological characteristics, and electrophysiological properties of SGN-like cells in otic organoids were similar to those of primary SGNs. Live-cell imaging of AAV-syn-EGFP-labeled neurons demonstrated temporal changes in cell morphology and revealed the toxic effects of ouabain (which causes SGN-specific damage in animal experiments) and cisplatin (a chemotherapeutic drug with ototoxic adverse effects). Furthermore, a cyclin-dependent kinase-2 inhibitor suppressed the toxic actions of cisplatin on SGN-like cells in otic organoids. The otic organoid described here is a candidate novel drug screening system and could be used to identify drugs for the prevention of cisplatin-induced neuropathy.

COVID-19-associated damage of the peripheral nervous system

Based on the available literature data, the article discusses the prevalence of various forms of damage of the peripheral nervous system in COVID-19 and in the post-COVID period. Information about the clinical features and the course of individual cranial neuropathies, chronic dysimmune neuropathies, Guillain-Barré syndrome, drug-induced neuropathies, fine fiber neuropathy, myasthenia gravis and polyneuropathy of critical conditions was systemized in the context of coronavirus infection. SARS-CoV-2 can trigger various stages of pathogenesis, including neuroimmune ones, which cause long-term consequences of COVID-19, including those associated with the damage of the peripheral nervous system. Awareness of COVID-19-associated pathological conditions will allow assessment of the possible risks of damage of the peripheral nervous system, recognize them at early stages and develop more effective approaches for treatment.

The Potential Role of Proinflammatory Cytokines and Complement Components in the Development of Drug-Induced Neuropathy in Patients with Multiple Myeloma.

The launch of novel chemotherapeutic agents—in particular, proteasome inhibitors and immunomodulatory drugs—dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1β, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1β in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.

Mapping Drug-Induced Neuropathy through In-Situ Motor Protein Tracking and Machine Learning.

Chemotherapy can induce toxicity in the central and peripheral nervous systems and result in chronic adverse reactions that impede continuous treatment and reduce patient quality of life. There is a current lack of research to predict, identify, and offset drug-induced neurotoxicity. Rapid and accurate assessment of potential neuropathy is crucial for cost-effective diagnosis and treatment. Here we report dynamic near-infrared upconversion imaging that allows intraneuronal transport to be traced in real time with millisecond resolution, but without photobleaching or blinking. Drug-induced neurotoxicity can be screened prior to phenotyping, on the basis of subtle abnormalities of kinetic characteristics in intraneuronal transport. Moreover, we demonstrate that combining the upconverting nanoplatform with machine learning offers a powerful tool for mapping chemotherapy-induced peripheral neuropathy and assessing drug-induced neurotoxicity.

Neurological presentations of inflammatory bowel diseases

The aim. To characterize the main types of neurological manifestations in inflammatory bowel diseases – Crohn’s disease and ulcerative colitis.Main concepts. Neurological disorders represent an important aspect of extraintestinal inflammatory bowel diseases (IBD) manifestations. According to publications, the incidence of psycho-neurological syndromes varies from 0.25% to 47.50% that apparently depends on the patient’s selection in studies. Neurological signs are not always associated with IBD activity and may precede the manifestation of intestinal inflammation. The most typical include cerebral thromboembolism, peripheral and cranial neuropathies, demyelinating disorders, and cerebral vasculitis. The incidence of ischemic stroke in IBD can reach 6.4%, with approx. 20% of affected persons under 17 y.o. Hemiparesis is the predominant consequence. The risk of intracranial venous thrombosis is increased depending on the activity of intestinal inflammation; this complication can precede manifestation of IBD. Fifty per cent increased risk of multiple sclerosis in IBD patients was shown. The types of peripheral nerves involvement include mononeuropathy, plexopathy, multiple mononeuropathy, compression neuropathy, polyneuropathy and cranial neuropathy. Peripheral neuropathy may be found in 32–37% of IBD patients with a special examination. Demyelinating type, sensory axonal polyneuropathy with thin and thick fibers damage, and motor axonal polyneuropathy with thick fibers damage are observed approximately in equal proportions. It is important to differentiate ‘primary’ neuropathy with vitamin B12 and folic acid deficient, alcoholic, diabetic and drug-induced neuropathy. Clinical improvement is usually seen in the course of immunosuppressive therapy. Cranial neuropathy (mostly of II, VI, VII, VIII of cranial nerves) is described in IBD. Neurological disorders associated with administration of metronidazole, sulfasalazine, cyclosporin A, antibodies to TNF-α and integrins α4 and α4ß7 continue to be highly actual.Conclusion. There is a variety of neurologic syndromes in IBD which represents an important part of extraintestinal manifestations. Mild psychoneurological disorders may be not recognized in time. The majority of symptoms and signs may regress in the course of treatment of IBD and nutrients deficiency correction. The special attention should be paid to neurological status control while the biologic and immunosuppressor agents and metronidazole are administered.

Investigation Into the Role of ERK in Tyrosine Kinase Inhibitor-Induced Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse event that can alter patient treatment options and halt candidate drug development. A case study is presented here describing the preclinical and clinical development of CC-90003, a small molecule extracellular signal-regulated kinase (ERK)1/2 inhibitor investigated as an oncology therapy. In a Phase Ia clinical trial, CC-90003 elicited adverse drug-related neuropathy and neurotoxicity that contributed to discontinued development of CC-90003 for oncology therapy. Preclinical evaluation of CC-90003 in dogs revealed clinical signs and electrophysiological changes consistent with peripheral neuropathy that were reversible. Mice did not exhibit signs of neuropathy upon daily dosing with CC-90003, supporting that rodents generally poorly predict CIPN. We sought to investigate the mechanism of CC-90003-induced peripheral neuropathy using a phenotypic in vitro assay. Translating preclinical neuropathy findings to humans proves challenging as no robust in vitro models of CIPN exist. An approach was taken to examine the influence of CIPN-associated drugs on human induced pluripotent stem cell-derived peripheral neuron (hiPSC-PN) electrophysiology on multielectrode arrays (MEA). The MEA assay with hiPSC-PNs was sensitive to CIPN-associated drugs cisplatin, sunitinib, colchicine, and importantly, to CC-90003 in concordance with clinical neuropathy incidence. Biochemical data together with in vitro MEA data for CC-90003 and 12 of its structural analogs, all having similar ERK inhibitory activity, revealed that CC-90003 disrupted in vitro neuronal electrophysiology likely via on-target ERK inhibition combined with off-target kinase inhibition and translocator protein inhibition. This approach could prove useful for assessing CIPN risk and interrogating mechanisms of drug-induced neuropathy.

Diagnosing peripheral neuropathy in South-East Asia: A focus on diabetic neuropathy.

Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping. Peripheral neuropathy in particular is often misdiagnosed or underdiagnosed because of a lack of awareness amongst both patients and physicians. Furthermore, crude screening tools, such as the 10‐g monofilament, only detect advanced neuropathy and a normal test will lead to false reassurance of those with small fiber mediated painful neuropathy. The underestimation of peripheral neuropathy is highly prevalent in the South‐East Asia region due to a lack of consensus guidance on routine screening and diagnostic pathways. Although neuropathy as a result of diabetes is the most common cause in the region, other causes due to infections (human immunodeficiency virus, hepatitis B or C virus), chronic inflammatory demyelinating polyneuropathy, drug‐induced neuropathy (cancer chemotherapy, antiretrovirals and antituberculous drugs) and vitamin deficiencies (vitamin B1, B6, B12, D) should be actively excluded.

Drug-induced toxic optic neuropathy

Drug-induced optic neuropathy is a group of disorders in which medications cause degeneration of the optic nerve. The true prevalence of drug-induced neuropathy has not been studied, although the percentage of patients who develop optic nerve damage is known for individual medications. The common pathophysiological mechanisms are believed to be mitochondrial damage and imbalance of intracellular and extracellular free radical homeostasis. Typical symptoms of drug-induced neuropathy are reduced visual acuity in the central area, which is often bilateral, visual field disturbances, dyschromatopsia, and edema of the optic nerve head. Early detection of drug-induced optic neuropathy can potentially prevent or minimize serious complications. For patients who develop drug-induced optic neuropathy, treatment is based on timely diagnosis and cancellation of the provoking drug. In most patients, vision usually recovers a few weeks or months after discontinuation of previous therapy, but there have been cases of irreversible vision loss. In addition to withdrawal of the drug that caused optic nerve lesion, treatment of drug-induced neuropathy may include use of drugs and treatment methods prescribed by neurologists for peripheral neuropathy, however, such treatment is seldom based on evidence.

Use of Nerve Conduction Assessments to Evaluate Drug-Induced Peripheral Neuropathy in Nonclinical Species—A Brief Review

The peripheral nervous system (PNS) is subject to a wide range of structural and functional insults including direct damage to axons, loss of myelin, and progressive deficits in saltatory conduction. Drugs that damage the PNS often result in neuropathies that impact the structure and function of targeted nerves. In most cases, both sensory and motor neurons are affected with damage initially evident in the distal extremities. Drug-induced neuropathies are potentially reversible following cessation of treatment, but early stages of neuropathy can be subclinical and asymptomatic making diagnosis difficult. Nerve biopsy is highly validated and provides definitive evidence of nerve injury and corresponding severity; however, it is limited in some respects and electrophysiological measures can complement histopathological assessments and provide a functional measure of potential toxicity. In a drug development setting, nerve conduction assessments are valuable to monitor nerve function longitudinally if nerve damage is suspected or confirmed, and importantly, can be used to monitor progression and/or recovery of a drug-induced neuropathy. This review will summarize the methodology used in nerve conduction assessments as well as discuss data interpretation and considerations for use in nonclinical species. Finally, the use of nerve conduction assessments in nonclinical drug development is discussed.

III. Metabolic, Nutritional, and Drug-induced Neuropathies

糖尿病，尿毒症，栄養欠乏，アルコール依存症ならびに薬物の副作用等による末梢神経障害（ニューロパチー）は，日常診療で遭遇する機会が多いにもかかわらず，見逃されることが多い疾患である．これらのニューロパチーでは，適切な対処によって進行の停止・改善を期待できることから，不可逆的な変化が生じる前に的確な診断を行うことが重要であり，それぞれの原因で起こり得る症候・検査所見等を常に念頭に置いて診療にあたる必要がある．

Interferon-α for Induction and Maintenance of Remission in Eosinophilic Granulomatosis with Polyangiitis: A Single-center Retrospective Observational Cohort Study.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by frequent relapses following induction therapy. Interferon-α (IFN-α) can reverse the underlying Th2-driven immune response and has successfully induced remission in previous reports. We undertook this study to investigate its efficacy and safety in patients with EGPA. We conducted a retrospective monocentric cohort study including 30 patients (16 women) with active EGPA under IFN-α treatment. Primary endpoints were remission induction, occurrence of relapses, prednisolone (PSL) dosage at time of remission, and adverse events. Remission was defined by a Birmingham Vasculitis Activity Score (BVAS) of 0. Pulmonary function tests were recorded at baseline and at time of remission. Health-related quality of life was analyzed by questionnaire at baseline and following 12 months of treatment. At baseline, the median BVAS was 6 (interquartile range 4-13.5) and remission or partial response was achieved in 25/30 patients. After initiation of IFN-α treatment, the median PSL dosages could be reduced from 17.5 mg/day at baseline to 5.5 mg/day at time of remission. Following remission, 17 relapses (5 major) in 16 patients were observed. Pulmonary function tests improved and the time of hospitalization decreased. Adverse events at initiation of treatment were common, but mostly transient. Severe adverse events occurred during treatment in 4 patients (autoimmune hepatitis, n = 1; drug-induced neuropathy, n = 3). IFN-α treatment results in high rate of remission and maintenance in EGPA with significant reduction in oral corticosteroids, although reversible adverse events may occur. IFN-α represents an alternative therapeutic option in cases of refractory to standard treatment.

An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US.

Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%–10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of μ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP.

Niflumic acid, a TRPV1 channel modulator, ameliorates stavudine-induced neuropathic pain.

TRP channels have been discovered as a specialized group of somatosensory neurons involved in the detection of noxious stimuli. Desensitization of TRPV1 located on dorsal root and trigeminal ganglia exhibits analgesic effect and makes it potential therapeutic target for treatment of neuropathic pain. With this background, the present study was aimed to investigate the protective effect of niflumic acid, a TRPV1 modulator, on stavudine (STV)-induced neuropathic pain in rats. Stavudine (50mg/kg) was administered intravenously via tail vein in rats to induce neuropathic pain. Various behavioral tests were performed to access neuropathic pain (hyperalgesia and allodynia) on 7th, 14th, 21st, and 28th days. Electrophysiology (motor nerve conduction velocity; MNCV) and biochemical estimations were conducted after 28th day. Niflumic acid (10, 15, and 20mg/kg) was administered intraperitoneally and evaluated against behavioral, electrophysiological (MNCV), and biochemical alterations in stavudine-treated rats. Pregabalin (30mg/kg) was taken as reference standard and administered intraperitoneally. Four weeks after stavudine injection, rats developed behavioral, electrophysiological (MNCV), and biochemical (oxidative, nitrosative stress, and inflammatory cytokines, TRPV1) alterations. Niflumic acid restored core and associated symptoms of peripheral neuropathy by suppressing oxidative-nitrosative stress, inflammatory cytokines (TNF-α, IL-1β) and TRPV1 level in stavudine-induced neuropathic pain in rats. Pharmacological efficacy of niflumic acid (20mg/kg) was equivalent to pregabalin (30mg/kg). In conclusion, niflumic acid attenuates STV-induced behavioral, electrophysiological and biochemical alterations by manipulating TRP channel activity in two manners: (1) direct antagonistic action against TRPV1 channels and (2) indirect inhibition of TRP channels by blocking oxidative and inflammatory surge. Therefore, NA can be developed as a potential pharmacotherapeutic adjunct for antiretroviral drug-induced neuropathy.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy

Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10-8, adjusted P = 5.88 × 10-7). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.

Guillain-Barre Syndrome Associated with Cyclosporine A

Guillain-Barre syndrome (GBS) is also known as an acute inflammatory demyelinating polyneuropathy (AIDP). It is an immune-mediated polyneuropathy commonly post-infectious in origin that presents with ascending weakness, loss of sensation and deep tendon reflexes resulting from demyelination of peripheral nerve. Drug-induced neuropathy has been describing before and remains a rare clinical entity. Development GBS after an episode of infections such as Campylobacter Jejuni, Epstein Barr Virus, and Mycoplasma pneumonia has been well described. However, GBS associated with Cyclosporine A (CsA) is rarely reported. Here we report a case of GBS developed two weeks after initiation of CsA in a patient with a known case of primary membranous nephropathy and responded well with cessation of the offending drug.