Browsing by Subject "Peripheral neuropathy"

Now showing 1 - 7 of 7
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    Charcot-Marie-Tooth gene, SBF2, associated with taxaneinduced peripheral neuropathy in African Americans
    (Impact Journals, 2016-12-13) Schneider, Bryan P.; Lai, Dongbing; Shen, Fei; Jiang, Guanglong; Radovich, Milan; Li, Lang; Gardner, Laura; Miller, Kathy D.; O’Neill, Anne; Sparano, Joseph A.; Xue, Gloria; Foroud, Tatiana; Sledge Jr., George W.; Department of Medicine, IU School of Medicine
    PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. EXPERIMENTAL DESIGN: Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. RESULTS: Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. CONCLUSION: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
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    Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103
    (American Association for Cancer Research, 2023) Shen, Fei; Jiang, Guanglong; Philips, Santosh; Gardner, Laura; Xue, Gloria; Cantor, Erica; Ly, Reynold C.; Osei, Wilberforce; Wu, Xi; Dang, Chau; Northfelt, Donald; Skaar, Todd; Miller, Kathy D.; Sledge, George W.; Schneider, Bryan P.; Medicine, School of Medicine
    Purpose: Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed. Experimental design: Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3-4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN. Results: Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10-6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN. Conclusions: Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.
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    Evaluating the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on perceived ability to work in breast cancer survivors during the first year post-treatment.
    (Springer, 2016) Zanville, Noah R.; Nudelman, Kelly N. H.; Smith, Dori J.; Von Ah, Diane; McDonald, Brenna C.; Champion, Victoria L.; Saykin, Andrew J.; IU School of Nursing
    Purpose: To describe the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on breast cancer survivors’ (BCS) perceived ability to work post-treatment. Methods: The sample included 22 chemotherapy-treated (Ctx+) and 22 chemotherapy-naïve (Ctx−) female BCS. Data was collected at the following three time points: baseline (post-surgery, pre-chemotherapy), 1 month (1 M) post-chemotherapy, and approximately 1 year (1 Y) later. The presence, frequency, number, and severity of CIPN-sx were self-reported using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity questionnaire (FACT/GOG-Ntx) version 4, a validated 11-item CIPN measure. Perceived ability to work was measured using an item from the Functional Well-Being subscale of the FACT/GOG-Ntx. Results: At 1 Y, more than 50 % of Ctx+ reported discomfort, numbness, or tingling in their hands or feet; weakness; or difficulty feeling small objects. The presence, number, and severity of these symptoms were correlated with being less able to work for Ctx+ at 1 M but not 1 Y. Results of a regression analysis using CIPN-sx to predict work ability found that models combining (1) hand numbness and trouble feeling small objects, (2) trouble buttoning buttons and trouble feeling small objects, (3) foot numbness and foot pain, (4) foot numbness and trouble walking, and (5) trouble hearing and hand pain each predicted survivors who were “not at all” able to work at 1 M. Conclusions: Unresolved CIPN-sx may play a role in challenges working for BCS post-treatment. These findings highlight the need for research to explore the impact that CIPN-sx have on BCS’ ability to work, as well as the development of interventions to improve work function in BCS with CIPN-sx.
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    Leveraging GWAS data derived from a large cooperative group trial to assess the risk of taxane-induced peripheral neuropathy (TIPN) in patients being treated for breast cancer: Part 2—functional implications of a SNP cluster associated with TIPN risk in patients being treated for breast cancer
    (Springer, 2023-02-21) Lustberg, Maryam; Wu, Xuan; Fernández-Martínez, Juan Luis; de Andrés-Galiana, Enrique J.; Philips, Santosh; Leibowitz, Jeffrey; Schneider, Bryan; Sonis, Stephen; Medicine, School of Medicine
    Introduction: Using GWAS data derived from a large collaborative trial (ECOG-5103), we identified a cluster of 267 SNPs which predicted CIPN in treatment-naive patients as reported in Part 1 of this study. To assess the functional and pathological implications of this set, we identified collective gene signatures were and evaluated the informational value of those signatures in defining CIPN's pathogenesis. Methods: In Part 1, we analyzed GWAS data derived from ECOG-5103, first identifying those SNPs that were most strongly associated with CIPN using Fisher's ratio. After identifying those SNPs which differentiated CIPN-positive from CIPN-negative phenotypes, we ranked them in order of their discriminatory power to produce a cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross validation (LOOCV). An uncertainty analysis was included. Using the best predictive SNP cluster, we performed gene attribution for each SNP using NCBI Phenotype Genotype Integrator and then assessed functionality by applying GeneAnalytics, Gene Set Enrichment Analysis, and PCViz. Results: Using aggregate data derived from the GWAS, we identified a 267 SNP cluster which was associated with a CIPN+ phenotype with an accuracy of 96.1%. We could attribute 173 genes to the 267 SNP cluster. Six long intergenic non-protein coding genes were excluded. Ultimately, the functional analysis was based on 138 genes. Of the 17 pathways identified by Gene Analytics (GA) software, the irinotecan pharmacokinetic pathway had the highest score. Highly matching gene ontology attributions included flavone metabolic process, flavonoid glucuronidation, xenobiotic glucuronidation, nervous system development, UDP glycosyltransferase activity, retinoic acid binding, protein kinase C binding, and glucoronosyl transferase activity. Gene Set Enrichment Analysis (GSEA) GO terms identified neuron-associated genes as most significant (p = 5.45e-10). Consistent with the GA's output, flavone, and flavonoid associated terms, glucuronidation were noted as were GO terms associated with neurogenesis. Conclusion: The application of functional analyses to phenotype-associated SNP clusters provides an independent validation step in assessing the clinical meaningfulness of GWAS-derived data. Functional analyses following gene attribution of a CIPN-predictive SNP cluster identified pathways, gene ontology terms, and a network which were consistent with a neuropathic phenotype.
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    Polyneuropathy: A Rare and Challenging Presentation of Essential Mixed Cryoglobulinemia
    (Sage, 2021) Taha, Ahmed; Taha, Mohamed; Ahmed, Roaa; Meckler, Gianna; Aeddula, Narothama; Meckler, Jason; Medicine, School of Medicine
    A 49-year-old male presented with acute chronic sensory motor bilateral lower extremity polyneuropathy. Electromyography showed bilateral acute sensory motor axonal polyneuropathy. Lumbar spine magnetic resonance imaging showed diffuse bone marrow replacement and bilateral ankylosing spondylitis. Laboratory workup revealed elevated inflammatory markers and low G6PD (glucose-6-phosphate dehydrogenase) level. Due to elevated acute phase reactants, inflammatory polyneuropathy was suspected; patient was treated accordingly with resolution of neuropathy. Three months later, he relapsed and presented with disabling polyneuropathy and renal impairment, which prompted renal biopsy. Renal histopathology revealed the, otherwise mysterious, etiology, essential mixed cryoglobulinemia. Essential mixed cryoglobulinemia was not considered initially due to the absence of classic systemic manifestations of autoimmune disorders.
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    Systems Pharmacology Modeling Identifies a Novel Treatment Strategy for Bortezomib-Induced Neuropathic Pain
    (Frontiers Media, 2022-01-19) Bloomingdale, Peter; Meregalli, Cristina; Pollard, Kevin; Canta, Annalisa; Chiorazzi, Alessia; Fumagalli, Giulia; Monza, Laura; Pozzi, Eleonora; Alberti, Paola; Ballarini, Elisa; Oggioni, Norberto; Carlson, Louise; Liu, Wensheng; Ghandili, Mehrnoosh; Ignatowski, Tracey A.; Lee, Kelvin P.; Moore, Michael J.; Cavaletti, Guido; Mager, Donald E.; Medicine, School of Medicine
    Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.
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    Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2-negative breast cancer: A trajectory analysis of adverse events
    (Wiley, 2021) Ip, Edward H.; Saldana, Santiago; Miller, Kathy D.; Carlos, Ruth C.; Gareen, Ilana F.; Sparano, Joseph A.; Graham, Noah; Zhao, Fengmin; Lee, Ju-Whei; O’Connell, Nathaniel S.; Cella, David; Peipert, John D.; Gray, Robert J.; Wagner, Lynne I.; Medicine, School of Medicine
    Background: E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease-free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient-reported outcomes (PROs). Methods: Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All-grade and high-grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE-related and any-reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy-Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. Results: More than half of all AEs (57.5%) were low-grade. A cluster of patients with broad and mixed AE (all-grade) trajectory grades was significantly associated with any-reason early treatment discontinuation (odds ratio [OR], 2.87; P = .01) as well as AE-related discontinuation (OR, 4.14; P = .001). This cluster had the highest count of all-grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well-being in comparison with a trajectory of no or few AEs (P < .01). A high-grade AE trajectory did not predict discontinuations. Conclusions: A sustained and cumulative burden of across-the-board toxicities, which were not necessarily all recognized as high-grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all-grade AEs may require additional attention for preventing deterioration in their physical well-being.