The association of chemotherapy-induced peripheral neuropathy with reduced executive function in chemotherapy-treated cancer survivors: A cross-sectional study.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN. MATERIALS AND METHODS: This cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function. RESULTS: Cancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03). DISCUSSION: In this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors.

Measuring treatment adverse event burden in myasthenia gravis: Single-center prospective evaluation utilizing the Adverse Event Unit (AEU).

INTRODUCTION/AIMS: We developed a patient- and physician-weighted consensus unit called the adverse event unit (AEU) that quantifies and compares adverse event (AE) burden among any group of medications in neurological patients. In this study we evaluated preliminary validity and feasibility of measuring AE burden with the AEU in myasthenia gravis (MG). METHODS: This is a single-center, prospective, 1-year, observational study of adult MG patients presenting for routine care between April 1, 2021 and March 31, 2022. The MG Activities of Daily Living (MG-ADL), the 15-item MG Quality of Life revised (MG-QOL15r), MG-Composite, and AEU scores were obtained at all visits. A priori primary feasibility metric was AEU completion rate equal to (within 3.8%, one-sided 95% confidence interval [CI]) or better than MG-ADL completion rate. Time to administer AEU and MG-ADL/MG-QOL15r, correlation between AEU total score and MG-QOL15r, and median AEU scores for each MG medication were evaluated. RESULTS: Fifty-four patients completed 67 study visits; side effects were reported at 75% of the visits. The study met the primary feasibility endpoint; AEU and MG-ADL were recorded at all visits. Times to administer the AEU (median 5 minutes) and MG-ADL/MG-QOL15r were similar. We observed a weak correlation of 0.29 (95% CI 0.03 to 0.51, P = .032) between AEU and MG-QOL15r scores. Non-statistically significant differences in median AEU scores were observed among MG medications. DISCUSSION: Our data demonstrate preliminary feasibility and validity of using the AEU to measure AE burden in MG. Future studies will compare AE burden among MG treatments and evaluate clinically meaningful AEU scores in MG.

Toxic Neuropathies.

OBJECTIVE: The purpose of this article is to provide an overview and update on the most clinically relevant toxic neuropathies. LATEST DEVELOPMENTS: Broadly, toxic neuropathies were previously quite rare with the notable exception of neuropathy from alcohol or older chemotherapeutics. The development of newer therapies, particularly immunotherapy to treat malignancy, has resulted in a substantial increase in the occurrence of toxic neuropathies that require timely recognition and treatment. The understanding of other toxic neuropathies continues to evolve, such as statin-induced neuropathy, which new evidence suggests is much less common than previously suspected. ESSENTIAL POINTS: Toxic neuropathies can be caused by medications, supplements, and recreational substances that injure peripheral nerves. Medications have evolved in the past 2 decades, as have the types of neuropathies that can be seen as related toxicities. In some areas of medicine, new classes and generations of drugs are associated with a lower incidence of toxic neuropathy.

Executive function is associated with balance and falls in older cancer survivors treated with chemotherapy: A cross-sectional study.

INTRODUCTION: Balance decrements and increased fall risk in older cancer survivors have been attributed to chemotherapy-induced peripheral neuropathy (CIPN). Cognition is also affected by chemotherapy and may be an additional contributing factor to poor balance through changes in executive functioning. We examined the association of executive function with balance and falls in older cancer survivors who had been treated with chemotherapy. MATERIALS AND METHODS: Fifty cancer survivors (aged 65.6 ± 11.5 years; 88% female) who were all treated with chemotherapy were included in this cross-sectional study at a tertiary medical center. Executive function was measured by Trails-B, Stroop, and rapid reaction accuracy, a measure emphasizing rapid inhibitory function. Balance was measured by five sit-to-stand time (5STS), repetitions of sit-to-stand in thirty seconds (STS30), and unipedal stance time (UST), which was the primary balance outcome measure. Self-reported falls in the past year were also recorded and was a secondary outcome. Bivariate analyses were conducted between executive function measures and balance variables. Multivariable models were constructed for UST and falls outcomes and included covariates of age and chemotherapy induced peripheral neuropathy status. RESULTS: Pearson correlations demonstrated significant relationships between two executive function measures (rapid reaction accuracy, Trails-B) and all the balance measures assessed (UST, STS30, and 5STS). Rapid reaction accuracy correlations were stronger than Trails-B. The Stroop measure correlated solely with UST. In multivariable models, rapid reaction accuracy was associated with better UST (standardized regression coefficient: 64.1, p < 0.01), decreased any fall (odds ratio = 0.000901, p = 0.04), and decreased recurrent falls (odds ratio = 0.0000044, p = 0.01). The interaction of CIPN with the inhibitory measures in the prediction of balance was not significant. DISCUSSION: Measures of executive function were associated with balance, but among the executive function tests, rapid reaction accuracy had the strongest correlations to balance and was independently associated with falls. The findings suggest that executive function should be considered when assessing fall risk and developing interventions intended to reduce fall risk in older chemotherapy-treated cancer survivors.

Associations Between Circulating Levels of Myostatin and Plasma ß-Amyloid 42/40 in a Biracial Cohort of Older Adults.

BACKGROUND: Myostatin, a cytokine produced by skeletal muscle, may influence Alzheimer's disease (AD) pathogenesis, but sparse evidence exists in humans. We assessed the association between circulating levels of myostatin at Year 1 and plasma levels of ß-amyloid 42/40 at Year 2, a marker of AD pathology, in a biracial cohort of older adults. METHODS: We studied 403 community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from Memphis, Tennessee, and Pittsburgh, PA. Mean age was 73.8 ± 3 years; 54% were female; and 52% were Black. Serum myostatin levels were measured at Year 1, plasma ß-amyloid 42/40 levels in Year 2 (higher ratio indicating lower amyloid load). Multivariable linear regression analyses tested the association of serum myostatin with plasma levels of ß-amyloid 42/40 adjusted for computed-tomography-derived thigh muscle cross-sectional area, demographics, APOe4 allele, and risk factors for dementia. We tested for 2-way.interactions between myostatin and race or sex; results were stratified by race and sex. RESULTS: In multivariable models, myostatin was positively associated with plasma levels of ß-amyloid 42/40 (standardized regression coefficient: 0.145, p = .004). Results were significant for white men and women (0.279, p = .009, and 0.221, p = .035, respectively) but not for Black men or women; interactions by race and gender were not statistically significant. CONCLUSIONS: Higher serum myostatin was associated with lower amyloid burden, independently of APOe4 alleles, muscle area and other established risk factors for dementia. The role of myostatin in AD pathogenesis and the influence of race should be further investigated.

Chemotherapy-induced peripheral neuropathy onset is associated with early risk of depression and anxiety in breast cancer survivors.

OBJECTIVE: The objective was to assess for an association between chemotherapy-induced peripheral neuropathy (CIPN) onset and development of depression and anxiety in breast cancer (BrCa) survivors. METHODS: A retrospective observational cohort was used and identified from Optum's De-identified Clinformatics® Data Mart Database years 2012-2015. Three groups of women were derived based on BrCa and CIPN status: BrCa+/CIPN+ (n = 244), BrCa+/CIPN- (n = 8870), and BrCa-/CIPN- (n = 1,125,711). The ratio of the prevalence ratios (RPR) determined if the change in risk of depression and anxiety from the 12-month preindex period to postindex period I (0-6 months) and II (7-12 months) was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. RESULTS: The adjusted RPR for depression was significantly elevated for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN- for postindex periods I (RPR = 1.35 [1.10,1.65] and 1.33 [1.08,1.63], respectively) and II (RPR = 1.53 [1.21,1.94] and 1.50 [1.17,1.93], respectively). The RPR for anxiety was significantly elevated for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN- for postindex periods I (RPR = 1.37 [1.12,1.67] and 1.31 [1.06,1.61], respectively) and II (RPR = 1.41 [1.13,1.76] and 1.28 [1.02,1.62], respectively). CONCLUSIONS: Among BrCa survivors, CIPN onset is associated with a subsequent increased 12-month risk of depression and anxiety. Depression and anxiety screening should be considered in BrCa+/CIPN+ survivors, particularly given their known impact on fall risk. The observed association between CIPN and an increased risk of depression and anxiety should be further studied in prospective studies.

Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: Systematic review and evidence-based recommendations.

Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.

Chemotherapy-induced peripheral neuropathy increases nontraumatic fracture risk in breast cancer survivors.

Chemotherapy is a common treatment for breast cancer (BrCa) and can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN contributes to falls, and is thus a potential risk factor for nontraumatic fractures (NTFx); yet, the effect of CIPN on NTFx risk has not been examined for BrCa survivors. We therefore investigated the association between CIPN and NTFx in BrCa survivors. Data were extracted from Optum's Deidentified Clinformatics® Data Mart Database years 2010-2015 in this retrospective cohort study. Among women, three groups were derived based on BrCa and CIPN status: BrCa+/CIPN+ (primary group of interest), BrCa+/CIPN- (first comparison group), and BrCa-/CIPN- (second comparison group). After propensity score matching the comparison groups to BrCa+/CIPN+ at a ratio of 1:11 (BrCa:control) for demographics, osteoporosis, glucocorticoid medication, comorbidities, and cancer-related variables for BrCa+/CIPN-, 1-year incidence rate (IR) of NTFx was determined for each group. The incident rate ratio (IRR) determined if the IR for NTFx was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. Cox proportional hazards regression models estimated the hazard ratios (HRs) after adjusting for covariates that were unable to be matched for. The crude IR (95% confidence interval [CI]) of NTFx was 4.54 (2.32-6.77) for BrCa+/CIPN+ (n = 359), 2.53 (2.03-3.04) for BrCa+/CIPN- (n = 3949), and 1.76 (1.35-2.18) for BrCa-/CIPN- (n = 3949). The crude IRR of NTFx was significantly elevated for BrCa+/CIPN+ as compared to BrCa+/CIPN- (IRR = 1.80; 95% CI, 1.06-3.05) and BrCa-/CIPN- (IRR = 2.58; 95% CI, 1.50-4.44). The elevated rate of NTFx for BrCa+/CIPN+ remained unchanged after adjusting for aromatase inhibitors compared to BrCa+/CIPN- (HR = 1.79; 95% CI, 1.06-3.04). Female BrCa survivors have an increased 1-year IR of NTFx after the onset of CIPN, suggesting that CIPN is an additive burden on NTFx risk among BrCa survivors. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Aromatase inhibitor use, side effects and discontinuation rates in gynecologic oncology patients.

OBJECTIVE: Aromatase inhibitors (AI) are frequently prescribed in gynecologic oncology. We sought to define the frequency and duration of AI use, characterize AI side effects and determine the reasons for discontinuation in these patients. METHODS: Uterine and ovarian cancer patients with AI use for gynecologic cancer therapy were identified retrospectively. Data were abstracted from the electronic medical record, including cancer type, stage, prior cancer treatments, body mass index, concurrent medications, prevalence of AI side effects before and during AI therapy, length of AI treatment and reason for AI discontinuation. RESULTS: 146 women received AI therapy, with 68 for ovarian cancer (46.6%) and 78 for uterine cancer (53.4%). The majority (71.9%) had advanced stage disease at diagnosis. 54.1% noted AI-associated side effects within the first three visits after starting AI therapy. The most common side effects were arthralgias (29.5%), hot flashes (25.3%), new/worsening fatigue (16.4%), muscle or joint stiffness (8.2%) and myalgias (6.8%). The mean duration of therapy was 14.7 months. Gabapentin or selective serotonin reuptake inhibitor (SSRI) use was associated with decreased musculoskeletal side effects (gabapentin: p < .001, OR 0.88, 95% CI 0.83-0.94; SSRI: p < .001, OR 0.82, 95% CI 0.77-0.89). The most common reason for AI discontinuation was disease progression (87.9%), with 5.0% discontinuing due to side effects and 7.1% for other reasons. CONCLUSION: AI therapy for gynecologic cancers is frequently associated with musculoskeletal side effects, but rarely leads to treatment discontinuation. Thus, AI side effects should be assessed in gynecologic cancer patients to allow potential mitigation of symptoms through adjunct therapies.

Primary cancer location predicts predominant level of brachial plexopathy.

BACKGROUND: Changes in radiation therapy practice and cancer incidence bring into question prior evidence suggesting that radiation therapy predominantly injures the brachial plexus upper trunk, while tumor invasion typically injures the lower trunk. METHODS: We reviewed electrodiagnostic brachial plexopathy reports in cancer survivors for predominant trunk involvement, injury mechanism (tumor invasion vs radiation), and primary cancer location. RESULTS: Fifty-six cases of cancer-associated brachial plexopathy were identified. There was no relationship between injury mechanism and brachial plexus injury level. However, primary cancer location superior/inferior to the clavicle increased the odds of predominantly upper/lower trunk involvement by a factor of 60.0 (95% confidence interval: 7.9, 1401, respectively). CONCLUSIONS: Cancers superior/inferior to the clavicle increase the likelihood of predominantly upper/lower trunk plexopathy, respectively, regardless plexus injury mechanism. These findings contrast with older work, possibly due to more precise radiation therapy techniques and increased incidence of radiosensitive head and neck cancers.

Predictors of operative failure in parathyroidectomy for primary hyperparathyroidism.

INTRODUCTION: Many adjuncts guide surgical decision making in parathyroidectomy, yet their independent associations with outcome are poorly characterized. We examined a broad range of perioperative factors and used multivariate techniques to identify independent predictors of operative failure (persistent disease) after parathyroidectomy. METHODS: This was a retrospective review of 2239 patients with primary hyperparathyroidism who underwent parathyroidectomy at a single-center from 1999 to 2014. We used multivariate logistic regress to measure associations between multiple perioperative factors and an operative failure (persistent hypercalcemia). RESULTS: Operative failure was identified in 67 patients (3.0%). The following variables were independently associated with operative failure on multivariate analysis: IOPTH criteria met (protective, OR = 0.22, P < 0.001), preoperative calcium (risk factor, OR = 2.27 per unit increase, P < 0.001), weight of excised gland(s) (protective, OR = 0.70 per two-fold increase, P = 0.003), and preoperative PTH (protective, OR = 0.55 per two-fold increase, P = 0.008). CONCLUSION: In addition to the well-established IOPTH criteria, we suggest that consideration of the above independent perioperative risk factors may further inform surgical decision-making in parathyroidectomy.

Correlation between prenatal urinary matrix metalloproteinase activity and the degree of kidney damage in a large animal model of congenital obstructive uropathy.

BACKGROUND/PURPOSE: We aimed to determine whether the profile of matrix metalloproteinase (MMP) activity in fetal urine correlates with the degree of kidney damage in the setting of congenital obstructive uropathy. METHODS: Fetal lambs underwent either a sham operation or creation of a complete urinary tract obstruction. Necropsies were performed before term, when urinary MMP profiling was performed by zymography; and kidney damage was assessed histologically by multiple semiquantitative analyses and histomorphometric measurements. RESULTS: There was a significant correlation between inner medullary thickness and MMP-9 (P = .005) and 63-kd MMP-2 (P = .019) activities. In like manner, the only MMPs associated with kidney fibrosis were MMP-9 and 63-kd MMP-2. Matrix metalloproteinase-9 activity was a highly significant independent predictor of the total combined kidney fibrosis score (P < .001) as well as of higher fibrosis grades in each of 6 kidney areas analyzed (all with P < .01). The activity of 63-kd MMP-2 correlated significantly with higher fibrosis in select areas. CONCLUSIONS: In a fetal ovine model, urinary MMP activity correlates with the degree of kidney damage. The presence of MMP-9 (in particular) and that of 63-kd MMP-2 are independent predictors of severity. Prenatal urinary MMP profiling may enhance patient stratification and counseling in the setting of congenital obstructive uropathy.

Prenatal urinary matrix metalloproteinase profiling as a potential diagnostic tool in fetal obstructive uropathy.

BACKGROUND/PURPOSE: The diagnostic evaluation, patient stratification, and prenatal counseling for congenital obstructive uropathy remain sub-optimal. Matrix metalloproteinase (MMP) expression profiles are emerging as a valuable diagnostic tool in assorted disease processes. We sought to determine whether congenital obstructive uropathy impacts MMP expression in fetal urine. METHODS: Fetal lambs (n = 25) were divided in two groups: group I (n = 12) underwent a sham operation and group II (n = 13) underwent creation of a complete urinary tract obstruction. Gelatin zymography panels for 4 MMP species were performed on fetal urine in both groups at comparable times post-operatively. Statistical analysis was by the Fisher's exact test (P < .05). RESULTS: Overall fetal survival was 80% (20/25). A variety of significant differences in MMP expression between the two groups were identified. The following profiles were present only in obstructed animals: any MMP other than MMP-2 (P = .029), including any MMP other than 63 kDa and 65 kDa (P = .009); 2 or more MMPs excluding MMP-2s (0.029); and 3 or more MMPs (P = .029). CONCLUSIONS: Limited matrix metalloproteinase expression is present in the urine of normal ovine fetuses. Fetal obstructive uropathy impacts urinary MMP expression in various distinguishable patterns. Prenatal urinary MMP profiling may become a practical and valuable diagnostic tool in the evaluation of congenital obstructive uropathy.