Association of fall rate and functional status by APOE genotype in cancer survivors after exercise intervention.

PURPOSE/OBJECTIVES: Cancer treatment survivors often report impaired functioning and increased falls. Not all survivors experience the same symptom burden, suggesting individual susceptibilities. APOE genotype is a potential genetic risk factor for cancer treatment related side effects. Lifestyle factors such as physical activity can mitigate the effect of APOE genotype on measures of clinical interest in individuals without a history of cancer. We tested the hypothesis that APOE genotype influences cancer treatment related side effects and symptoms as well as response to exercise intervention. MATERIALS AND METHODS: Data from a subsample of a study of fall prevention exercise in post-treatment female cancer survivors aged 50-75 years old (https://clinicaltrials.gov NCT01635413) were used to conduct a secondary data analysis. ApoE genotype was determined by serum sampling. Physical functioning, frequency of falls, and symptom burden were assessed using survey instruments. RESULTS: Data from 126 female cancer survivors a median of 49 months out from cancer diagnosis were analyzed. ApoE4 carriers trended toward a higher fall rate at baseline (p = 0.059), but after exercise intervention had a fall rate lower than E4 non-carriers both immediately after structured intervention (p = 0.013) and after 6 months of follow up (p = 0.002). E2 carriers did not show improved measures of depressive symptoms and self-report disability after exercise intervention. E3 homozygotes showed increased self report physical activity after the 6 month exercise intervention, but E4 and E2 carriers did not. CONCLUSIONS: APOE genotype may modulate cancer treatment related side effects and symptoms and response to exercise intervention.

Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.

DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3-4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.

Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice.

BACKGROUND: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. OBJECTIVE: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. METHODS: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. RESULTS: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer's disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. CONCLUSION: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

Effects of Chronic Secondhand Smoke (SHS) Exposure on Cognitive Performance and Metabolic Pathways in the Hippocampus of Wild-Type and Human Tau Mice.

BACKGROUND: Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3-4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline. OBJECTIVE: The goal of this study was to assess the effects of chronic SHS exposure (10 months' exposure to ∼30 mg/m3) on behavioral and cognitive function, metabolism, and neuropathology in mice. METHODS: Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExpose™ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression. RESULTS: Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, IGF1ß, and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice. DISCUSSION: The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. https://doi.org/10.1289/EHP8428.

Retinal thickness fluctuations in patients receiving fluocinolone acetonide implant for diabetic macular edema.

Objectives: To evaluate central foveal thickness (CFT) variability and accompanying changes in visual acuity (VA) 12 months before and after treatment with the 190 mcg fluocinolone acetonide (FAc) intravitreal implant for diabetic macular edema (DME).Methods: The Iluvien Clinical Evidence cohort study in the United Kingdom (ICE-UK) investigated the effectiveness of the FAc implant in people treated at 13 hospitals from April 2013 to April 2015. The following parameters were calculated for CFT for each patient: mean, standard deviation (SD), retinal thickness amplitude (RTA, the difference between maximum and minimum values), and coefficient of variation (CV).Results: In 149 eyes with ≥2 CFT observations both before and after FAc implantation, the median VA was 50 ETDRS letters at implantation. Mean CFT was 487 µm at implantation and 135 µm at 12 months post-implant. Before implantation, the mean CV and mean SD for CFT were 24.6% and 112 µm, respectively; the mean RTA was 254 µm. A statistically significant (p < .001) decrease in all three parameters was observed after implantation (18.3%, 68.2 µm and 146 µm, respectively). There was an association between CFT change between extremes and the corresponding change in VA (Pearson's correlation coefficient, r = -0.292, p < .001, prior to the implant; r = -0.379, p < .001, post-implant).Conclusions: After accounting for the reduction in CFT, retinal thickness stabilized following FAc implantation. There might be VA benefits in reducing variability in CFT over time. This merits further exploration but would require more frequent CFT observations in order to properly determine patterns of retinal thickness variability.

Comparison of data characterizing the clinical effectiveness of the fluocinolone intravitreal implant (ILUVIEN) in patients with diabetic macular edema from the real world, non-interventional ICE-UK study and the FAME randomized controlled trials.

Objective: To compare the effectiveness and safety of the fluocinolone acetonide (FAc) intravitreal implant between the observational Iluvien Clinical Evidence study in the United Kingdom (ICE-UK) and the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) randomized controlled trials (RCTs) in people with diabetic macular edema (DME). Clinical Trials Registration: NCT00344968. Methods: This study selected patients randomized to receive 0.2 µg/day FAc insert (FAc treated eyes) or sham injection (control eyes) from the FAME RCTs, and patients' first FAc treated eye and non-FAc treated fellow (control) eye from the ICE-UK study. Outcomes included change in visual acuity (VA), central foveal thickness (CFT), and intraocular pressure (IOP). Results: After 12 months follow-up, mean change in VA was 5.0 letters improvement (p < .001) and 1.6 letters improvement (p = .003) in FAME FAc treated and control eyes, and 3.8 letters (p = .012) and -2.1 letters (p = .056) in ICE-UK FAc treated and control eyes, respectively. Mean change in CFT was -144 µm (p < .001) vs -72 µm (p < .001) in FAME FAc treated and control eyes and -113 µm (p < .001) vs -13 µm (p < .001) in ICE-UK FAc treated and control eyes. For eyes with a follow-up of 12 months, 77 (22.3%) and 15 (8.6%) FAME FAc treated and control eyes and 25 (18.7%) and six (4.3%) ICE-UK FAc treated and control eyes required emergent IOP-lowering therapy. Conclusions: Statistically significant improvements in VA 12 months after FAc implantation were observed in both the real-world study and in the RCTs. The improvement in VA and CFT in the RCTs was marginally greater than in the real-world study; however, recruits in the real-world study had more severe visual morbidity at baseline. Whilst there were many changes in the care of people with DME over this time, these data all support the value of treatment with FAc intravitreal implant.

Evaluation of the clinical effectiveness of fluocinolone acetonide 190 µg intravitreal implant in diabetic macular edema: a comparison between study and fellow eyes.

OBJECTIVES: To compare visual and anatomical outcomes between eyes treated with fluocinolone acetonide (FAc) 190 µg intravitreal implant for clinically significant chronic diabetic macular edema (DME) and fellow eyes not treated with FAc implant using data from the Iluvien Clinical Evidence study in the UK (ICE-UK) study. METHODS: In this retrospective cohort study, data on people attending hospital eye services and treated with the FAc implant between April 1, 2013 and April 15, 2015 were collected. Changes in visual acuity (VA), central foveal thickness (CFT) and intraocular pressure (IOP) were compared between study eyes (intervention) and fellow eyes. RESULTS: A total of 208 people were selected. Mean age was 68.1 years and 62% were male. Mean change in VA was -0.09 LogMAR units for study eyes and 0.04 LogMAR units for fellow eyes at 12 months post-implant (p < .001). Over the same period, ≥5 letter, ≥10 letter and ≥15 letter improvements in Early Treatment Diabetic Retinopathy Study (ETDRS) score were achieved by more FAc treated eyes than by fellow eyes (41% versus 23%, p < .001; 28% versus 11%, p < .001; and 18% versus 4%, p < .001 at 12 months, respectively). Differences in the mean change in CFT (-113 µm versus -13 µm, p < .001) and IOP (3.2 mmHg versus -0.2 mmHg, p < .001) were also observed between study and fellow eyes at 12 months. CONCLUSION: Visual acuity improved in study eyes over the 12 months following FAc implant and worsened in fellow eyes. Over the same period, study eyes showed a larger improvement in central foveal thickness. Intraocular pressure worsened in study eyes only. Change in visual acuity, central foveal thickness and intraocular pressure between FAc implant and the end of the 12-month follow-up period differed significantly between study and fellow eyes.

Health-economic evaluation of fluocinolone acetonide 190 µg implant in people with diabetic macular edema.

OBJECTIVES: To assess healthcare resource use and costs of treating people with clinically significant diabetic macular edema (DME) with fluocinolone acetonide (FAc) 190 µg intravitreal implant in routine clinical practice. METHODS: The retrospective Iluvien Clinical Evidence (ICE-UK) study collected data on people prescribed the FAc implant in any one of 13 ophthalmology centers between April 1, 2013 and April 15, 2015. Data were collected for 12 months before and after implantation. Standard UK costs were attributed to healthcare resource use. RESULTS: In total, 208 people contributing 233 FAc-treated eyes were selected. Mean age was 68.1 years and 62% were male. The mean (standard deviation, SD) number of anti-vascular endothelial growth factor (anti-VEGF) injections per FAc treated eye in the 12 months prior to implant was 2.8 (2.5), decreasing to 0.6 (1.4) for the same period after implant (p < .001). The corresponding figures for other steroid injections (dexamethasone and triamcinolone) were 0.14 (0.4) before and 0.08 (0.4) after implant (p = .016). There was no statistically significant difference in the number of laser therapies required in the 12 months before and after FAc implant (mean = 0.12 vs 0.11, respectively; p = .626). Overall, mean (SD) healthcare costs were £2,691 (£1,850) before and £1,239 (£1,203) after FAc implant (p < .001). The unit drug and administration cost per FAc implant was £5,680. CONCLUSIONS: Excluding the cost of the FAc implant, healthcare costs were significantly reduced in the 12 months post-implant. FAc implant has a duration of 3 years. This needs to be considered when interpreting the cost associated with the FAc implant.

Evaluation of the clinical effectiveness in routine practice of fluocinolone acetonide 190 µg intravitreal implant in people with diabetic macular edema.

OBJECTIVE: The aim of the Iluvien Clinical Evidence study in the UK (ICE-UK) was to assess the real-world effectiveness of fluocinolone acetonide (FAc) 190 µg intravitreal implant for the treatment of clinically significant chronic diabetic macular edema (DME) in routine clinical practice. METHODS: This retrospective study collected data from patient medical records in 13 ophthalmology centers for people with DME prescribed FAc intravitreal implant between April 1, 2013 and April 15, 2015. Visual acuity (VA) and intraocular pressure (IOP) measurements were collected for 12 months prior to and after implant. RESULTS: Two hundred and eight people, contributing 233 eyes, treated with FAc implant were included. Mean age was 68.1 years and 62% were male. In the 12 months prior to FAc implant, VA declined. Median (interquartile range, IQR) VA was 0.66 (0.48-1.00) LogMAR units (equivalent to 52.0 ETDRS letters) at implant, improving to 0.60 (0.38-0.90) LogMAR units (55.0 letters) at 12 months post-implant (p < 0.001). In total, 44%, 30%, and 18% of people achieved an improvement in ETDRS score of ≥5, ≥10, and ≥15 letters, respectively, over the same period. A small but significant (p < .001) increase in median IOP was observed (median = 15.0, IQR = 13.0-18.0 mmHg at implant to 18.0, 15.0-21.0 mmHg at 12 months). In the 12 months following implant, additional IOP-lowering therapy was prescribed in 15% of subjects previously not requiring such therapy. CONCLUSION: Following FAc implant, an overall significant improvement in VA was observed over a period of 12 months, accompanied by a significant but small increase in IOP.

Patterns of retinal thickness prior to and following treatment with fluocinolone acetonide 190 µg intravitreal implant for diabetic macular edema.

OBJECTIVES: To compare retinal thickness before and after treatment with the fluocinolone acetonide (FAc) 190 µg intravitreal implant in people with diabetic macular edema (DME) using data from the Iluvien Clinical Evidence study in the UK (ICE-UK). METHODS: For this retrospective cohort study, data on people attending any one of 13 participating ophthalmology departments and treated with FAc intravitreal implant between April 1, 2013 and April 15, 2015 were collected for 12 months prior to and at least 12 months after implantation. Cross-sectional and longitudinal patterns of central foveal thickness (CFT) were compared before and after FAc implant. RESULTS: There were 208 people who contributed data from 233 individual eyes treated with the FAc implant. Mean age was 68.1 years and 62% were male. Median (interquartile range) CFT decreased from 462 µm (354-603 µm) at time of implant to 309 µm (222-433 µm) at 12 months post-implant (p < .001). Over the same period, a reduction of ≥10%, ≥25%, and ≥50% in CFT was observed in 113 (65%), 87 (50%), and 37 (21%) treated eyes, respectively. Eyes with a CFT of ≥400 µm at the time of implant were significantly more likely to achieve a reduction in CFT of ≥10%, ≥25%, and ≥50% at 12 months (all p < .001) compared with eyes with a CFT of <400 µm at implant. Both retinal thickness and changes in retinal thickness were loosely correlated with visual acuity. CONCLUSION: A marked reduction in retinal thickness was observed in people following FAc intravitreal implant for DME. The response was related to the degree of retinal thickness prior to treatment.

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: A retrospective cohort study.

AIMS: Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide-based regimens prescribed as once-weekly (EQW) or twice-daily (EBID) formulations, compared with regimens based on basal insulin (BI). MATERIALS AND METHODS: This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes-related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. RESULTS: Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient-year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91-0.92) for EQW and 0.82 (95% CI, 0.82-0.82) for EBID. Corresponding costs for the propensity-matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80-0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84-0.84) for EBID vs BI. CONCLUSION: Overall, exenatide once-weekly and twice-daily-based regimens were associated with reduced healthcare resource use and costs compared with basal-insulin-based regimens.

Cost of dose escalation in people with rheumatoid arthritis treated with tumour necrosis factor inhibitors across Europe.

OBJECTIVES: The aim of this study was to calculate the marginal cost of dose escalation in people with rheumatoid arthritis treated with tumour necrosis factor (TNF) inhibitors across Europe. METHODS: The proportion of people who escalate their dose of TNF inhibitor and the average percentage increase in TNF inhibitor cost associated with escalators versus non-escalators was calculated from previously published estimates, weighted by the sample size for each study. The number of people with rheumatoid arthritis treated with TNF inhibitors and the corresponding total drug sales were obtained for five European countries from Decision Resources' Pharmacor Market Forecast. Method 1 assumed that total sales of a TNF inhibitor represented the cost of an escalator multiplied by the number of escalators plus the cost of a non-escalator multiplied by the number of non-escalators. Method 2 assumed that the drug cost per day used to forecast total sales was calculated using the dose of TNF inhibitor used by non-escalators. The marginal cost of TNF inhibitor dose escalation was estimated by multiplying the difference in cost between escalators and non-escalators by the number of escalators. RESULTS: The estimated increase in TNF inhibitor costs associated with dose escalation in people with rheumatoid arthritis across five European countries (Germany, France, UK, Spain and Italy) was €51.5-54.4 million for adalimumab, €44.8-52.8 million for infliximab and €5.8-5.9 million for etanercept. CONCLUSIONS: Dose escalation of the TNF inhibitors adalimumab, etanercept and infliximab in people with rheumatoid arthritis has resulted in an increase in TNF inhibitor costs across five European countries.

Association between Insulin Monotherapy versus Insulin plus Metformin and the Risk of All-Cause Mortality and Other Serious Outcomes: A Retrospective Cohort Study.

AIMS: To determine if concomitant metformin reduced the risk of death, major adverse cardiac events (MACE), and cancer in people with type 2 diabetes treated with insulin. METHODS: For this retrospective cohort study, people with type 2 diabetes who progressed to insulin with or without metformin from 2000 onwards were identified from the UK Clinical Practice Research Datalink (≈7% sample of the UK population). The risks of all-cause mortality, MACE and incident cancer were evaluated using multivariable Cox models comparing insulin monotherapy with insulin plus metformin. We accounted for insulin dose. RESULTS: 12,020 subjects treated with insulin were identified, including 6,484 treated with monotherapy. There were 1,486 deaths, 579 MACE (excluding those with a history of large vessel disease), and 680 cancer events (excluding those in patients with a history of cancer). Corresponding event rates were 41.5 (95% CI 39.4-43.6) deaths, 20.8 (19.2-22.5) MACE, and 21.6 (20.0-23.3) cancer events per 1,000 person-years. The adjusted hazard ratios (aHRs) for people prescribed insulin plus metformin versus insulin monotherapy were 0.60 (95% CI 0.52-0.68) for all-cause mortality, 0.75 (0.62-0.91) for MACE, and 0.96 (0.80-1.15) for cancer. For patients who were propensity-score matched, the corresponding aHRs for all-cause mortality and cancer were 0.62 (0.52-0.75) and 0.99 (0.78-1.26), respectively. For MACE, the aHR was 1.06 (0.75-1.49) prior to 1,275 days and 1.87 (1.22-2.86) after 1,275 days post-index. CONCLUSIONS: People with type 2 diabetes treated with insulin plus concomitant metformin had a reduced risk of death and MACE compared with people treated with insulin monotherapy. There was no statistically significant difference in the risk of cancer between people treated with insulin as monotherapy or in combination with metformin.

Diabetes and Cancer.

Diabetes and cancer are common conditions, affecting 384 million and 33 million people worldwide, respectively. Therefore, there is great potential for overlap, with people with diabetes also developing cancer and vice versa. However, people with diabetes may be at increased risk of developing cancer when compared with the general population. This is due to both shared risk factors associated with the two diseases and the metabolic derangements associated with diabetes, such as hyperglycaemia, insulin resistance, hyperinsulinaemia and oxidative stress. Glucose-lowering therapies may influence the risk of cancer in people with type 2 diabetes due to these therapies' effects on risk factors that are common to both conditions, including hyperglycaemia and obesity, as well as effects that are specific to the class of drug or drugs. Drugs that reduce circulating insulin levels, such as metformin, may reduce cancer risk, and drugs that increase circulating insulin levels, including exogenous insulin and insulin secretagogues, may increase cancer risk. The influence of glucose-lowering therapies on cancer risk may become an important consideration when selecting glucose-lowering therapies to treat people with type 2 diabetes and a high risk of cancer occurrence or recurrence.