No abstract

Over 230,000 new cases of breast cancer are expected to be diagnosed in the United States in 2015. Taxane-based chemotherapy is often an effective treatment, but can also cause adverse symptoms in patients due to neurotoxicity. These side effects can impair postural control in patients; however, this instability has scarcely been quantified. The purpose of this pilot study was to gain insight into the natural history of postural instability in breast cancer patients being treated with taxane-based chemotherapy. Thirty-two breast cancer patients (31 female/ 1 male; 47.6 ± 11.2 yr; 16 stage II/ 16 stage III) completed eyes open and eyes closed quiet standing trials in the oncology clinic where they were being treated. These trials were collected at five timepoints throughout their chemotherapy treatment: (1) before initiating chemotherapy to provide a baseline, (2–4) before starting subsequent chemotherapy cycles, and (5) 1–3 months after receiving their last taxane infusion. After the first chemotherapy cycle, patients demonstrated increases in 95% confidence ellipse area of center of pressure (CoP) [45.2%, p=0.01] and root mean squared CoP excursion [18%, p=0.006] compared to baseline values for the eyes closed condition. These balance deficiencies progressed with cumulative taxane exposure. Postural instability persisted 1–3 months after completing chemotherapy with increases in 95% CoP ellipse area [86.8%, p=0.002], root mean squared CoP excursion [32.6%, p=0.001], and mean CoP velocity [30.4%, p=0.024]. The balance impairments demonstrated by patients in this study appear to be clinically relevant when compared to balance impairments previously reported in other patient populations.

No abstract

Microglia, the principal resident immune cell in the retina, play constitutive roles in immune surveillance and synapse maintenance, and are also associated with retinal disease, including those occurring in the macula. Perspectives on retinal microglia function have derived largely from rodent models and how these relate to the macula-bearing primate retina is unclear. In this study, we examined microglial distribution and cellular morphology in the adult rhesus macaque retina, and performed comparative characterizations in three retinal locations along the center-to-periphery axis (parafoveal, macular, and the peripheral retina). We found that microglia density peaked in the parafoveal retina and decreased in the peripheral retina. Individual microglial morphology reflected macular specialization, with macular microglia demonstrating the largest and most complex dendritic arbors relative to other retinal locations. Comparing retinal microglia between young and middle-aged animals, microglial density increased in the macular, but not in the peripheral, retina with age, while microglial morphology across all locations remained relatively unchanged. Our findings indicate that microglial distribution and morphology demonstrate regional specialization in the retina, correlating with gradients of other retinal cell types. As microglia are innate immune cells implicated in age-related macular diseases, age-related microglial changes may be related to the increased vulnerability of the aged macula to immune-related neurodegeneration.

No ECs and ECDP were observed in effluents collected after injecting medium alone and NAgPlts, whereas AgPlts and Polybeads drastically dislodged ECs, releasing ECs and ECDP in effluents as the time increased. Effluents collected when endothelial cell damage was seen showed increased presence of von Willebrand factor as compared to control effluents. Furthermore, we analyzed the presence of ECs and ECDPs in heart failure subjects, as well as animal plasma samples. Our study demonstrates that circulating AgPlts denude the endothelium and release ECs and ECDP. Direct mechanical disruption and shear stress caused by circulating AgPlts could be the underlying mechanism of the observed endothelium damage.

Background: The presence of circulating endothelial cells (CECs) in systemic circulation might be an indicator of endothelial damage and/or denudation, and thus the body’s response to repair and revascularization. Thus, we hypothesized that aggregated platelets (AgPlts) can disrupt and denude the endothelium, and contribute to the presence of CEC and EC-derived particles (ECDP). In this study, we used endothelial cells and sheep carotid artery segments. Methods: Endothelial cells (sheep aortic and human umbilical vein) were grown in glass tubes and tagged with/without 0.5 μm fluorescent beads. These glass tubes as well as sheep carotid artery segments were connected to a Mini-Pump Variable Flow System to study the effect of circulating AgPlts on the endothelium. ECs in glass tube/artery segment were exposed to medium alone, non-aggregated platelets (NAgPlts), AgPlts and 90 micron polystyrene beads at a flow rate of 20-85 ml/minute for various time intervals (0, 30 seconds, 1, and 5 min). Collected effluents were cultured and incubated for 72 hrs to analyze the growth potential of dislodged but intact ECs. Inflammatory genes of the damaged endothelium were analyzed by RT-PCR and the presence of ECDP was further assessed by western blot analysis using an antibody to human von Willebrand factor (VWF). Results: No ECs and ECDP were observed in effluents collected after injecting medium alone or medium and NAgPlts, whereas AgPlts and Polybeads drastically dislodged ECs and released ECs and ECDP in effluents. There were no ECs and ECDP in samples collected at 0 and 30 seconds. However, the number of ECs and EDCP in samples collected at 1 and 5 minutes was proportionately increased. Effluents collected when endothelial cell damage was seen showed an increased presence of VWF as compared to control effluents. Conclusion: Our study demonstrates that circulating AgPlts denude the endothelium and release ECs and ECDP. Direct mechanical disruption and shear stress caused by circulating AgPlts could be the underlying mechanism of the observed endothelial damage. Moreover, a major source of the CECs in the blood circulation could be the damaged endothelium.

Purpose: To assess the efficacy of a 0.18 mg intravitreal fluocinolone acetonide (FA) implant (Yutiq, EyePoint Pharmaceuticals, Watertown, MA) as a treatment option for patients with radiation retinopathy-related cystoid macular edema. Methods: A retrospective review of seven patients treated for uveal melanoma who developed radiation retinopathy-related cystoid macular edema. They were initially treated with intravitreal anti–vascular endothelial growth factor and/or steroid injections and then transitioned to intravitreal FA implant. Primary outcomes include best-corrected visual acuity, central subfield thickness, and number of additional injections. Results: After FA implant insertion, best-corrected visual acuity and central subfield thickness remained stable in all patients. The variance in best-corrected visual acuity decreased from 75.5 ETDRS letters (range 0–199 letters) to 29.8 (range 1.2–134) after FA implant insertion. Mean central subfield thickness was 384 µm (range 165–641) and 354 µm (range 282–493) before and after FA implant insertion, resulting in a 30-µm mean reduction. The number of intravitreal injections (average 4.9, range 2–10) decreased after intravitreal FA implant insertion with only two patients requiring one additional FA implant (average 0.29, range 0–1) over a mean of 12.1 months (range 0.9–18.5) follow-up. Conclusion: Intravitreal FA implant is an effective treatment for cystoid macular edema radiation retinopathy. The slow release of steroid allows for sustained control of macular edema, which correlated with stable visual acuity and decreased injection burden for patients.

Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several chemotherapy drug classes, including taxanes. Peripheral neuropathies have been shown to lead to pain, falls, and difficulty in walking and performing activities of daily living in a variety of patient populations. Although the prevalence of CIPN has been noted in cancer patients, the development of self-reported symptoms, gait changes and balance changes during treatment have not been well explored to date. We hypothesized that the use of taxane-based chemotherapy will result in significant changes in spatiotemporal gait and balance parameters, as well as self-reported quality of life and function. Methods We characterized the alterations in gait and balance that occur in non-metastatic breast cancer patients during taxane chemotherapy. We evaluated (1) spatiotemporal gait parameters, including cadence and step length, and (2) balance parameters, including time-to-contact and 95% ellipse area, using each patient as her own control. Laboratory assessment of gait and balance was conducted at baseline and at completion of therapy in selected patients. We compared the natural history of changes in gait and balance parameters with changes in CIPN status as measured by validated patient reported outcomes, including EORTC QLQ-C30, CIPN-20, and Brief Pain Inventory Short Form (BPI-SF), and the Duke Activity Status Index (DASI). Time points included pre-chemotherapy, after each cycle of chemotherapy, and one month after the end of therapy to collect information on neuropathy, pain and functional capacity. The preliminary data were illustrated using individual plots; trend lines (changing over time) were based on least square means at each time point, which were estimated using the linear mixed models for repeated measures. Results To date, 15 patients with localized breast cancer have been enrolled; patient recruitment is ongoing. The median age is 42 years (range 25-67). Ten patients (67%) received weekly paclitaxel, 1 patient (7%) received paclitaxel every 2 weeks, and 4 patients (27%) received docetaxel every 3 weeks. Preliminary results with these 15 patients, based on least square means at each timepoint, showed trends in several parameters. As treatments progressed, patients tended to develop more difficulty in quiet balance and in their ability to actively shift weight in the sagittal and frontal planes. From the CIPN-20, they also tended to develop increased difficulty with sensory and motor systems. From the QLQ-C30, their global health status also tended to worsen. For most of these parameters, the largest changes were observed between the 2nd and 3rd treatments, though some changes were not observed until the 4th treatment. From the BPI-SF, no trends in pain symptoms or pain interference were observed within this preliminary cohort. Conclusions Gait and balance testing is feasible in the clinical setting. Preliminary observations suggest that balance, function and quality of life may all be affected by taxane therapy, even without pain symptoms. The findings of this study will enable us to better characterize the neurotoxic effect of taxanes and to ultimately test the effectiveness of preventative measures and interventions. Funding by NCI R03CA182165-01. Citation Format: Maryam B Lustberg, Scott Monfort, Janani Singaravelu, Raquel E Reinbolt, Xueliang Pan, Bhuvaneswari Ramaswamy, Rachel M Layman, Robert Wesolowski, Ewa Mrozek, Erin Macrae, Charles Shapiro, Robyn Patrick, Charles L Loprinzi, Ajit Chaudhari. Longitudinal evaluation of taxane-induced neuropathy in early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-04.