Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells.

The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in ßII- and ßIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of ßIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing ßII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity-an effect at least in part mediated by the down-regulation of ßIII-tubulin expression. Furthermore, our study suggests that ßIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy.

Carotid-Cochlear Apex Dehiscence: A Family Affair.

We report two cases of carotid-cochlea dehiscence involving the cochlear apex, with, to our knowledge, the first description of this anomaly in two members of a family (mother-daughter). Pure tone audiometry revealed a bilateral mild sensorineural hearing loss predominantly on the left in the daughter, and a left mild mixed hearing loss with a predominance of sensorineural loss in the medium frequencies in the mother Carotid-cochlear dehiscence is a rare anomaly with a multiform expression, which should be investigated in cases of third mobile window symptoms, but also atypical sensorineural hearing loss, or before any cochlear implantation. Laryngoscope, 2023.

Facial nerve stimulation in adult cochlear implant recipients with far advanced otosclerosis.

Objectives: The objective of this study was to predict occurrence of facial nerve stimulation (FNS) in cochlear implanted patients for far-advanced otosclerosis (FAO) by correlating preoperative computed tomography (CT)-scan data to FNS and to evaluate FNS impact on hearing outcomes. Methods: Retrospective analysis on 91 ears (76 patients) implanted for FAO. Electrodes were straight (50%) or perimodiolar (50%). Demographic data, extension of otosclerosis on preoperative CT scan, occurrence of FNS, and speech performance were analyzed. Results: Prevalence of FNS was 21% (19 ears). FNS appeared during the first month (21%), 1-6 months (26%), 6-12 months (21%), and over 1 year (32%) postimplantation. Cumulative incidence of FNS at 15 years was 33% (95% CI = [14-47%]). Extension of otosclerotic lesions on preimplantation CT-scan was more severe in FNS ears compared to No-FNS (p < .05): for Stage III, 13/19 (68%) and 18/72 (25%) ears for FNS and No-FNS groups, respectively (p < .05). Location of otosclerotic lesions relative to the facial nerve canal was similar whatever the presence or not of FNS. Electrode array had no impact on FNS occurrence. At 1 year post-implantation, duration of profound hearing loss (≥5 years) and previous stapedotomy were negatively associated with speech performance. FNS did not impact hearing outcomes, despite a lower percentage of activated electrodes (p < .01) in the FNS group. Nevertheless, FNS were associated with a decrease of speech performance both in quiet (p < .001) and in noise (p < .05). Conclusion: Cochlear implanted patients for FAO are at greater risk of developing FNS affecting speech performance over time, probably due to a higher percentage of deactivated electrodes. High resolution CT-scan is an essential tool allowing FNS prediction but not time of onset. Level of evidence: 2b, Laryngoscope Investigative Otolaryngology, 2022.

Systematic review of cochlear implantation in patients with inner ear malformations.

OBJECTIVES: To evaluate the outcomes of cochlear implantation in patients with severe to profound sensorineural hearing loss due to inner ear malformations (IEMs) when compared to patients without IEMs. We discussed audiological outcomes such as open-set testing, closed-set testing, CAP score, and SIR score as well as postoperative outcomes such as cerebrospinal fluid gusher and incomplete insertion rate associated with cochlear implantation in individuals with IEMs. DATA SOURCES: PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. REVIEW METHODS: After screening a total of 222 studies, twelve eligible original articles were included in the review to analyze the speech and hearing outcomes of implanted patients with IEMs. Five reviewers independently screened, selected, and extracted data. The "Tool to Assess Risk of Bias in Cohort Studies" published by the CLARITY group was used to perform quality assessment on eligible studies. Systematic review registration number: CRD42021237489. RESULTS: IEMs are more likely to be associated with abnormal position of the facial nerve, raising the risk of intraoperative complications. These patients may benefit from cochlear implantation, but audiological outcomes may also be less favorable than in individuals without IEMs. Furthermore, due to the risk of cerebrospinal fluid gusher, incomplete insertion of electrodes, and postoperative facial nerve stimulation, surgeons can employ precautionary measures such as preoperative imaging and proper counseling. Postoperative imaging is suggested to be beneficial in ensuring proper electrode placement. CONCLUSIONS: Cochlear implants (CIs) have the potential to provide auditory rehabilitation to individuals with IEMs. Precise classification of the malformation, preoperative imaging and anatomical mapping, appropriate electrode selection, intra-operative techniques, and postoperative imaging are recommended in this population.

Pupillometry Assessment of Speech Recognition and Listening Experience in Adult Cochlear Implant Patients.

OBJECTIVE: The aim of the present study was to investigate the pupillary response to word identification in cochlear implant (CI) patients. Authors hypothesized that when task difficulty (i.e., addition of background noise) increased, pupil dilation markers such as the peak dilation or the latency of the peak dilation would increase in CI users, as already observed in normal-hearing and hearing-impaired subjects. METHODS: Pupillometric measures in 10 CI patients were combined to standard speech recognition scores used to evaluate CI outcomes, namely, speech audiometry in quiet and in noise at +10 dB signal-to-noise ratio (SNR). The main outcome measures of pupillometry were mean pupil dilation, maximal pupil dilation, dilation latency, and mean dilation during return to baseline or retention interval. Subjective hearing quality was evaluated by means of one self-reported fatigue questionnaire, and the Speech, Spatial, and Qualities (SSQ) of Hearing scale. RESULTS: All pupil dilation data were transformed to percent change in event-related pupil dilation (ERPD, %). Analyses show that the peak amplitudes for both mean pupil dilation and maximal pupil dilation were higher during the speech-in-noise test. Mean peak dilation was measured at 3.47 ± 2.29% noise vs. 2.19 ± 2.46 in quiet and maximal peak value was detected at 9.17 ± 3.25% in noise vs. 8.72 ± 2.93% in quiet. Concerning the questionnaires, the mean pupil dilation during the retention interval was significantly correlated with the spatial subscale score of the SSQ Hearing scale [r(8) = -0.84, p = 0.0023], and with the global score [r(8) = -0.78, p = 0.0018]. CONCLUSION: The analysis of pupillometric traces, obtained during speech audiometry in quiet and in noise in CI users, provided interesting information about the different processes engaged in this task. Pupillometric measures could be indicative of listening difficulty, phoneme intelligibility, and were correlated with general hearing experience as evaluated by the SSQ of Hearing scale. These preliminary results show that pupillometry constitutes a promising tool to improve objective quantification of CI performance in clinical settings.

γ-Actin plays a key role in endothelial cell motility and neovessel maintenance.

BACKGROUND: Angiogenesis plays a crucial role in development, wound healing as well as tumour growth and metastasis. Although the general implication of the cytoskeleton in angiogenesis has been partially unravelled, little is known about the specific role of actin isoforms in this process. Herein, we aimed at deciphering the function of γ-actin in angiogenesis. METHODS: Localization of ß- and γ-actin in vascular endothelial cells was investigated by co-immunofluorescence staining using monoclonal antibodies, followed by the functional analysis of γ-actin using siRNA. The impact of γ-actin knockdown on the random motility and morphological differentiation of endothelial cells into vascular networks was investigated by timelapse videomicroscopy while the effect on chemotaxis was assessed using modified Boyden chambers. The implication of VE-cadherin, VEGFR-2 and ROCK signalling was then examined by Western blotting and using pharmacological inhibitors. RESULTS: The two main cytoplasmic isoforms of actin strongly co-localized in vascular endothelial cells, albeit with some degree of spatial preference. While ß-actin knockdown was not achievable without major cytotoxicity, γ-actin knockdown did not alter the viability of endothelial cells. Timelapse videomicroscopy experiments revealed that γ-actin knockdown cells were able to initiate morphological differentiation into capillary-like tubes but were unable to maintain these structures, which rapidly regressed. This vascular regression was associated with altered regulation of VE-cadherin expression. Interestingly, knocking down γ-actin expression had no effect on endothelial cell adhesion to various substrates but significantly decreased their motility and migration. This anti-migratory effect was associated with an accumulation of thick actin stress fibres, large focal adhesions and increased phosphorylation of myosin regulatory light chain, suggesting activation of the ROCK signalling pathway. Incubation with ROCK inhibitors, H-1152 and Y-27632, completely rescued the motility phenotype induced by γ-actin knockdown but only partially restored the angiogenic potential of endothelial cells. CONCLUSIONS: Our study thus demonstrates for the first time that ß-actin is essential for endothelial cell survival and γ-actin plays a crucial role in angiogenesis, through both ROCK-dependent and -independent mechanisms. This provides new insights into the role of the actin cytoskeleton in angiogenesis and may open new therapeutic avenues for the treatment of angiogenesis-related disorders.