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1.
Hear Res ; 447: 109023, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733710

RESUMO

Limited auditory input, whether caused by hearing loss or by electrical stimulation through a cochlear implant (CI), can be compensated by the remaining senses. Specifically for CI users, previous studies reported not only improved visual skills, but also altered cortical processing of unisensory visual and auditory stimuli. However, in multisensory scenarios, it is still unclear how auditory deprivation (before implantation) and electrical hearing experience (after implantation) affect cortical audiovisual speech processing. Here, we present a prospective longitudinal electroencephalography (EEG) study which systematically examined the deprivation- and CI-induced alterations of cortical processing of audiovisual words by comparing event-related potentials (ERPs) in postlingually deafened CI users before and after implantation (five weeks and six months of CI use). A group of matched normal-hearing (NH) listeners served as controls. The participants performed a word-identification task with congruent and incongruent audiovisual words, focusing their attention on either the visual (lip movement) or the auditory speech signal. This allowed us to study the (top-down) attention effect on the (bottom-up) sensory cortical processing of audiovisual speech. When compared to the NH listeners, the CI candidates (before implantation) and the CI users (after implantation) exhibited enhanced lipreading abilities and an altered cortical response at the N1 latency range (90-150 ms) that was characterized by a decreased theta oscillation power (4-8 Hz) and a smaller amplitude in the auditory cortex. After implantation, however, the auditory-cortex response gradually increased and developed a stronger intra-modal connectivity. Nevertheless, task efficiency and activation in the visual cortex was significantly modulated in both groups by focusing attention on the visual as compared to the auditory speech signal, with the NH listeners additionally showing an attention-dependent decrease in beta oscillation power (13-30 Hz). In sum, these results suggest remarkable deprivation effects on audiovisual speech processing in the auditory cortex, which partially reverse after implantation. Although even experienced CI users still show distinct audiovisual speech processing compared to NH listeners, pronounced effects of (top-down) direction of attention on (bottom-up) audiovisual processing can be observed in both groups. However, NH listeners but not CI users appear to show enhanced allocation of cognitive resources in visually as compared to auditory attended audiovisual speech conditions, which supports our behavioural observations of poorer lipreading abilities and reduced visual influence on audition in NH listeners as compared to CI users.


Assuntos
Estimulação Acústica , Atenção , Implante Coclear , Implantes Cocleares , Surdez , Eletroencefalografia , Pessoas com Deficiência Auditiva , Estimulação Luminosa , Percepção da Fala , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Implante Coclear/instrumentação , Adulto , Estudos Prospectivos , Estudos Longitudinais , Pessoas com Deficiência Auditiva/psicologia , Pessoas com Deficiência Auditiva/reabilitação , Surdez/fisiopatologia , Surdez/reabilitação , Surdez/psicologia , Estudos de Casos e Controles , Idoso , Percepção Visual , Leitura Labial , Fatores de Tempo , Audição , Potenciais Evocados Auditivos , Córtex Auditivo/fisiopatologia , Potenciais Evocados
2.
J Dtsch Dermatol Ges ; 22(5): 730-747, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38679790

RESUMO

Sebaceous gland carcinomas are rare malignant cutaneous adnexal tumors with sebocytic differentiation. The typical predilection area is the head and neck region, where sebaceous gland carcinomas are the most common malignant adnexal tumors of the skin. According to their localization a distinction is made between periocular and extraocular sebaceous gland carcinomas. Muir-Torre syndrome (MTS) should always be ruled out if it is suspected. In terms of prognosis, sebaceous gland carcinomas are potentially aggressive tumors with a clear tendency to recur and metastasize. Only small extraocular sebaceous gland carcinomas that have been completely resected have a very good prognosis. Sebaceous gland carcinomas most frequently metastasize lymphogenously to regional or distant lymph nodes; organ metastasis occurs less frequently. Periocular sebaceous gland carcinomas have a higher metastasis rate (up to 15%) than extraocular sebaceous gland carcinomas (up to 2%). Complete micrographically controlled surgery (MCS) of the primary tumor is the therapy of first choice, regardless of periocular or extraocular localization. Adjuvant or therapeutic radiotherapy may be considered. There is currently no established standard therapy for advanced, inoperable, or metastatic sebaceous gland carcinomas. Local procedures and systemic therapies such as chemotherapy or immunotherapy can be considered. The procedure should be determined individually by an interdisciplinary tumor board. Close follow-up care is recommended for these potentially aggressive carcinomas.


Assuntos
Neoplasias das Glândulas Sebáceas , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/terapia , Neoplasias das Glândulas Sebáceas/diagnóstico , Humanos , Síndrome de Muir-Torre/patologia , Síndrome de Muir-Torre/diagnóstico , Síndrome de Muir-Torre/terapia , Prognóstico , Adenocarcinoma Sebáceo/patologia , Adenocarcinoma Sebáceo/terapia , Adenocarcinoma Sebáceo/diagnóstico , Dermatologia/normas , Alemanha , Cirurgia de Mohs , Guias de Prática Clínica como Assunto
4.
Clin Neurophysiol ; 154: 141-156, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37611325

RESUMO

OBJECTIVE: Hearing with a cochlear implant (CI) is difficult in noisy environments, but the use of noise reduction algorithms, specifically ForwardFocus, can improve speech intelligibility. The current event-related potentials (ERP) study examined the electrophysiological correlates of this perceptual improvement. METHODS: Ten bimodal CI users performed a syllable-identification task in auditory and audiovisual conditions, with syllables presented from the front and stationary noise presented from the sides. Brainstorm was used for spatio-temporal evaluation of ERPs. RESULTS: CI users revealed an audiovisual benefit as reflected by shorter response times and greater activation in temporal and occipital regions at P2 latency. However, in auditory and audiovisual conditions, background noise hampered speech processing, leading to longer response times and delayed auditory-cortex-activation at N1 latency. Nevertheless, activating ForwardFocus resulted in shorter response times, reduced listening effort and enhanced superior-frontal-cortex-activation at P2 latency, particularly in audiovisual conditions. CONCLUSIONS: ForwardFocus enhances speech intelligibility in audiovisual speech conditions by potentially allowing the reallocation of attentional resources to relevant auditory speech cues. SIGNIFICANCE: This study shows for CI users that background noise and ForwardFocus differentially affect spatio-temporal cortical response patterns, both in auditory and audiovisual speech conditions.


Assuntos
Implante Coclear , Implantes Cocleares , Percepção da Fala , Humanos , Percepção da Fala/fisiologia , Potenciais Evocados , Ruído/efeitos adversos
5.
Polym Chem ; 14(21): 2599-2609, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37261292

RESUMO

Linear polyglycerol is known as a highly hydrophilic and biocompatible polymer that is currently considered for numerous medical applications. Derived from this well-known structure, the synthesis of highly biocompatible, thermoresponsive polyether copolymers via statistical anionic ring-opening copolymerization of ethyl glycidyl ether (EGE) and ethoxy ethyl glycidyl ether (EEGE) is described. Subsequent deprotection of the acetal groups of EEGE yields copolymers of linear glycerol (linG) and EGE, P(linG-co-EGE). These copolymers showed monomodal and narrow molecular weight distributions with dispersities D ≤ 1.07. The microstructure was investigated via in situ1H NMR kinetics experiments, revealing reactivity ratios of rEEGE = 1.787 ± 0.007 and rEGE = 0.560 ± 0.002, showing a slightly favored incorporation of EEGE over EGE. Due to the deliberate incorporation of rather hydrophobic EGE units into the water soluble linPG, tunable thermoresponsive behavior is achieved with cloud point temperatures Tcp between 9.0-71.4 °C. Besides the commonly utilized method turbidimetry, temperature-dependent 1H NMR measurements were used for more accurate and reproducible results. The change of the hydrodynamic radii rH of the copolymers and their aggregates upon reaching Tcp was investigated via DOSY NMR spectroscopy. To explore possible biomedical applications, as an example, the cell viability and immunology of an exemplary P(linG-co-EGE) copolymer sample was investigated. Since both, cell viability and immunology are comparable to the gold standard PEG, the herein presented copolymers show high potential as biocompatible and thermoresponsive alternatives to PEG for biomedical applications.

6.
Front Oncol ; 13: 1111119, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36959781

RESUMO

Mutations in the NRAS gene are common alterations in malignant melanoma. However, there are no specific treatment options approved for NRAS-mutated melanoma patients besides immune checkpoint inhibition. Since preclinical data suggests a synergistic effect of a MEK inhibitor (MEKi) and the oncolytic virus talimogene laherparepvec (T-VEC), we have treated three melanoma patients with this combination. All of the three patients had been suffering from recurring cutaneous and subcutaneous in-transit metastases. Upon treatment one patient (case 1) presented full regression of locoregional metastases and remained progression-free until date, for almost three years. The second patient (case 2) showed a partial regression of painful gluteal satellite metastases but died from brain metastases. The third patient (case 3) showed a durable response of locoregional metastases for seven months. The combination treatment was well tolerated with common adverse events known for each single agent. This report is the first case series presenting a clinical benefit of the combined T-VEC and MEKi treatment. We suggest the combination of T-VEC and MEKi as an off-label treatment option for patients with NRAS mutations, especially with recurrent in-transit or satellite metastases.

7.
Front Immunol ; 14: 1065767, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36860876

RESUMO

Purpose: Although the treatment of advanced melanoma patients with immune checkpoint inhibitors (ICI) significantly increased the therapeutic efficiency, many patients remain resistant to ICI that could be due to immunosuppression mediated by myeloid-derived suppressor cells (MDSC). These cells are enriched and activated in melanoma patients and could be considered as therapeutic targets. Here we studied dynamic changes in immunosuppressive pattern and activity of circulating MDSC from melanoma patients treated with ICI. Experimental design: MDSC frequency, immunosuppressive markers and function were evaluated in freshly isolated peripheral blood mononuclear cells (PBMC) from 29 melanoma patients receiving ICI. Blood samples were taken prior and during the treatment and analyzed by flow cytometry and bio-plex assay. Results: MDSC frequency was significantly increased before the therapy and through three months of treatment in non-responders as compared to responders. Prior to the ICI therapy, MDSC from non-responders displayed high levels of immunosuppression measured by the inhibition of T cell proliferation assay, whereas MDSC from responding patients failed to inhibit T cells. Patients without visible metastasis were characterized by the absence of MDSC immunosuppressive activity during the ICI treatment. Moreover, non-responders showed significantly higher IL-6 and IL-8 concentrations before therapy and after the first ICI application as compared to responders. Conclusions: Our findings highlight the role of MDSC during melanoma progression and suggest that frequency and immunosuppressive activity of circulating MDSC before and during the ICI treatment of melanoma patients could be used as biomarkers of response to ICI therapy.


Assuntos
Melanoma , Células Supressoras Mieloides , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Leucócitos Mononucleares , Melanoma/tratamento farmacológico , Imunossupressores
8.
J Endovasc Ther ; 30(4): 600-608, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35466775

RESUMO

OBJECTIVES: This study's objective was to evaluate Endurant II (Medtronic Inc, Minneapolis, Minnesota) stent graft's early and midterm outcomes and compare the results according to the anatomic severity grade (ASG) scores. METHODS: This was a retrospective study of patients treated with the Endurant II stent graft between January 2013 and May 2021. The patients were divided into 2 independent groups, including those with a low ASG score (score <14) and a high ASG score (score >14). RESULTS: A total of 165 consecutive patients (89% males, age 74±8 years) were included. There were 110 (67%) patients in the low-score group and 55 (33%) patients in the high-score group. Technical success was achieved in all cases. Primary clinical success at 30 days was 100% and at 1 year was 96%. Median operative time was longer in the high-score group with no statistical significance (133 vs 120 minutes, p=0.116). The median dose area product of low-score patients (50.9 Gy·cm2; IQR 22.4-75.5 Gy·cm2) was significantly lower than high-score patients (85.0 Gy·cm2; IQR 46.5-127.9 Gy·cm2) with p=0.025. Median fluoroscopic time was lower in low-score patients (17 minutes; IQR 13-24 minutes) compared with high-score patients (19 minutes; IQR 16-23 minutes) without a significant difference at p=0.148. At a midterm follow-up of 32 months (range 2-63 months), combined complications (29% vs 8%, p<0.001) and implant-related complications (13% vs 4%, p=0.043) were higher in the high-score group. Systemic complications at 30 days were higher in the high-score group without a statistically significant difference (15% vs 11%, p=0.500). The Kaplan-Meier estimate of freedom from reintervention was significantly higher in the low-risk group at 1 (97% vs 90%), 2 (96% vs 88%), and 3 years (96% vs 85%) with (p=0.035). The cumulative survival rate was significantly higher in the low-score group than high-score group (p=0.001) at 1 (99% vs 87%), 2 (98% vs 85%), and 3 years (96% vs 82%). CONCLUSIONS: Endurant II endovascular aneurysm repair seems to be safe in both low-score and high-score patients. However, patients in the high-score group showed more implant-related complications and midterm mortalities than those in the low-score group.


Assuntos
Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Masculino , Humanos , Idoso , Idoso de 80 Anos ou mais , Feminino , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/efeitos adversos , Aneurisma da Aorta Abdominal/cirurgia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Desenho de Prótese , Fatores de Tempo , Procedimentos Endovasculares/efeitos adversos , Stents/efeitos adversos , Complicações Pós-Operatórias/etiologia
9.
Curr Res Neurobiol ; 3: 100059, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405629

RESUMO

Hearing with a cochlear implant (CI) is limited compared to natural hearing. Although CI users may develop compensatory strategies, it is currently unknown whether these extend from auditory to visual functions, and whether compensatory strategies vary between different CI user groups. To better understand the experience-dependent contributions to multisensory plasticity in audiovisual speech perception, the current event-related potential (ERP) study presented syllables in auditory, visual, and audiovisual conditions to CI users with unilateral or bilateral hearing loss, as well as to normal-hearing (NH) controls. Behavioural results revealed shorter audiovisual response times compared to unisensory conditions for all groups. Multisensory integration was confirmed by electrical neuroimaging, including topographic and ERP source analysis, showing a visual modulation of the auditory-cortex response at N1 and P2 latency. However, CI users with bilateral hearing loss showed a distinct pattern of N1 topography, indicating a stronger visual impact on auditory speech processing compared to CI users with unilateral hearing loss and NH listeners. Furthermore, both CI user groups showed a delayed auditory-cortex activation and an additional recruitment of the visual cortex, and a better lip-reading ability compared to NH listeners. In sum, these results extend previous findings by showing distinct multisensory processes not only between NH listeners and CI users in general, but even between CI users with unilateral and bilateral hearing loss. However, the comparably enhanced lip-reading ability and visual-cortex activation in both CI user groups suggest that these visual improvements are evident regardless of the hearing status of the contralateral ear.

10.
Plast Reconstr Surg Glob Open ; 10(10): e4604, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36299815

RESUMO

Collagenase Clostridium histolyticum (CCH) injection and percutaneous needle fasciotomy (PNF) are minimally invasive procedures aiming to relieve Dupuytren disease (DD) by disrupting the cord and restoring the normal functionality of the hand. The purpose of this study is to compare the outcomes and recurrence rates for treatment of DD in the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints with either collagenase or percutaneous needle at 3-year follow-up. Moreover, we aim to determine the role of these therapeutic modalities and their impact on hand functionality and quality of life. Methods: In this retrospective analysis, we compare treatment outcomes in 35 patients, of whom 22 were treated with PNF and 13 with CCH injection. Results: The mean outcome in contracture degrees at 3-year follow-up was 9 degrees for MCP joints for both treatment groups, 34 degrees for PNF, and 28 degrees for CCH for PIP joints. There was no statistical significance between the treatment groups in MCP joints (P = 0.786) or in PIP joints (P = 0.474). Contracture recurrences were similar in PIP joints of both groups and greater in MCP joints in the CCH group compared to PNF. The Disabilities of the Arm, Shoulder, and Hand and the Unité Rhumatologique des Affections de la Main scores showed a reduction in impairment in both groups without significant differences between the two groups. Conclusions: The results of this study show that PNF appears to be as effective and minimally invasive as CCH injection, but at significantly lower cost. Considering these factors, the authors prefer and recommend the use of PNF over CCH.

11.
Eur J Cancer ; 173: 307-316, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35973360

RESUMO

BACKGROUND: Image-based cancer classifiers suffer from a variety of problems which negatively affect their performance. For example, variation in image brightness or different cameras can already suffice to diminish performance. Ensemble solutions, where multiple model predictions are combined into one, can improve these problems. However, ensembles are computationally intensive and less transparent to practitioners than single model solutions. Constructing model soups, by averaging the weights of multiple models into a single model, could circumvent these limitations while still improving performance. OBJECTIVE: To investigate the performance of model soups for a dermoscopic melanoma-nevus skin cancer classification task with respect to (1) generalisation to images from other clinics, (2) robustness against small image changes and (3) calibration such that the confidences correspond closely to the actual predictive uncertainties. METHODS: We construct model soups by fine-tuning pre-trained models on seven different image resolutions and subsequently averaging their weights. Performance is evaluated on a multi-source dataset including holdout and external components. RESULTS: We find that model soups improve generalisation and calibration on the external component while maintaining performance on the holdout component. For robustness, we observe performance improvements for pertubated test images, while the performance on corrupted test images remains on par. CONCLUSIONS: Overall, souping for skin cancer classifiers has a positive effect on generalisation, robustness and calibration. It is easy for practitioners to implement and by combining multiple models into a single model, complexity is reduced. This could be an important factor in achieving clinical applicability, as less complexity generally means more transparency.


Assuntos
Melanoma , Neoplasias Cutâneas , Dermoscopia/métodos , Humanos , Melanoma/diagnóstico por imagem , Sensibilidade e Especificidade , Neoplasias Cutâneas/diagnóstico por imagem , Melanoma Maligno Cutâneo
12.
Brain Topogr ; 35(4): 431-452, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668310

RESUMO

Cochlear implants (CIs) allow to restore the hearing function in profoundly deaf individuals. Due to the degradation of the stimulus by CI signal processing, implanted individuals with single-sided deafness (SSD) have the specific challenge that the input highly differs between their ears. The present study compared normal-hearing (NH) listeners (N = 10) and left- and right-ear implanted SSD CI users (N = 10 left, N = 9 right), to evaluate cortical speech processing between CI- and NH-ears and to explore for side-of-implantation effects. The participants performed a two-deviant oddball task, separately with the left and the right ear. Auditory event-related potentials (ERPs) in response to syllables were compared between proficient and non-proficient CI users, as well as between CI and NH ears. The effect of the side of implantation was analysed on the sensor and the source level. CI proficiency could be distinguished based on the ERP amplitudes of the N1 and the P3b. Moreover, syllable processing via the CI ear, when compared to the NH ear, resulted in attenuated and delayed ERPs. In addition, the left-ear implanted SSD CI users revealed an enhanced functional asymmetry in the auditory cortex than right-ear implanted SSD CI users, regardless of whether the syllables were perceived via the CI or the NH ear. Our findings reveal that speech-discrimination proficiency in SSD CI users can be assessed by N1 and P3b ERPs. The results contribute to a better understanding of the rehabilitation success in SSD CI users by showing that cortical speech processing in SSD CI users is affected by CI-related stimulus degradation and experience-related functional changes in the auditory cortex.


Assuntos
Córtex Auditivo , Implante Coclear , Implantes Cocleares , Surdez , Perda Auditiva Unilateral , Percepção da Fala , Implante Coclear/métodos , Humanos , Percepção da Fala/fisiologia
13.
Int J Pediatr Otorhinolaryngol ; 156: 111117, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35366421

RESUMO

OBJECTIVE: The aim of the study was to investigate if a directional microphone mode improves speech perception in noise and sound localization in experienced pediatric bilateral cochlear implant users. METHODS: 15 bilaterally implanted children were included in the analysis. Speech perception in 4 noise conditions (S0N0, S0N90, S0N-90, S0N180) and sound localization were measured when using the OPUS 2 audio processor (omnidirectional mode) and the SONNET audio processor (omnidirectional and natural mode). RESULTS: Speech perception in all 4 noise conditions was better with the SONNET natural mode than with the omnidirectional mode of either SONNET or OPUS 2. The root-mean-square error of the sound localization test was smaller with the natural mode of SONNET than with the omnidirectional mode of either SONNET or OPUS 2. The performance of the audio processors in the omnidirectional mode did not differ significantly except in the S0N0 condition of the speech perception test. CONCLUSION: The natural microphone mode of the SONNET audio processor improved speech perception in noise and sound localization in bilaterally implanted children.


Assuntos
Implante Coclear , Implantes Cocleares , Localização de Som , Percepção da Fala , Criança , Humanos , Ruído
14.
Neuroimage Clin ; 34: 102982, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35303598

RESUMO

A cochlear implant (CI) is an auditory prosthesis which can partially restore the auditory function in patients with severe to profound hearing loss. However, this bionic device provides only limited auditory information, and CI patients may compensate for this limitation by means of a stronger interaction between the auditory and visual system. To better understand the electrophysiological correlates of audiovisual speech perception, the present study used electroencephalography (EEG) and a redundant target paradigm. Postlingually deafened CI users and normal-hearing (NH) listeners were compared in auditory, visual and audiovisual speech conditions. The behavioural results revealed multisensory integration for both groups, as indicated by shortened response times for the audiovisual as compared to the two unisensory conditions. The analysis of the N1 and P2 event-related potentials (ERPs), including topographic and source analyses, confirmed a multisensory effect for both groups and showed a cortical auditory response which was modulated by the simultaneous processing of the visual stimulus. Nevertheless, the CI users in particular revealed a distinct pattern of N1 topography, pointing to a strong visual impact on auditory speech processing. Apart from these condition effects, the results revealed ERP differences between CI users and NH listeners, not only in N1/P2 ERP topographies, but also in the cortical source configuration. When compared to the NH listeners, the CI users showed an additional activation in the visual cortex at N1 latency, which was positively correlated with CI experience, and a delayed auditory-cortex activation with a reversed, rightward functional lateralisation. In sum, our behavioural and ERP findings demonstrate a clear audiovisual benefit for both groups, and a CI-specific alteration in cortical activation at N1 latency when auditory and visual input is combined. These cortical alterations may reflect a compensatory strategy to overcome the limited CI input, which allows the CI users to improve the lip-reading skills and to approximate the behavioural performance of NH listeners in audiovisual speech conditions. Our results are clinically relevant, as they highlight the importance of assessing the CI outcome not only in auditory-only, but also in audiovisual speech conditions.


Assuntos
Implante Coclear , Implantes Cocleares , Percepção da Fala , Estimulação Acústica/métodos , Percepção Auditiva/fisiologia , Potenciais Evocados , Humanos , Fala , Percepção da Fala/fisiologia , Percepção Visual/fisiologia
15.
J Immunother Cancer ; 10(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35301236

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma. METHODS: In vitro generated murine MDSC and primary MDSC from melanoma-bearing mice were used to investigate the effects of Napabucasin on MDSC in vitro. The RET transgenic mouse model of malignant melanoma was used to examine Napabucasin therapy efficiency and its underlying mechanisms in vivo. Furthermore, STAT3 activation and its correlation with survival were explored in MDSC from 19 patients with malignant melanoma and human in vitro generated monocytic myeloid-derived suppressor cell (M-MDSC) were used to evaluate the effects of Napabucasin. RESULTS: Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8+ T-cell proliferation. The STAT3 inhibitor induced apoptosis in murine MDSC, significantly increased expression of molecules associated with antigen processing and presentation, as well as slightly decreased expression of immunosuppressive factors on these cells. RET transgenic mice treated with Napabucasin showed prolonged survival accompanied by a strong accumulation of tumor-infiltrating antigen-presenting cells and activation of CD8+ and CD4+ T cells. Interestingly, patients with malignant melanoma with high expression of activated STAT3 in circulating M-MDSC showed significantly worse progression-free survival (PFS) than patients with low levels of activated STAT3. In addition, Napabucasin was able to abrogate suppressive capacity of human in vitro generated M-MDSC. CONCLUSION: Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.


Assuntos
Melanoma , Células Supressoras Mieloides , Animais , Benzofuranos , Humanos , Melanoma/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Naftoquinonas , Fator de Transcrição STAT3/metabolismo
16.
Front Neurosci ; 16: 1005859, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36620447

RESUMO

A cochlear implant (CI) can partially restore hearing in individuals with profound sensorineural hearing loss. However, electrical hearing with a CI is limited and highly variable. The current study aimed to better understand the different factors contributing to this variability by examining how age affects cognitive functions and cortical speech processing in CI users. Electroencephalography (EEG) was applied while two groups of CI users (young and elderly; N = 13 each) and normal-hearing (NH) listeners (young and elderly; N = 13 each) performed an auditory sentence categorization task, including semantically correct and incorrect sentences presented either with or without background noise. Event-related potentials (ERPs) representing earlier, sensory-driven processes (N1-P2 complex to sentence onset) and later, cognitive-linguistic integration processes (N400 to semantically correct/incorrect sentence-final words) were compared between the different groups and speech conditions. The results revealed reduced amplitudes and prolonged latencies of auditory ERPs in CI users compared to NH listeners, both at earlier (N1, P2) and later processing stages (N400 effect). In addition to this hearing-group effect, CI users and NH listeners showed a comparable background-noise effect, as indicated by reduced hit rates and reduced (P2) and delayed (N1/P2) ERPs in conditions with background noise. Moreover, we observed an age effect in CI users and NH listeners, with young individuals showing improved specific cognitive functions (working memory capacity, cognitive flexibility and verbal learning/retrieval), reduced latencies (N1/P2), decreased N1 amplitudes and an increased N400 effect when compared to the elderly. In sum, our findings extend previous research by showing that the CI users' speech processing is impaired not only at earlier (sensory) but also at later (semantic integration) processing stages, both in conditions with and without background noise. Using objective ERP measures, our study provides further evidence of strong age effects on cortical speech processing, which can be observed in both the NH listeners and the CI users. We conclude that elderly individuals require more effortful processing at sensory stages of speech processing, which however seems to be at the cost of the limited resources available for the later semantic integration processes.

17.
Zentralbl Chir ; 146(5): 506-520, 2021 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-34666364

RESUMO

BACKGROUND: Aortic complications after intravesical Bacillus Calmette-Guérin (BCG) application are a rare complication of the treatment of non-muscle invasive bladder cancer. The aim of this systematic review was to perform a descriptive analysis of previously published studies and to discuss the particular challenges of diagnosis and treatment of this rare complication. MATERIAL AND METHODS: A literature search was performed in PubMed (1949-2021) and Web of Science (1900-2021) using the search terms "mycobacterium" OR "bovis" OR "BCG" AND "aorta" OR "aneurysm". In a staged review process, publications with the following inclusion criteria were included in data analysis: original paper, full-text availability in English or German and aortic complication after intravesical BCG instillation. We focused on the analysis of BCG-specific medical history data as well as treatment strategies in relation to patient outcome and the occurrence of graft infections during follow-up. RESULTS: A total of 60 individual cases were described in 55 published articles. BCG-induced mycotic aortic aneurysms can occur in all segments of the thoracoabdominal aorta, but the infrarenal aortic segment was most commonly affected (65% of cases). The most common configuration was saccular outpouchings (65%). Concomitant infections in other tissues were typical (65%). Patients with mycotic aneurysm presented with or without consecutive aortic rupture in 28% and 63%, respectively. Diagnosis was based on a combination of pathological and microbiological examinations. A common treatment algorithm was surgical infection treatment (85%) and antitubercular therapy (83%). Performed simultaneously, they resulted in a long-term survival of 81%. Graft infection after initial aortic repair with alloplastic material (n = 40) developed in ten patients (25%) during follow-up. DISCUSSION: Diagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. Diagnosis is based on obtaining sample material of affected regions and the combination of patient's history, clinical presentation and pathological or microbiological examinations. Currently, no consensus guideline for optimal medical treatment options of aortic complications secondary to BCG instillation exists. The combination of surgical treatment and supportive antitubercular therapy seems to achieve the best results. Since the risk of prosthetic infection after the use of alloplastic materials remains high (25%), we strongly suggest evaluating autologous or allogenic aortic replacement during initial aortic repair.


Assuntos
Aneurisma Infectado , Mycobacterium bovis , Neoplasias da Bexiga Urinária , Administração Intravesical , Aneurisma Infectado/terapia , Aorta , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico
18.
J Speech Lang Hear Res ; 64(8): 3343-3356, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34310192

RESUMO

Purpose The aim of the study was to assess the susceptibility to energetic and informational masking in patients with single-sided deafness (SSD) with one normal-hearing (NH) ear and a cochlear implant (CI) in the contralateral ear, understand the effect on speech recognition when spatially separating noise and speech maskers, and investigate the influence of the CI in situations with energetic and informational masking. Method Speech recognition was measured in the presence of either a modulated speech-shaped noise or one of two competing speech maskers in 11 SSD-CI listeners. The speech maskers were manipulated with respect to fundamental frequency to consider the effect of different voices. Measurements were conducted in the unaided (NH) and aided (NHCI) conditions. Spatial release from masking (SRM) was calculated for each masker type and both listening conditions (NH and NHCI) by subtracting scores of the colocated target and masker condition (S0N0) from the spatially separated target and masker conditions (S0N≠0). Results Speech recognition was highly variable depending on the type of masker. SRM occurred in the unaided (NH) and aided (NHCI) conditions when the speech masker had the same gender as the target talker. Adding the CI improved speech recognition when this speech masker was ipsilateral to the NH ear. Conclusions The amount of informational masking is substantial in SSD-CI listeners with both colocated and spatially separated target and masker signals. The contribution of SRM to better speech recognition largely depends on the masker and is considerable when no differences in voices between the target and the competing talker occur. There is only a slight improvement in speech recognition by adding the CI.


Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Percepção da Fala , Humanos , Mascaramento Perceptivo , Fala
19.
Hautarzt ; 72(7): 619-632, 2021 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-34137901

RESUMO

Malignant adnexal neoplasms of the skin are a heterogeneous group of rare malignancies with eccrine, apocrine, sebaceous and follicular differentiation. Essential clinical practice recommendations for the overall management of these cancers are presented. Moreover, specific evidence-based findings according to diagnosis, therapy and follow-up of porocarcinoma, sebaceous carcinoma and microcystic adnexcarcinoma will be explained.


Assuntos
Adenocarcinoma Sebáceo , Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Pele , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/terapia
20.
Int J Surg Case Rep ; 81: 105845, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33887863

RESUMO

INTRODUCTION AND IMPORTANCE: Aneurysms of the carotid artery are rare and potentially a risk factor for developing neurological events. This case report describes the treatment of a giant saccular aneurysm of the right extracranial internal carotid artery (ICA) with adhesion to the vagus verve. CASE PRESENTATION: An 85-year-old female presented with an asymptomatic pulsating mass on the right neck. Ultrasonography and MR angiography revealed a giant aneurysm of the right internal carotid artery with a massive tortuosity. Intraoperatively, a massive adhesion of the vagus nerve to the aneurysm was found. A resection of the aneurysm followed by a spatulated end-to-end anastomosis was performed. Postprocedural neurological symptoms included a transient paralysis of the vagus nerve that recovered within six weeks. CLINICAL DISCUSSION: The treatment options of ICA aneurysms include open surgical and endovascular interventions. Endovascular treatment may be a good option for aneurysms with a particular morphology. However, open surgery is the favorable option for immense ICA aneurysms with a tortuous anatomical path. CONCLUSION: Aneurysm resection with end-to-end anastomosis is a possible surgical option in the case of tortuous extracranial ICA aneurysms. Leaving parts of the aneurysmal wall prevented occurring persisting damage of the adhesive vagus nerve.

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