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SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough ) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).
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Encéfalo , Proteína Serina-Treonina Quinases de Interação com Receptores , Adulto , Humanos , Voluntários Saudáveis , Relação Dose-Resposta a Droga , Área Sob a Curva , Meia-Vida , Método Duplo-CegoRESUMO
Pompe disease is a rare, autosomal recessive, degenerative neuromuscular disease caused by deficiency of acid α-glucosidase, a lysosomal enzyme that degrades α-1,4 and α-1,6 linkages in glycogen. The objectives of this study (PAPAYA; NCT01410890) were to (1) characterize the pharmacokinetics of 20 mg/kg body weight alglucosidase alfa manufactured at the 4000-L scale following a single intravenous dose in participants aged less than 18 and 18 years or older with Pompe disease and (2) evaluate the relationship between anti-alglucosidase alfa antibody titers and the pharmacokinetics of alglucosidase alfa. Mean maximum plasma concentration and area under the concentration-time curve from time zero and extrapolated to infinite time were 204 µg/mL and 1110 µg ⢠h/mL for participants aged less than 18 years (n = 10), respectively, and 307 µg/mL and 1890 µg ⢠h/mL for participants aged 18 years or older (n = 10), respectively. Mean terminal half-life was 5.43 hours in participants aged less than 18 years with a high variability (70%) and 3.84 hours in participants aged 18 years or older with a low variability (21%). Mean maximum plasma concentration and area under the concentration-time curve from time zero and extrapolated to infinite time were 256 µg/mL and 1452 µg ⢠h/mL, respectively, in anti-alglucosidase alfa-negative participants (n = 12) and 262 µg/mL and 1703 µg ⢠h/mL, respectively, in anti-alglucosidase alfa-positive participants (n = 7). The study findings enrich available data from existing information on alglucosidase alfa without changing its known risks and benefits.
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Doença de Depósito de Glicogênio Tipo II , alfa-Glucosidases , Humanos , alfa-Glucosidases/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Resultado do Tratamento , Administração IntravenosaRESUMO
BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. TRIAL REGISTRATION: Clinical trial registration NCT03816839.
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Neoplasias da Mama , Antagonistas de Estrogênios , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , População do Leste Asiático , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/farmacocinética , Antagonistas de Estrogênios/uso terapêutico , Dose Máxima Tolerável , Receptores de Estrogênio/genética , Genes erbB-2/genética , Administração Oral , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/uso terapêuticoRESUMO
Experiments are carried out to study the interaction of a spray of spherical micronic oil droplets with a turbulent plane air jet impacting a wall. The context is the separation of a contaminated atmosphere with passive particles from a clean atmosphere by using a dynamical air curtain. A spinning disk is used to produce the spray of oil droplets close to the air jet. The diameter of the produced droplets varies between 0.3 and 7 µ m. The jet and particulate Reynolds numbers and the jet and Kolmogorov-Stokes numbers are, respectively, equal to Re j = 13500 , 0.2 ≤ Re p ≤ 5 , 0.002 ≤ St j ≤ 0.8 and 0.03 ≤ St K ≤ 15 . The ratio of the jet height to nozzle width is H / e = 10 . The flow properties in the experiments are measured by particle image velocimetry and are in good agreement with large eddy simulation results. The droplet/particle passing rate (PPR) through the air jet is measured by an optical particle counter. The PPR decreases with the increase in the droplet diameter for the studied droplet size range. Whatever the droplet size is, the PPR increases with time due to the presence of two large vortices on each side of the air jet that bring the droplets back to the jet. The accuracy and repeatability of the measurements are verified. The present results can be used to validate Eulerian/Lagrangian numerical simulations on the interaction of micronic droplets with a turbulent air jet.
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INTRODUCTION: Cochlear implantation is a recent approach proposed to treat single-sided deafness (SSD) and asymmetric hearing loss (AHL). Several cohort studies showed its effectiveness on tinnitus and variable results on binaural hearing. The main objective of this study is to assess the outcomes of cochlear implantation and other treatment options in SSD/AHL on quality of life. METHODS: This prospective multicenter study was conducted in 7 tertiary university hospitals and included an observational cohort study of SSD/AHL adult patients treated using contralateral routing of the signal (CROS) hearing aids or bone-anchored hearing systems (BAHSs) or who declined all treatments, and a randomized controlled trial in subjects treated by cochlear implantation, after failure of CROS and BAHS trials. In total, 155 subjects with SSD or AHL, with or without associated tinnitus, were enrolled. After 2 consecutive trials with CROS hearing aids and BAHSs on headband, all subjects chose any of the 4 treatment options (abstention, CROS, BAHS, or cochlear implant [CI]). The subjects who opted for a CI were randomized between 2 arms (CI vs. initial observation). Six months after the treatment choice, quality of life was assessed using both generic (EuroQoL-5D, EQ-5D) and auditory-specific quality-of-life indices (Nijmegen Cochlear implant Questionnaire [NCIQ] and Visual Analogue Scale [VAS] for tinnitus severity). Performances for speech-in-noise recognition and localization were measured as secondary outcomes. RESULTS: CROS was chosen by 75 subjects, while 51 opted for cochlear implantation, 18 for BAHSs, and 11 for abstention. Six months after treatment, both EQ-5D VAS and auditory-specific quality-of-life indices were significantly better in the "CI" arm versus "observation" arm. The mean effect of the CI was particularly significant in subjects with associated severe tinnitus (mean improvement of 20.7 points ± 19.7 on EQ-5D VAS, 20.4 ± 12.4 on NCIQ, and 51.4 ± 35.4 on tinnitus). No significant effect of the CI was found on binaural hearing results. Before/after comparisons showed that the CROS and BAHS also improved significantly NCIQ scores (for CROS: +7.7, 95% confidence interval [95% CI] = [4.5; 10.8]; for the BAHS: +14.3, 95% CI = [7.9; 20.7]). CONCLUSION: Cochlear implantation leads to significant improvements in quality of life in SSD and AHL patients, particularly in subjects with associated severe tinnitus, who are thereby the best candidates to an extension of CI indications.
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Implante Coclear , Implantes Cocleares , Surdez , Perda Auditiva Unilateral , Perda Auditiva , Percepção da Fala , Adulto , Surdez/cirurgia , Perda Auditiva Unilateral/cirurgia , Humanos , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Childhood cancer survivors are at risk for cardiovascular disease (CVD) because of intensive cancer therapies often accompanied by an unhealthy lifestyle. This study was aimed at 1) describing modifiable CVD risk factors in survivors and 2) investigating the association between different aspects of physical fitness and CVD risk factors. METHODS: The authors analyzed cross-sectional data from ≥5-year survivors who were 16 years old or younger at their cancer diagnosis and 16 years old or older at the time of the study. Single CVD risk factors (waist circumference, blood pressure, fasting glucose, inverse high-density lipoprotein, and triglycerides), a composite CVD risk score (combined z scores of all CVD risk factors), and metabolic syndrome were evaluated. Physical fitness measures included cardiopulmonary exercise testing (CPET), a handgrip test, and a 1-minute sit-to-stand test (STS). Multivariable logistic regression was used for the association between fitness measures and CVD risk factors, with adjustments made for demographic factors and cancer therapy. RESULTS: This study included 163 survivors with a median age at diagnosis of 7 years and a median age at the time of the study of 28 years. Among those survivors, 27% had a high waist circumference, 32% had high blood pressure, 19% had high triglycerides, 20% had an increased composite CVD risk score, and 10% had metabolic syndrome. A better performance during CPET, handgrip testing, and STS was associated with a lower probability of having a high waist circumference, high triglycerides, and metabolic syndrome. CONCLUSIONS: Better aerobic fitness (CPET) and, to a lesser extent, handgrip and STS were associated with fewer CVD risk factors. Further investigations are warranted to investigate which fitness measures should preferably be used to screen survivors to promote physical activity in those with impaired test performance. LAY SUMMARY: This study investigated the relationship between physical fitness of adult childhood cancer survivors and their risk factors for cardiovascular disease. Cardiovascular risk factors such as high blood pressure, a high waist circumference, and high blood lipids were frequently found in childhood cancer survivors. Survivors with better physical fitness (measured by a cycling test or simple strength and endurance tests) had a lower chance of having cardiovascular risk factors. This suggests that childhood cancer survivors could benefit from physical activity and general fitness by increasing their physical fitness and possibly decreasing their risk of cardiovascular disease.
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Sobreviventes de Câncer , Doenças Cardiovasculares , Aptidão Física , Adolescente , Adulto , Sobreviventes de Câncer/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Fatores de Risco de Doenças Cardíacas , HumanosRESUMO
Rationale: Childhood cancer survivors are at risk of long-term pulmonary dysfunction, but we lack sensitive outcome measures to detect early pulmonary damage.Objectives: To assess the ability of nitrogen multiple-breath washout (N2MBW) for detecting pulmonary dysfunction compared with spirometry in long-term survivors of childhood cancer.Methods: We analyzed cross-sectional data from long-term (≥5-yr) survivors of childhood cancer, aged ≤16 years at cancer diagnosis, ≥16 years at study (assessment period 2015-2019). We categorized survivors by risk: high risk for those having had pulmotoxic chemotherapy, chest radiation, thoracic surgery, and/or hematopoietic stem cell transplantation, and standard risk for other cancer therapies. Primary outcomes were the global lung clearance index (LCI) and acinar ventilation inhomogeneity index (SACIN) from N2MBW, and forced expiratory volume in 1 second (FEV1) and functional vital capacity (FVC) from spirometry. We calculated z-scores for N2MBW and spirometry parameters and compared pulmonary dysfunction between risk groups. Pulmonary dysfunction was defined as z-score +1.64 for N2MBW and -1.64 for spirometry.Results: We studied 46 survivors, median age at diagnosis 10 years (interquartile range, 4-14), median age at study 30 years (interquartile range, 25-40). Thirty-seven percent were at high risk and 63% at standard risk for pulmonary dysfunction. LCI and SACIN were higher in the high-risk group compared with the standard-risk group (mean LCI z-scores 2.09, standard deviation [SD] 2.39 vs. 0.95, SD 2.81; mean SACINz-scores 2.45, SD 3.29 vs. 0.65, SD 2.79). FEV1 and FVC were lower in the high-risk compared with the standard-risk group (mean FEV1z-scores -0.94, SD 1.39 vs. -0.10, SD 1.07; mean FVC z-scores -1.14, SD 1.23 vs. 0.15, SD 1.61). Overall, LCI, SACIN, FEV1, and FVC were abnormal in 60%, 53%, 33%, and 33% of high-risk patients compared with 23%, 21%, 0%, and 4% of standard-risk patients.Conclusions: N2MBW identified more cases of pulmonary dysfunction in long-term survivors of childhood cancer than spirometry, even in patients who had cancer therapy not specifically known as being pulmotoxic. N2MBW could be a complementary screening tool for early pulmonary damage after treatment for childhood cancer.Clinical trial registered with www.clinicaltrials.gov (NCT02730767).
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Neoplasias , Criança , Estudos Transversais , Volume Expiratório Forçado , Humanos , Pulmão , Neoplasias/terapia , Testes de Função Respiratória , EspirometriaRESUMO
OBJECTIVES: To describe the treatment choice in a cohort of subjects with single-sided deafness (SSD) and asymmetric hearing loss (AHL). To assess the reliability of the treatment trials. DESIGN: In this national, multicentre, prospective study, the choice of subjects was made after two consecutive trials of Contralateral Routing Of the Signal (CROS) hearing aids and a Bone Conduction Device (BCD) on a headband. Subjects could proceed with one of these two options, opt for cochlear implantation or decline all treatments. SETTING: Seven tertiary university hospitals. PARTICIPANTS: One hundred fifty-five subjects with SSD or AHL fulfilling the candidacy criteria for cochlear implantation, with or without associated tinnitus. MAIN OUTCOME MEASURES: After the two trials, the number of subjects choosing each option was described. Repeated assessments of both generic and auditory-specific quality of life were conducted, as well as hearing assessments (speech recognition in noise and horizontal localization). RESULTS: CROS was chosen by 75 subjects, followed by cochlear implantation (n = 51), BCD (n = 18) and abstention (n = 11). Patients who opted for cochlear implantation had a poorer quality of life (P = .03). The improvement of quality of life indices after each trial was significantly associated with the final treatment choice (P = .008 for generic indices, P = .002 for auditory-specific indices). The follow-up showed that this improvement had been overestimated in the CROS group, with a long-term retention rate of 52.5%. CONCLUSIONS: More than one third of SSD/AHL subjects are unsatisfied after CROS and BCD trials. Repeated quality of life assessments help counselling the patient for his/her treatment choice.
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Perda Auditiva Unilateral/reabilitação , Condução Óssea , Comportamento de Escolha , Implantes Cocleares , Feminino , França , Auxiliares de Audição , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Teste do Limiar de Recepção da FalaRESUMO
BACKGROUND: Cardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcomes. OBJECTIVE: In our study, we aim to assess the prevalence of preclinical cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography; determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension); investigate the development of cardiac dysfunction longitudinally in a defined cohort; study the association between cardiac dysfunction and other health outcomes like pulmonary disease, endocrine disease, renal disease, quality of life, fatigue, strength and endurance, and physical activity; and gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications. METHODS: For this retrospective cohort study, we will invite ≥5-year childhood cancer survivors who were treated at the University Children's Hospital Bern, Switzerland with any chemotherapy or cardiac radiation since 1976 and who are ≥18 years of age at the time of the study for a cardiac assessment at the University Hospital Bern. This includes 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and echocardiography including 2-dimensional speckle tracking. RESULTS: We will invite 544 eligible childhood cancer survivors (median age at the time of the study, 32.5 years; median length of time since diagnosis, 25.0 years) for a cardiac assessment. Of these survivors, 300 (55%) are at high risk, and 244 (45%) are at standard risk of cardiac dysfunction. CONCLUSIONS: This study will determine the prevalence of preclinical cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children with cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17724.
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OBJECTIVE: To perform a long-term evaluation of the localisation capabilities in the horizontal plane of single-sided deaf patients fitted with a BAHA device. DESIGN: Single-centre retrospective study. PARTICIPANTS: Twenty-one adults with single-sided deafness (SSD) with normal hearing in the contralateral ear (pure tone average <20 dB, SDS > 90%) rehabilitated with a Cochlear BAHA device from 2003 to 2012 on the deaf side over a median follow-up of 8 years. OUTCOME MEASURES: The task used in this paper is a sound localisation identification task with a set-up of seven loudspeakers on a semi-circular array at 30-degree intervals performed at three periods: before BAHA, initially and at last follow-up. Our main criterion of judgement was the root-mean-square (RMS) localisation error. In addition, the Bern Benefit in Single-Sided Deafness Questionnaire (BBSS) was administered. RESULTS: The mean RMS localisation error was initially estimated at 64° without any rehabilitation (for a chance level RMS estimated at 81°). Initially, with the BAHA device, the RMS localisation error dropped to 51°. At the last follow-up evaluation, a significant decrease at 23° was noted. Concerning the Bern Questionnaire, 19% of the patients (n = 4) did not report any change (score of 0), 33% (n = 7) are satisfied (score of +1 or +2) and 48% (n = 10) are very satisfied with the BAHA device (score better than +3). CONCLUSION: Improvement of sound localisation in the horizontal plane for some SSD patients is likely related to altered processing of monaural spectral cues. The time needed to learn to use the azimuth-dependent spectral cues takes time. Long-term follow-up should be considered for studies investigating sound localisation performance.
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Surdez/reabilitação , Auxiliares de Audição , Perda Auditiva Unilateral/reabilitação , Localização de Som , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Retrospectivos , Percepção da Fala , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Hearing response following an osteodural decompression of the internal auditory canal (IAC) is controversial. OBJECTIVE: To evaluate the course of auditory brainstem responses (ABRs) and the early hearing response during the first year following IAC decompression for small to medium-sized vestibular schwannomas occurring in neurofibromatosis type 2 (NF2). METHODS: Retrospective chart review of middle fossa craniotomy for IAC osteodural decompression in NF2-related vestibular schwannomas. RESULTS: Twelve NF2 patients were operated on from 2011 to 2016 for IAC decompression. All had NF2 according to the Manchester criteria. All had a progressive change of their ABRs documented from the diagnosis of NF2 over a mean period of 6.25 [0.36;10.9] yr. Treatment was proposed to stop hearing progression based on the speech discrimination scores (SDSs; n = 4) or for hearing maintenance (n = 8). In patients with prior hearing progression, hearing responses were observed in 3 of the 4 patients during the first year. One patient kept on progressing. In the hearing maintenance group, the SDSs remained stable. SDSs improved from 85% [20-100] to 92.5% [60-100] on average (n = 12) and from 55% [20-80] to 77.5% [50-100] in the hearing progression group (n = 4). ABRs improved in 4 patients following decompression. CONCLUSION: IAC decompression allows early objective hearing responses in select patients. We suggest that the procedure should be offered to patients with hearing progression based on their SDSs and/or associated progressive increases in their wave III and V latencies on ABRs.
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Descompressão Cirúrgica/métodos , Orelha Interna/fisiologia , Orelha Interna/cirurgia , Testes Auditivos/métodos , Audição/fisiologia , Neurofibromatose 2/cirurgia , Adolescente , Adulto , Criança , Estudos de Coortes , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/diagnóstico , Estudos RetrospectivosRESUMO
Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.
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Antineoplásicos/efeitos adversos , Sobreviventes de Câncer , Atenção à Saúde/normas , Neoplasias/tratamento farmacológico , Ototoxicidade/diagnóstico , Ototoxicidade/prevenção & controle , Adolescente , Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Irradiação Craniana/efeitos adversos , Medicina Baseada em Evidências , Humanos , Neoplasias/radioterapia , Ototoxicidade/etiologia , Ototoxicidade/terapia , Compostos de Platina/efeitos adversos , Vigilância da População , Adulto JovemRESUMO
BACKGROUND: Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. OBJECTIVE: This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. METHODS: From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. RESULTS: The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. CONCLUSIONS: This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels.
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Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Produtos Biológicos/farmacocinética , Hipercolesterolemia/metabolismo , Modelos Biológicos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticolesterolemiantes/farmacologia , Produtos Biológicos/farmacologia , LDL-Colesterol/sangue , Feminino , Voluntários Saudáveis , Humanos , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To determine whether cervical vestibular evoked myogenic potentials (cVEMPs) are predictive of hearing preservation in patients undergoing vestibular schwannoma removal through middle fossa craniotomy approach. STUDY DESIGN: Retrospective case study. SETTING: Tertiary referral center. PATIENTS: Eighteen patients who underwent a middle fossa craniotomy for vestibular schwannoma (stage I or II of Koos classification) with attempted hearing preservation from January 2008 to February 2016 were retrospectively reviewed. INTERVENTION: Pre-surgical cVEMPs test, videonystagmography (caloric test), and magnetic resonance imaging (MRI) as well as a pre- and post-surgical audiometry test. MAIN OUTCOME MEASURES: cVEMPs parameters including amplitude asymmetry ratio (AR), P13, and N23 latencies and peak-to-peak amplitude between P13 and N23 waves were calculated. Hearing data were classified according to the AAO-HNS hearing classes. The nerve of origin of the tumor was specified during surgery and the largest tumor diameter was measure on MRI axial plane on T2-CISS weighed images. RESULTS: Preoperative amplitude asymmetry ratio was lower (nâ=â15, Mann-Whitney U test, pâ<â0.001) in the group with postoperative hearing preservation (nâ=â11) compared with the group with postoperative hearing preservation failure (nâ=â4). The positive predictive value of an AR less than 24% to assess postoperative hearing preservation is 91.6%. Tumor size and localization were not correlated with cVEMPs, nor with caloric testing in this group of small-sized intracanalicular vestibular schwannomas. CONCLUSIONS: Our data suggest that cVEMPs may help predict hearing preservation outcome in vestibular schwannoma surgery via the middle fossa craniotomy approach.
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Craniotomia/efeitos adversos , Perda Auditiva Neurossensorial/etiologia , Neuroma Acústico/cirurgia , Potenciais Evocados Miogênicos Vestibulares/fisiologia , Adulto , Idoso , Craniotomia/métodos , Feminino , Audição/fisiologia , Perda Auditiva Neurossensorial/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: We aimed to evaluate the outcome of patients who underwent salvage microsurgery for vestibular schwannoma (VS) that failed primary Gammaknife radiosurgery (GKS). PATIENTS AND METHODS: Among the 1098 patients who received GKS for the treatment of VS in our center between January 2004 and December 2012, the follow-up was organized in our institution for 290 patients who lived in our recruitment area. Tumor progression was noted in 23 patients. A salvage microsurgical resection was performed in 11 patients, who were included in our study. Grading of facial function was done according to the House & Brackman scale. RESULTS: The mean age at diagnosis was 50.2 years (19-68 years) and the mean follow-up was 9.4 years (4-13 years). The mean dose was 11.8â¯Gy (11-12â¯Gy) and the mean volume was 922â¯mm3 (208-2500â¯mm3). The mean period between GKS and diagnosis of tumor progression was 32 months (18-72 months). Concerning salvage microsurgery, complete resection was obtained in 8 patients. Small residual tumor on the facial nerve was deliberately left in 3 patients and no tumor progression was noted with a mean follow-up of 26 months. At last follow-up, facial nerve function was grade 1 in 4 patients, grade 2 in 3 patients, grade 3 in 1 patient and grade 4 in 3 patients. CONCLUSION: Salvage surgery of recurrent vestibular schwannoma after failed initial GKS remains a good treatment. However, facial nerve preservation is more challenging in this case and small tumor remnant could be sometimes deliberately left.
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Nervo Facial/cirurgia , Microcirurgia/efeitos adversos , Neuroma Acústico/cirurgia , Radiocirurgia , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Radiocirurgia/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: This study aims to describe the clinical and molecular presentation of pediatric neurofibromatosis type 2 (NF2) and the subsequent management of vestibular schwannomas (VS) and hearing rehabilitation. METHODS: This is a single-center retrospective study of neurofibromatosis type 2 diagnosed before the age of 18 years old from 1997. Natural history of vestibular schwannomas and surgical outcomes were evaluated using volumetric MRI, hearing, and facial nerve assessment. Patients included in chemotherapy protocols were excluded. RESULTS: From a database of 80 patients followed up for NF2 on a regular basis, 25 patients were eligible (11 sporadic cases, 14 inherited in five families). The mean age at diagnosis was 11.6 years old. The average clinical follow-up was 6.5 years. NF2 mutation was identified in 81 % of the probands. The average growth rate based on the maximum linear diameter (DGR) was 1.68 mm/year (n = 33, average follow-up 4.22 years) and 545 mm3/year in volumetric assessment (VGR) for VS larger than 1 cm (n = 21, average follow-up 3.4 years). In unoperated ears, hearing was stable in about 50 % of ears. The mean change in dB HL was 9.5 dB/year for pure-tone average and 3.5 for speech-recognition threshold (n = 34, 5.5 years 1-12). Eight children required removal through a translabyrinthine approach (mean follow-up was 4.5 years), six patients were operated on for hearing preservation (mean postoperative follow-up 4.3 years). Six patients were eligible for hearing rehabilitation with cochlear implantation (I), and five received placement of an auditory brainstem implant. CONCLUSION: Early diagnosis and treatment of small growing VS should be carefully discussed considering familial history and possible rehabilitation with a CI.
Assuntos
Correção de Deficiência Auditiva/métodos , Neurofibromatose 2/complicações , Neuroma Acústico/diagnóstico , Neuroma Acústico/etiologia , Neuroma Acústico/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Testes Auditivos , Humanos , Masculino , Estudos RetrospectivosRESUMO
Fertility preservation (FP) is an important topic of discussion in the field of oncology, particularly in pediatric oncology. Despite the awareness of severe impact of infertility on quality of life and different guidelines available in this area, the options in FP are not routinely discussed with the pediatric cancer patients and their parents. To the best of our knowledge, this is the first survey report concerned to FP counseling and procedures in pediatric and adolescent cancer patients in Switzerland. This survey was conducted from June 2014 to October 2014 on the counseling and procedures performed between 2009 and 2013; the questionnaire was completed by one of the professional from hematology/oncology centers in Switzerland. Currently, only four out of nine centers have a program for FP. In 2013, 45/301 (15%) patients received FP counseling and 36/301 (12%) underwent an FP procedure. The most commonly performed procedures from 2009 to 2013 were administration of gonadotropin releasing hormone agonist (3%) and cryopreservation of ovarian tissue in females (3%) and cryopreservation of sperms in males (6%); the most frequently cited reason for the absence of FP counseling was lack of time (55%). Therefore, this survey should help to develop and harmonize practices with respect to FP counseling and procedures in Switzerland, and to establish FP as a standard of care during cancer treatment.
Assuntos
Preservação da Fertilidade/psicologia , Comunicação em Saúde/normas , Infertilidade/prevenção & controle , Neoplasias/fisiopatologia , Adolescente , Criança , Aconselhamento , Estudos Transversais , Tomada de Decisões , Feminino , Preservação da Fertilidade/métodos , Humanos , Masculino , Neoplasias/psicologia , Pesquisa Qualitativa , Qualidade de Vida , Inquéritos e Questionários , SuíçaRESUMO
The Mongolian gerbil (Meriones unguiculatus) is commonly used in hearing research because the hearing frequency spectrum of the gerbil is rather similar to that of the human being. However, a precise description of the surgical post-auricular route has not been reported. The aim of this technical note is to provide details on the procedure and the surgical anatomy of the post-auricular route in the Mongolian gerbil. Surgery was performed under general anesthesia on eight (2 males and 6 females) adult Mongolian gerbils. All steps of the post-auricular route were detailed. This surgery provided an access to the following structures: the semi-circular posterior and lateral canals, the external auditory meatus, the tympanic membrane, the round window, the stapes, the stapedial artery and the reliefs of the cochlea. No anatomic variation was noticed among the 8 animals. This post-auricular route in the Mongolian gerbil defines a brief and simple surgery, overall standardized as a consequence of the absence of common anatomic variation, with painless and uncomplicated post-operative stage.
Assuntos
Procedimentos Cirúrgicos Otológicos/métodos , Membrana Timpânica/anatomia & histologia , Membrana Timpânica/cirurgia , Animais , Pavilhão Auricular , Feminino , Gerbillinae , Audição , Humanos , Masculino , Período Pós-Operatório , Estribo/anatomia & histologia , Cirurgia do EstriboRESUMO
Vestibular schwannoma is a benign neoplasm arising from the Schwann cell sheath of the auditory-vestibular nerve. It most commonly affects both sides in the genetic condition Neurofibromatosis type 2, causing progressive high frequency sensorineural hearing loss. Here, we describe a microsurgical technique and stereotactic coordinates for schwannoma cell grafting in the vestibular nerve region that recapitulates local tumor growth in the cerebellopontine angle and inner auditory canal with resulting hearing loss. Tumor growth was monitored by bioluminescence and MRI in vivo imaging, and hearing assessed by auditory brainstem responses. These techniques, by potentially enabling orthotopic grafting of a variety of cell lines will allow studies on the pathogenesis of tumor-related hearing loss and preclinical drug evaluation, including hearing endpoints, for NF2-related and sporadic schwannomas.
Assuntos
Modelos Animais de Doenças , Perda Auditiva/fisiopatologia , Neuroma Acústico/fisiopatologia , Transplante Homólogo , Animais , Linhagem Celular Tumoral , Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Neurofibromatose 2/genética , Neuroma Acústico/complicações , Nervo Vestibulococlear/cirurgiaRESUMO
OBJECTIVES/HYPOTHESIS: To determine the long-term growth rate of vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2) patients based on volumetric measurements. STUDY DESIGN: Retrospective review. METHODS: We retrospectively reviewed magnetic resonance imaging (MRI) scans acquired from patients with NF2 from 1999 to 2013. Patients with an annual radiologic follow-up over at least 3 consecutive years were included. Volumetric VS growth was prospectively measured using a three-dimensional imaging workstation and through manual contouring of the lesion. Time to tumor progression was assessed according to the Response Evaluation in Neurofibromatosis and Schwannomatosis Tumor Measurement Group. RESULTS: Eighteen patients presenting with a total of 26 VSs were included. The mean age at diagnosis was 26.1 years (range, 7 to 49 years). One hundred five MRI scans were analyzed during a median radiological follow-up of 5.6 years (range, 3 to 12 years). The annual volume and diameter growth rates were respectively 218.3 mm(3) /yr (range, -10 to 1,250 mm(3) /yr) and 0.9 mm/yr (range, -0.5 to 4.5 mm/yr). Time to tumor progression was 3 years (median survival). There was a weak correlation between volumetric and linear measurements (P < .0001, linear regression, n = 26, r(2) = 0.58). Among the 26 VSs, 76.9% (20/26) showed progression (VS growth more than 20%), 19.2% were stable, and 3.9% (1/26) exhibited shrinkage (spontaneous regression of more than 20% of the initial volume). CONCLUSIONS: This study helps to assess the long-term growth profile of VS in a population of NF2 patients with untreated VS. These data could help to better acknowledge VS natural growth history. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2358-2362, 2016.