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1.
Ann Neurol ; 95(4): 720-732, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38086777

RESUMO

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.


Assuntos
Neuromielite Óptica , Humanos , Aquaporina 4 , Glicoproteína Mielina-Oligodendrócito , Autoanticorpos , Imunoglobulina G , Recidiva
2.
Artigo em Inglês | MEDLINE | ID: mdl-39084862

RESUMO

BACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

3.
Mult Scler ; 29(7): 819-831, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36786424

RESUMO

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.


Assuntos
Esclerose Múltipla , Neuromielite Óptica , Humanos , Neuromielite Óptica/complicações , Neuromielite Óptica/epidemiologia , Estudos Prospectivos , Aquaporina 4 , Cognição , Imunoglobulina G , Autoanticorpos
4.
Int J Gynecol Cancer ; 33(4): 562-570, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36564099

RESUMO

OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. METHODS: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. RESULTS: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. CONCLUSIONS: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02751918.


Assuntos
Imunoconjugados , Neoplasias Ovarianas , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Imunoconjugados/efeitos adversos , Neoplasias Ovarianas/patologia , Polietilenoglicóis
5.
Lancet Oncol ; 23(4): 540-552, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35358455

RESUMO

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.


Assuntos
Imunoconjugados , Mesotelioma Maligno , Adolescente , Adulto , Humanos , Artrogripose , Imunoconjugados/efeitos adversos , Maitansina/análogos & derivados , Mesotelina , Mesotelioma Maligno/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Vinorelbina/efeitos adversos
6.
Br J Cancer ; 116(12): 1505-1512, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28463960

RESUMO

BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Transdução de Sinais/genética , Sulfóxidos/administração & dosagem , Sulfóxidos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/farmacocinética , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/genética , Neoplasias Ovarianas/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Vômito/induzido quimicamente
7.
Cell Chem Biol ; 31(7): 1247-1263.e16, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38537632

RESUMO

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos , Proliferação de Células , Ensaios de Triagem em Larga Escala , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Sinalização YAP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Camundongos , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Linhagem Celular Tumoral , Fosfoproteínas/metabolismo , Fosfoproteínas/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Alquil e Aril Transferases/antagonistas & inibidores , Alquil e Aril Transferases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Descoberta de Drogas , Camundongos Nus , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Fenótipo , Relação Estrutura-Atividade , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
8.
Artigo em Inglês | MEDLINE | ID: mdl-36693760

RESUMO

BACKGROUND AND OBJECTIVES: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). METHODS: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. RESULTS: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). DISCUSSION: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease.


Assuntos
COVID-19 , Neuromielite Óptica , Humanos , Feminino , Masculino , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/terapia , Pandemias , Glicoproteína Mielina-Oligodendrócito , Estudos Transversais , Vacinas contra COVID-19 , Qualidade de Vida , COVID-19/epidemiologia , SARS-CoV-2 , Imunoglobulina G
9.
Neurology ; 98(11): e1184-e1196, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35082170

RESUMO

BACKGROUND AND OBJECTIVES: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. RESULTS: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. DISCUSSION: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.


Assuntos
Neuromielite Óptica , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4 , Autoanticorpos , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicoproteína Mielina-Oligodendrócito , Qualidade de Vida , Adulto Jovem
10.
Stud Health Technol Inform ; 163: 105-11, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21335771

RESUMO

This paper presents an advanced method of visualizing the surface appearance of living brain tissue. We have been granted access to the operating theatre during neurosurgical procedures to obtain colour data via calibrated photography of exposed brain tissue. The specular reflectivity of the brain's surface is approximated by analyzing a gelatine layer applied to animal flesh. This provides data for a bidirectional reflectance distribution function (BRDF) that is then used the rendering process. Rendering is achieved in realtime by utilizing the GPU, and includes support for ambient occlusion, advanced texturing, sub surface scattering and specularity. Our goal is to investigate whether realistic visualizations of living anatomy can be produced and so provide added value to anatomy education.


Assuntos
Encéfalo/anatomia & histologia , Gráficos por Computador , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Iluminação/métodos , Modelos Anatômicos , Fotografação/métodos , Algoritmos , Simulação por Computador , Humanos , Aumento da Imagem/métodos , Reconhecimento Automatizado de Padrão/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Interface Usuário-Computador
11.
Artigo em Inglês | MEDLINE | ID: mdl-33334856

RESUMO

OBJECTIVE: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. METHODS: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13). RESULTS: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD. CONCLUSIONS: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Neuromielite Óptica/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Rituximab/efeitos adversos , Adulto , Estudos de Coortes , Feminino , Alemanha , Humanos , Fatores Imunológicos/efeitos adversos , Gravidez , Resultado da Gravidez
12.
Bioorg Med Chem Lett ; 20(1): 157-60, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19945875

RESUMO

A series of tetrahydro-beta-carbolines were identified by HTS as inhibitors of the kinesin Eg5. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of removing potential metabolic liabilities and improving cellular potency.


Assuntos
Carbolinas/química , Inibidores Enzimáticos/química , Cinesinas/antagonistas & inibidores , Regulação Alostérica , Animais , Sítios de Ligação , Carbolinas/síntese química , Carbolinas/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ensaios de Triagem em Larga Escala , Humanos , Cinesinas/metabolismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
13.
Z Med Phys ; 20(4): 309-15, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20884187

RESUMO

This article presents a non-invasive sensor setup for objective analysis of the pre-corneal human tear-film involving a time-resolved videokeratoscopy and simultaneous imaging of the lipid layer of the tear-film by a second CMOS-camera. This paper describes in detail the mechanical and optical design of the sensor setup, the realization of the entire illumination component with an integrated Placido grid projection, and the calculation of the image formation using the Placido grid. This concept is demonstrated here with a test subject in the full inter-blink period. All images were taken under physiological conditions. The sensor can assist the ophthalmologist in diagnosing Dry-Eye Syndrome. Results and other potential applications are discussed.


Assuntos
Piscadela/fisiologia , Olho/anatomia & histologia , Fenômenos Fisiológicos Oculares , Lágrimas/fisiologia , Síndromes do Olho Seco/fisiopatologia , Humanos , Iluminação , Lipídeos/análise , Lipídeos/fisiologia , Índice de Gravidade de Doença
14.
Cancer Treat Res Commun ; 25: 100260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33310366

RESUMO

OBJECTIVES: We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland. METHODS: Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression. RESULTS: Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71-10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35-6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97-4.67) for MSLN+/PD-L1- patients. CONCLUSIONS: Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Antígeno B7-H1/metabolismo , Proteínas Ligadas por GPI/uso terapêutico , Mesotelioma Maligno/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/farmacologia , Estudos de Coortes , Feminino , Finlândia , Proteínas Ligadas por GPI/farmacologia , Humanos , Masculino , Mesotelina , Prognóstico
15.
J Clin Oncol ; 38(16): 1824-1835, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213105

RESUMO

PURPOSE: This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS: This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS: Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION: Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Proteínas Ligadas por GPI/antagonistas & inibidores , Imunoconjugados/administração & dosagem , Maitansina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Masculino , Dose Máxima Tolerável , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/farmacocinética , Mesotelina , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/patologia , Intervalo Livre de Progressão
16.
J Opt Soc Am A Opt Image Sci Vis ; 26(10): 2219-25, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19798403

RESUMO

A novel measurement setup for determining the change in color perception due to laser protection filters is described. The developed system overcomes color space limitations common to thin-film transistor displays by using a LED illumination system, creating a large gamut covering a wide range of human color perception, and allowing adjustment of the respective spectra. An objective color matching method is used that is based on the work of MacAdam [J. Opt. Soc. Am. A32, 247 (1942)] and enhanced by employing discrimination ellipses fitted on color discrimination thresholds on axes in the CIE 1976 USC chromaticity diagram. We present several measured color discrimination ellipses with and without laser protection filters.


Assuntos
Percepção de Cores , Equipamentos e Provisões Elétricas , Adulto , Tubo de Raio Catódico , Humanos , Lasers , Reprodutibilidade dos Testes , Transistores Eletrônicos
17.
Eur J Cancer ; 109: 103-110, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30711772

RESUMO

BACKGROUND: Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies. MATERIAL AND METHODS: In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose-response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated. RESULTS: Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment. CONCLUSION: The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.


Assuntos
Benzodiazepinas/farmacocinética , Benzodiazepinas/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Adulto , Idoso , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Distribuição Tecidual
18.
J Cell Biochem ; 104(3): 1075-86, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18286467

RESUMO

The Cdc7/Dbf4 kinase is required for initiation of DNA replication and also plays a role in checkpoint function in response to replication stress. Exactly how Cdc7/Dbf4 mediates those activities remains to be elucidated. Cdc7/Dbf4 physically interacts with and phosphorylates the minichromosome maintenance complex (MCM), such as MCM2, MCM4 and MCM6. Cdc7/Dbf4 activity is required for association of Cdc45 followed by recruitment of DNA polymerase on the chromatin. Using high resolution mass spectrometry, we identified six phosphorylation sites on MCM2, two of them have not been described before. We provide evidence that Cdc7/Dbf4 mediates phosphorylation on serine 108 and serine 40 on human MCM2 in vitro and in vivo in cancer cells in the absence of DNA damage. Antibodies specific to pS108 or pS40 confirmed the sites and established useful read-outs for inhibition of Cdc7/Dbf4. This report demonstrates the utility of an in vitro to in vivo workflow utilizing immunoprecipitation and mass spectrometry to map phosphorylation sites on endogenous kinase substrates. The approach can be readily generalized to identify target modulation read-outs for other potential kinase cancer targets.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Apoptose , Linhagem Celular Tumoral , Cromatina/metabolismo , Humanos , Espectrometria de Massas/métodos , Componente 2 do Complexo de Manutenção de Minicromossomo , Dados de Sequência Molecular , Mutagênese , Fosforilação
20.
Cell Rep ; 21(7): 1953-1967, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29141225

RESUMO

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.


Assuntos
Xenoenxertos/patologia , Melanoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Células Cultivadas , Xenoenxertos/metabolismo , Humanos , Melanoma/classificação , Melanoma/genética , Camundongos
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