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1.
N Engl J Med ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38912654

RESUMO

BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

3.
Otolaryngol Head Neck Surg ; 171(2): 578-587, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38613204

RESUMO

OBJECTIVE: Positive airway pressure (PAP) titration during drug-induced sleep endoscopy (DISE) provides objective measures of upper airway collapsibility. While skeletal measurements relate to collapsibility measures on DISE, the influence of soft tissue dimensions on upper airway collapsibility is not known. We analyzed the relationship of measures of upper airway soft tissue volumes, specifically soft palate, pharyngeal lateral walls, and tongue, with metrics of collapsibility. STUDY DESIGN: Cross-sectional analysis from a prospective cohort. SETTING: Academic medical center. METHODS: Patients seeking PAP alternative therapies for obstructive sleep apnea (OSA) underwent standardized supine computed tomography (CT) acquisition and DISE protocols. The CT analysis primarily focused on soft tissue volumes and, secondarily, on airway and skeletal volumetric measures. DISE with PAP administration (DISE-PAP) enabled the determination of the pressure at which inspiratory airflow first commenced (pharyngeal critical pressure, PcritA) and the pressure at which inspiratory flow limitation was abolished (pharyngeal opening pressure, PhOP). Both unadjusted and adjusted correlation analyses were performed to understand the relationship between upper airway anatomy and either PcritA or PhOP. RESULTS: One hundred thirty-nine subjects completed both CT and DISE-PAP. On average, patients were male (70.5%), white (84.2%), middle-aged (56.6 ± 13.5 years), and overweight (29.6 ± 4.7 kg/m2), with moderate-severe apnea-hypopnea index (29.7 ± 21.3 events/h). Adjusted for age, sex, body mass index, and skeletal volumes, soft palate, and lateral pharyngeal wall volumes were not associated with PhOP or PcritA, but a larger tongue was associated with more positive PhOP (⍴ = 0.20, P = .02), and more positive PcritA (⍴ = 0.16, P = .07). Exploratory analyses revealed smaller minimum cross-sectional retropalatal area and intramandibular volume were also associated with increased collapsibility measures. CONCLUSION: After controlling for clinical factors and skeletal volume, greater tongue volume was associated with more severe collapsibility during DISE. These results, in concert with previous work, suggest that greater tongue volume in a smaller skeletal dimensions contribute to the severity of airway collapsibility, a key driver of OSA pathogenesis.


Assuntos
Endoscopia , Palato Mole , Faringe , Apneia Obstrutiva do Sono , Tomografia Computadorizada por Raios X , Língua , Humanos , Masculino , Feminino , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos Transversais , Estudos Prospectivos , Palato Mole/diagnóstico por imagem , Palato Mole/fisiopatologia , Faringe/diagnóstico por imagem , Faringe/fisiopatologia , Língua/diagnóstico por imagem , Língua/fisiopatologia , Adulto , Polissonografia , Pressão Positiva Contínua nas Vias Aéreas , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/fisiopatologia
4.
Ann Am Thorac Soc ; 21(6): 949-960, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38507612

RESUMO

Rationale: Apneic individuals have reduced airway caliber during sleep. The biomechanical changes in upper airway anatomy contributing to this airway narrowing are largely unknown. Objectives: We sought to investigate the state-dependent (wake vs. sleep) biomechanical behavior of the upper airway soft-tissue and craniofacial structures. Methods: Upper airway magnetic resonance imaging was performed in 15 sleep-deprived control subjects (apnea-hypopnea index, <5; 0.3 ± 0.5 events per hour) and 12 sleep-deprived apneic subjects (apnea-hypopnea index, ⩾5; 35.2 ± 18.1 events per hour) during wake and sleep and analyzed for airway measures and soft-tissue/mandibular movement. Results: In the retropalatal region, control subjects showed sleep-dependent reductions (P ⩽ 0.037) in average cross-sectional airway area (CSA), minimum CSA, and anteroposterior and lateral dimensions. Apneic subjects showed sleep-dependent reductions (P ⩽ 0.002) in average CSA, minimum CSA, and anteroposterior and lateral dimensions. In the retroglossal region, control subjects had no sleep-dependent airway reductions. However, apneic subjects had sleep-dependent reductions in minimal CSA (P = 0.001) and lateral dimensions (P = 0.014). Control subjects only showed sleep-dependent posterior movement of the anterior-inferior tongue octant (P = 0.039), whereas apneic subjects showed posterior movement of the soft palate (P = 0.006) and all tongue octants (P ⩽ 0.012). Sleep-dependent medial movement of the lateral walls was seen at the retropalatal minimum level (P = 0.013) in control subjects and at the retropalatal and retroglossal minimum levels (P ⩽ 0.017) in apneic subjects. There was posterior movement of the mandible in apneic subjects (P ⩽ 0.017). Conclusions: During sleep, control and apneic subjects showed reductions in retropalatal airway caliber, but only the apneic subjects showed retroglossal airway narrowing. Reductions in anteroposterior and lateral airway dimensions were primarily due to posterior soft palate, tongue and mandibular movement and to medial lateral wall movement. These data provide important initial insights into obstructive sleep apnea pathogenesis.


Assuntos
Imageamento por Ressonância Magnética , Orofaringe , Estudo de Prova de Conceito , Apneia Obstrutiva do Sono , Humanos , Masculino , Feminino , Orofaringe/diagnóstico por imagem , Orofaringe/fisiopatologia , Pessoa de Meia-Idade , Fenômenos Biomecânicos , Adulto , Apneia Obstrutiva do Sono/fisiopatologia , Estudos de Casos e Controles , Polissonografia , Sono/fisiologia , Língua/diagnóstico por imagem , Língua/fisiopatologia , Palato Mole/diagnóstico por imagem , Palato Mole/fisiopatologia
5.
Contemp Clin Trials ; 141: 107516, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38547961

RESUMO

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.


Assuntos
Obesidade , Apneia Obstrutiva do Sono , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Massa Corporal , Pressão Positiva Contínua nas Vias Aéreas/métodos , Método Duplo-Cego , Obesidade/complicações , Polissonografia , Projetos de Pesquisa , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/terapia , Apneia Obstrutiva do Sono/tratamento farmacológico , Redução de Peso/efeitos dos fármacos
7.
Breast Cancer Res ; 26(1): 32, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-38408999

RESUMO

BACKGROUND: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Eligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV. RESULTS: Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. CONCLUSION: The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. TRIAL REGISTRATION: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Paclitaxel/uso terapêutico , Receptor ErbB-2/genética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
8.
J Neurosci Res ; 102(3): e25313, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38415989

RESUMO

A key function of sleep is to provide a regular period of reduced brain metabolism, which is critical for maintenance of healthy brain function. The purpose of this work was to quantify the sleep-stage-dependent changes in brain energetics in terms of cerebral metabolic rate of oxygen (CMRO2 ) as a function of sleep stage using quantitative magnetic resonance imaging (MRI) with concurrent electroencephalography (EEG) during sleep in the scanner. Twenty-two young and older subjects with regular sleep hygiene and Pittsburgh Sleep Quality Index (PSQI) in the normal range were recruited for the study. Cerebral blood flow (CBF) and venous oxygen saturation (SvO2 ) were obtained simultaneously at 3 Tesla field strength and 2.7-s temporal resolution during an 80-min time series using OxFlow, an in-house developed imaging sequence. The method yields whole-brain CMRO2 in absolute physiologic units via Fick's Principle. Nineteen subjects yielded evaluable data free of subject motion artifacts. Among these subjects, 10 achieved slow-wave (N3) sleep, 16 achieved N2 sleep, and 19 achieved N1 sleep while undergoing the MRI protocol during scanning. Mean CMRO2 was 98 ± 7(µmol min-1 )/100 g awake, declining progressively toward deepest sleep stage: 94 ± 10.8 (N1), 91 ± 11.4 (N2), and 76 ± 9.0 µmol min-1 /100 g (N3), with each level differing significantly from the wake state. The technology described is able to quantify cerebral oxygen metabolism in absolute physiologic units along with non-REM sleep stage, indicating brain oxygen consumption to be closely associated with depth of sleep, with deeper sleep stages exhibiting progressively lower CMRO2 levels.


Assuntos
Imageamento por Ressonância Magnética , Fases do Sono , Humanos , Sono , Oxigênio , Espectroscopia de Ressonância Magnética
9.
Brain Imaging Behav ; 18(3): 510-518, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38194040

RESUMO

Sleep apnea, affecting an estimated 1 in 4 American adults, has been reported to be associated with both brain structural abnormality and impaired cognitive function. Obstructive sleep apnea is known to be affected by upper airway anatomy. To better understand the contribution of upper airway anatomy to pathways linking sleep apnea with impaired cognitive function, we investigated the association of upper airway anatomy with structural brain abnormalities. Based in the Multi-Ethnic Study of Atherosclerosis, a longitudinal cohort study of community-dwelling adults, a comprehensive sleep study and an MRI of the upper airway and brain were performed on 578 participants. Machine learning models were used to select from 74 upper airway measures those measures most associated with selected regional brain volumes and white matter hyperintensity volume. Linear regression assessed associations between the selected upper airway measures, sleep measures, and brain structure. Maxillary divergence was positively associated with hippocampus volume, and mandible length was negatively associated with total white and gray matter volume. Both coefficients were small (coefficients per standard deviation 0.063 mL, p = 0.04, and - 7.0 mL, p < 0.001 respectively), and not affected by adjustment for sleep study measures. Self-reported snoring >2 times per week was associated with larger hippocampus volume (coefficient 0.164 mL, p = 0.007), and higher percentage of time in the N3 sleep stage was associated with larger total white and gray matter volume (4.8 mL, p = 0.004). Despite associations of two upper airway anatomy measures with brain volume, the evidence did not suggest that these upper airway and brain structure associations were acting primarily through the pathway of sleep disturbance.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Idoso , Estudos Longitudinais , Aterosclerose/patologia , Pessoa de Meia-Idade , Tamanho do Órgão , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Apneia Obstrutiva do Sono/patologia , Idoso de 80 Anos ou mais , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Ronco/diagnóstico por imagem , Ronco/patologia , Aprendizado de Máquina
10.
Sleep ; 47(3)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38038363

RESUMO

STUDY OBJECTIVES: This study aimed to evaluate and compare measurements of standardized craniofacial and intraoral photographs between clinical and general population samples, between groups of individuals with an apnea-hypopnea index (AHI) ≥ 15 and AHI < 15, and their interaction, as well as the relationship with the presence and severity of obstructive sleep apnea (OSA). METHODS: We used data from 929 participants from Sleep Apnea Global Interdisciplinary Consortium, in which 309 patients from a clinical setting and 620 volunteers from a general population. RESULTS: AHI ≥ 15 were observed in 30.3% of the total sample and there were some interactions between facial/intraoral measures with OSA and both samples. Mandibular volume (p < 0.01) and lateral face height (p = 0.04) were higher in the AHI ≥ 15 group in the clinical sample compared to the AHI ≥ 15 group in the general population and AHI < 15 group in the clinical sample. When adjusted for sex and age, greater mandible width (p < 0.01) differed both in the clinical and in the general population samples, reflecting AHI severity and the likelihood of OSA. The measure of smaller tongue curvature (p < 0.01) reflected the severity and probability of OSA in the clinical sample and the higher posterior mandibular height (p = 0.04) showed a relationship with higher AHI and higher risk of OSA in the general population. When adjusted for sex, age, and body mass index, only smaller tongue curvature (p < 0.01) was associated with moderate/severe OSA. CONCLUSIONS: Measures of greater tongue and mandible were associated with increased OSA risk in the clinical sample and craniofacial measurement was associated in the general population sample.


Assuntos
Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Face , Mandíbula , Índice de Massa Corporal
12.
BMC Neurol ; 23(1): 394, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37907860

RESUMO

BACKGROUND: Numerous upper airway anatomy characteristics are risk factors for sleep apnea, which affects 26% of older Americans, and more severe sleep apnea is associated with cognitive impairment. This study explores the pathophysiology and links between upper airway anatomy, sleep, and cognition. METHODS: Participants in the Multi-Ethnic Study of Atherosclerosis underwent an upper airway MRI, polysomnography to assess sleep measures including the apnea-hypopnea index (AHI) and completed the Cognitive Abilities Screening Instrument (CASI). Two model selection techniques selected from among 67 upper airway measures those that are most strongly associated with CASI score. The associations of selected upper airway measures with AHI, AHI with CASI score, and selected upper airway anatomy measures with CASI score, both alone and after adjustment for AHI, were assessed using linear regression. RESULTS: Soft palate volume, maxillary divergence, and upper facial height were significantly positively associated with higher CASI score, indicating better cognition. The coefficients were small, with a 1 standard deviation (SD) increase in these variables being associated with a 0.83, 0.75, and 0.70 point higher CASI score, respectively. Additional adjustment for AHI very slightly attenuated these associations. Larger soft palate volume was significantly associated with higher AHI (15% higher AHI (95% CI 2%,28%) per SD). Higher AHI was marginally associated with higher CASI score (0.43 (95% CI 0.01,0.85) per AHI doubling). CONCLUSIONS: Three upper airway measures were weakly but significantly associated with higher global cognitive test performance. Sleep apnea did not appear to be the mechanism through which these upper airway and cognition associations were acting. Further research on the selected upper airway measures is recommended.


Assuntos
Aterosclerose , Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Humanos , Idoso , Síndromes da Apneia do Sono/complicações , Polissonografia/efeitos adversos , Fatores de Risco , Aterosclerose/complicações
13.
Diabetes Obes Metab ; 25(12): 3621-3631, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37667658

RESUMO

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/uso terapêutico , Hemoglobinas Glicadas , Estudos Cross-Over , Compostos Benzidrílicos/uso terapêutico , Fígado/diagnóstico por imagem , Fígado/metabolismo , Peso Corporal , Metabolismo Energético , Método Duplo-Cego , Resultado do Tratamento , Glicemia/metabolismo
14.
Breast Cancer Res Treat ; 199(2): 281-291, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37029329

RESUMO

PURPOSE: ROR1 and ROR2 are Type 1 tyrosine kinase-like orphan receptors for Wnt5a that are associated with breast cancer progression. Experimental agents targeting ROR1 and ROR2 are in clinical trials. This study evaluated whether expression levels of ROR1 or ROR2 correlated with one another or with clinical outcomes. METHODS: We interrogated the clinical significance of high-level gene expression of ROR1 and/or ROR2 in the annotated transcriptome dataset from 989 patients with high-risk early breast cancer enrolled in one of nine completed/graduated/experimental and control arms in the neoadjuvant I-SPY2 clinical trial (NCT01042379). RESULTS: High ROR1 or high ROR2 was associated with breast cancer subtypes. High ROR1 was more prevalent among hormone receptor-negative and human epidermal growth factor receptor 2-negative (HR-HER2-) tumors and high ROR2 was less prevalent in this subtype. Although not associated with pathologic complete response, high ROR1 or high ROR2 each was associated with event-free survival (EFS) in distinct subtypes. High ROR1 associated with a worse EFS in HR + HER2- patients with high post-treatment residual cancer burden (RCB-II/III) (HR 1.41, 95% CI = 1.11-1.80) but not in patients with minimal post-treatment disease (RCB-0/I) (HR 1.85, 95% CI = 0.74-4.61). High ROR2 associated with an increased risk of relapse in patients with HER2 + disease and RCB-0/I (HR 3.46, 95% CI = 1.33-9.020) but not RCB-II/III (HR 1.07, 95% CI = 0.69-1.64). CONCLUSION: High ROR1 or high ROR2 distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if high ROR1 or high ROR2 may identify high-risk populations for studies of targeted therapies.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Recidiva Local de Neoplasia , Expressão Gênica
16.
Ann Am Thorac Soc ; 20(6): 880-890, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36780658

RESUMO

Rationale: Craniofacial and pharyngeal morphology influences risk for obstructive sleep apnea (OSA). Quantitative photography provides phenotypic information about these anatomical factors and is feasible in large samples. However, whether associations between morphology and OSA severity differ among populations is unknown. Objectives: The aim of this study was to examine this question in a large sample encompassing people from different ancestral backgrounds. Methods: Participants in SAGIC (Sleep Apnea Global Interdisciplinary Consortium) with genotyping data were included (N = 2,393). Associations between photography-based measures and OSA severity were assessed using linear regression, controlling for age, sex, body mass index, and genetic ancestry. Subgroups (on the basis of 1000 Genomes reference populations) were identified: European (EUR), East Asian, American, South Asian, and African (AFR). Interaction tests were used to assess if genetically determined ancestry group modified these relationships. Results: Cluster analysis of genetic ancestry proportions identified four ancestrally defined groups: East Asia (48.3%), EUR (33.6%), admixed (11.7%; 46% EUR, 27% Americas, and 22% AFR), and AFR (6.4%). Multiple anatomical traits were associated with more severe OSA independent of ancestry, including larger cervicomental angle (standardized ß [95% confidence interval (CI)] = 0.11 [0.06-0.16]; P < 0.001), mandibular width (standardized ß [95% CI] = 0.15 [0.10-0.20]; P < 0.001), and tongue thickness (standardized ß [95% CI] = 0.06 [0.02-0.10]; P = 0.001) and smaller airway width (standardized ß [95% CI] = -0.08 [-0.15 to -0.002]; P = 0.043). Other traits, including maxillary and mandibular depth angles and lower face height, demonstrated different associations with OSA severity on the basis of ancestrally defined subgroups. Conclusions: We confirm that multiple facial and intraoral photographic measurements are associated with OSA severity independent of ancestral background, whereas others differ in their associations among the ancestrally defined subgroups.


Assuntos
Face , Apneia Obstrutiva do Sono , Humanos , Cefalometria , Face/anatomia & histologia , Apneia Obstrutiva do Sono/genética , Índice de Massa Corporal , Faringe
18.
Acad Radiol ; 30(3): 421-430, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35606257

RESUMO

RATIONALE AND OBJECTIVES: Accurate segmentation of the upper airway lumen and surrounding soft tissue anatomy, especially tongue fat, using magnetic resonance images is crucial for evaluating the role of anatomic risk factors in the pathogenesis of obstructive sleep apnea (OSA). We present a convolutional neural network to automatically segment and quantify upper airway structures that are known OSA risk factors from unprocessed magnetic resonance images. MATERIALS AND METHODS: Four datasets (n = [31, 35, 64, 76]) with T1-weighted scans and manually delineated labels of 10 regions of interest were used for model training and validations. We investigated a modified U-Net architecture that uses multiple convolution filter sizes to achieve multi-scale feature extraction. Validations included four-fold cross-validation and leave-study-out validations to measure generalization ability of the trained models. Automatic segmentations were also used to calculate the tongue fat ratio, a biomarker of OSA. Dice coefficient, Pearson's correlation, agreement analyses, and expert-derived clinical parameters were used to evaluate segmentations and tongue fat ratio values. RESULTS: Cross-validated mean Dice coefficient across all regions of interests and scans was 0.70 ± 0.10 with highest mean Dice coefficient in the tongue (0.89) and mandible (0.81). The accuracy was consistent across all four folds. Also, leave-study-out validations obtained comparable accuracy across uniquely acquired datasets. Segmented volumes and the derived tongue fat ratio values showed high correlation with manual measurements, with differences that were not statistically significant (p < 0.05). CONCLUSION: High accuracy of automated segmentations indicate translational potential of the proposed method to replace time consuming manual segmentation tasks in clinical settings and large-scale research studies.


Assuntos
Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/diagnóstico por imagem , Redes Neurais de Computação , Imageamento por Ressonância Magnética/métodos , Língua/diagnóstico por imagem , Fatores de Risco , Processamento de Imagem Assistida por Computador/métodos
19.
Future Oncol ; 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36268941

RESUMO

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.


Patients with triple-negative breast cancer generally do very poorly with the current available therapies. A vaccine with a totally different mechanism of action is being investigated in these patients to see how they do with this new therapy. This trial is a very early investigation and is currently ongoing. Clinical Trial Registration: NCT03562637 (ClinicalTrials.gov).

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