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1.
medRxiv ; 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38712112

RESUMO

Background: Variability in treatment response may be attributable to organ-level heterogeneity in tumor lesions. Radiomic analysis of medical images can elucidate non-invasive biomarkers of clinical outcome. Organ-specific radiomic comparison across immunotherapies and targeted therapies has not been previously reported. Methods: We queried UPMC Hillman Cancer Center registry for patients with metastatic melanoma (MEL) treated with immune checkpoint inhibitors (ICI) (anti-PD1/CTLA4 [ipilimumab+nivolumab; I+N] or anti-PD1 monotherapy) or BRAF targeted therapy. Best overall response was measured using RECIST v1.1. Lesions were segmented into discrete volume-of-interest with 400 radiomics features extracted. Overall and organ-specific machine-learning models were constructed to predict disease control (DC) versus progressive disease (PD) using XGBoost. Results: 291 MEL patients were identified, including 242 ICI (91 I+N, 151 PD1) and 49 BRAF. 667 metastases were analyzed, including 541 ICI (236 I+N, 305 PD1) and 126 BRAF. Across cohorts, baseline demographics included 39-47% female, 24-29% M1C, 24-46% M1D, and 61-80% with elevated LDH. Among patients experiencing DC, the organs with the greatest reduction were liver (-88%±12%, I+N; mean±S.E.M.) and lung (-72%±8%, I+N). For patients with multiple same-organ target lesions, the highest inter-lesion heterogeneity was observed in brain among patients who received ICI while no intra-organ heterogeneity was observed in BRAF. 267 patients were kept for radiomic modeling, including 221 ICI (86 I+N, 135 PD1) and 46 BRAF. Models consisting of optimized radiomic signatures classified DC/PD across I+N (AUC=0.85) and PD1 (0.71) and within individual organ sites (AUC=0.72∼0.94). Integration of clinical variables improved the models' performance. Comparison of models between treatments and across organ sites suggested mostly non-overlapping DC or PD features. Skewness, kurtosis, and informational measure of correlation (IMC) were among the radiomic features shared between overall response models. Kurtosis and IMC were also utilized by multiple organ-site models. Conclusions: Differential organ-specific response was observed across BRAF and ICI with within organ heterogeneity observed for ICI but not for BRAF. Radiomic features of organ-specific response demonstrated little overlap. Integrating clinical factors with radiomics improves the prediction of disease course outcome and prediction of tumor heterogeneity.

2.
Dev Neurosci ; 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37906983

RESUMO

INTRODUCTION: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. METHODS: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 - 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. RESULTS: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR 4.5 - 5.8). The incidence of injury to the deep grey nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n=414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. CONCLUSION: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

3.
Neonatology ; 120(6): 760-767, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37742617

RESUMO

OBJECTIVE: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes. STUDY DESIGN: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site. RESULT: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56). CONCLUSION: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.


Assuntos
Asfixia Neonatal , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Recém-Nascido , Lactente , Criança , Humanos , Feminino , Gravidez , Pré-Escolar , Placenta , Hipóxia-Isquemia Encefálica/patologia , Deficiências do Desenvolvimento/terapia , Asfixia/terapia , Asfixia Neonatal/complicações , Asfixia Neonatal/terapia , Asfixia Neonatal/patologia
4.
N Engl J Med ; 387(2): 148-159, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35830641

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).


Assuntos
Eritropoetina , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Fármacos Neuroprotetores , Administração Intravenosa , Paralisia Cerebral/etiologia , Método Duplo-Cego , Eritropoetina/administração & dosagem , Eritropoetina/efeitos adversos , Eritropoetina/uso terapêutico , Humanos , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico
5.
J Pediatr ; 237: 190-196, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34144032

RESUMO

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.


Assuntos
Hipóxia-Isquemia Encefálica/patologia , Doenças Placentárias/diagnóstico , Doenças Placentárias/epidemiologia , Doença Aguda , Doença Crônica , Estudos de Coortes , Método Duplo-Cego , Eritropoetina/uso terapêutico , Feminino , Idade Gestacional , Humanos , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
6.
Front Immunol ; 12: 660795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828564

RESUMO

Background: Immune-checkpoint inhibition has improved outcomes in metastatic melanoma. However, limited data describes the safety and efficacy of this treatment in the setting of cardiac allograft. Emerging translational and clinical evidence suggests that the majority of the benefit from these therapies is driven by the initial dose(s), and that attenuated dosing schedules may be as effective as continuous treatment. Case presentation: We present a case vignette of a cardiac transplant recipient with metastatic melanoma who experienced six months of clinical benefit after one dose of pembrolizumab and did not suffer allograft rejection. Conclusion: This case adds to the current available literature on the administration of checkpoint inhibitors in patients with cardiac allografts. Further, it explores potential markers of immunotherapy response and supports the potential of shorter or individualized immune-checkpoint blockade dosing strategies.


Assuntos
Aloenxertos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Coração , Melanoma/tratamento farmacológico , Melanoma/secundário , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Masculino , Melanoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Transplantados
7.
Pediatr Res ; 89(1): 74-84, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32221474

RESUMO

The next phase of clinical trials in neonatal encephalopathy (NE) focuses on hypothermia adjuvant therapies targeting alternative recovery mechanisms during the process of hypoxic brain injury. Identifying infants eligible for neuroprotective therapies begins with the clinical detection of brain injury and classification of severity. Combining a variety of biomarkers (serum, clinical exam, EEG, movement patterns) with innovative clinical trial design and analyses will help target infants with the most appropriate and timely treatments. The timing of magnetic resonance imaging (MRI) and MR spectroscopy after NE both assists in identifying the acute perinatal nature of the injury (days 3-7) and evaluates the full extent and evolution of the injury (days 10-21). Early, intermediate outcome of neuroprotective interventions may be best defined by the 21-day neuroimaging, with recognition that the full neurodevelopmental trajectory is not yet defined. An initial evaluation of each new therapy at this time point may allow higher-throughput selection of promising therapies for more extensive investigation. Functional recovery can be assessed using a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action. As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow safe, efficient, and targeted therapeutics. IMPACT: As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow faster development of safe, effective, and targeted therapeutics. This article provides a multidisciplinary perspective on the future of clinical trials in NE; novel trial design; study management and oversight; biostatistical methods; and a combination of serum, imaging, and neurodevelopmental biomarkers can advance the field and improve outcomes for infants affected by NE. Innovative clinical trial designs, new intermediate trial end points, and a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action can help address common challenges in NE clinical trials and allow for faster selection and validation of promising therapies for more extensive investigation.


Assuntos
Pesquisa Biomédica/tendências , Encefalopatias/terapia , Ensaios Clínicos como Assunto , Doenças do Recém-Nascido/terapia , Neonatologia/tendências , Projetos de Pesquisa/tendências , Biomarcadores/sangue , Encefalopatias/diagnóstico por imagem , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Consenso , Técnica Delphi , Difusão de Inovações , Previsões , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico por imagem , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/fisiopatologia , Neuroimagem , Sociedades Médicas , Sociedades Científicas , Fatores de Tempo , Resultado do Tratamento
8.
Pediatr Res ; 87(5): 879-884, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31261373

RESUMO

BACKGROUND: Newborns with hypoxic-ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. METHODS: Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. RESULTS: Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. CONCLUSION: Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.


Assuntos
Encefalopatias/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Eritropoetina/uso terapêutico , Hipóxia-Isquemia Encefálica/patologia , Placenta/patologia , Encéfalo/patologia , Método Duplo-Cego , Feminino , Humanos , Hipotermia Induzida , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Gravidez
9.
Neonatology ; 113(4): 331-338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29514165

RESUMO

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. OBJECTIVES: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. METHODS: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. RESULTS AND CONCLUSIONS: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.


Assuntos
Asfixia/terapia , Eritropoetina/administração & dosagem , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/terapia , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Estudos Multicêntricos como Assunto , Neuroproteção , Fármacos Neuroprotetores/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Cephalalgia ; 37(5): 423-434, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27165493

RESUMO

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2-1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.


Assuntos
Cefaleia Histamínica/diagnóstico , Cefaleia Histamínica/terapia , Terapia por Estimulação Elétrica/tendências , Gânglios Parassimpáticos/fisiologia , Neuroestimuladores Implantáveis/tendências , Adulto , Idoso , Cefaleia Histamínica/fisiopatologia , Estudos de Coortes , Terapia por Estimulação Elétrica/instrumentação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
11.
J Headache Pain ; 17(1): 67, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27461394

RESUMO

BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 ± 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point "after remission" was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 ± 86 (range 21-272) days after initiation of stimulation. On average, each patient's longest remission period lasted 149 ± 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % ± 25 % before, 49 % ± 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 ± 6.0 before, 55.2 ± 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability.


Assuntos
Cefaleia Histamínica/diagnóstico , Cefaleia Histamínica/terapia , Terapia por Estimulação Elétrica/métodos , Gânglios Parassimpáticos , Adulto , Terapia por Estimulação Elétrica/tendências , Feminino , Seguimentos , Gânglios Parassimpáticos/fisiologia , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Indução de Remissão/métodos , Fatores de Tempo
12.
Cephalalgia ; 33(10): 816-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23314784

RESUMO

BACKGROUND: The pain and autonomic symptoms of cluster headache (CH) result from activation of the trigeminal parasympathetic reflex, mediated through the sphenopalatine ganglion (SPG). We investigated the safety and efficacy of on-demand SPG stimulation for chronic CH (CCH). METHODS: A multicenter, multiple CH attack study of an implantable on-demand SPG neurostimulator was conducted in patients suffering from refractory CCH. Each CH attack was randomly treated with full, sub-perception, or sham stimulation. Pain relief at 15 minutes following SPG stimulation and device- or procedure-related serious adverse events (SAEs) were evaluated. FINDINGS: Thirty-two patients were enrolled and 28 completed the randomized experimental period. Pain relief was achieved in 67.1% of full stimulation-treated attacks compared to 7.4% of sham-treated and 7.3% of sub-perception-treated attacks ( P < 0.0001). Nineteen of 28 (68%) patients experienced a clinically significant improvement: seven (25%) achieved pain relief in ≥50% of treated attacks, 10 (36%), a ≥50% reduction in attack frequency, and two (7%), both. Five SAEs occurred and most patients (81%) experienced transient, mild/moderate loss of sensation within distinct maxillary nerve regions; 65% of events resolved within three months. INTERPRETATION: On-demand SPG stimulation using the ATI Neurostimulation System is an effective novel therapy for CCH sufferers, with dual beneficial effects, acute pain relief and observed attack prevention, and has an acceptable safety profile compared to similar surgical procedures.


Assuntos
Cefaleia Histamínica/terapia , Terapia por Estimulação Elétrica/métodos , Eletrodos Implantados , Gânglios Parassimpáticos/fisiologia , Medição da Dor/métodos , Adolescente , Adulto , Idoso , Cefaleia Histamínica/fisiopatologia , Terapia por Estimulação Elétrica/instrumentação , Feminino , Humanos , Masculino , Microeletrodos , Pessoa de Meia-Idade , Fossa Pterigopalatina/fisiologia , Resultado do Tratamento , Adulto Jovem
13.
J Headache Pain ; 13(3): 239-41, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22395639

RESUMO

Migraine attacks are believed to involve activation of the trigeminovascular system and trigeminal-parasympathetic reflex, which is mediated through the sphenopalatine ganglion (SPG). An implantable SPG neurostimulator has been developed to apply on-demand SPG stimulation for the treatment of severe primary headache. The neurostimulator is implanted via an oral incision and placed along the maxilla, with the lead placed at the SPG. The neurostimulator contains no battery and is powered and controlled via a handheld remote controller. The potential interest of patients with high-frequency, high-disability migraine in having a SPG neurostimulator implanted to treat migraine is unknown. We aimed to evaluate patient interest to undergo such an implantation procedure and to participate in a clinical investigation of on-demand SPG stimulation for migraine by conducting a survey at the Ghent University Hospital in 41 migraineurs. Seventy-seven percent (77%) of subjects expressed an interest in participating in a clinical investigation requiring implantation of a SPG neurostimulator when headache frequency and severity were considered and 69% when pain relief experienced with current migraine treatment was considered. Preventive and acute medications were used in 64 and 95% of the subjects, respectively, and provided a reported reduction of headache frequency, duration and pain. However, acute medications were frequently associated with headache recurrence and bothersome side effects. Results indicate that a majority of high-frequency, high-disability migraineurs, many of whom achieve pain relief with their current medications, have an interest in participating in a clinical investigation of an implantable SPG neurostimulator for the treatment of migraine headache.


Assuntos
Coleta de Dados , Neuroestimuladores Implantáveis , Transtornos de Enxaqueca/terapia , Adolescente , Adulto , Idoso , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
J Thorac Cardiovasc Surg ; 142(5): 1038-45, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21397269

RESUMO

BACKGROUND: The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns. METHODS: Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined. RESULTS: Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 ± 0.1 vs 6.1 ± 0.2 cm and 31.6% ± 0.5% vs 16.2% ± 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid-left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted. CONCLUSIONS: In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished.


Assuntos
Cardiomiopatia Dilatada/terapia , Circulação Coronária , Hemodinâmica , Implantação de Prótese/instrumentação , Animais , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Estimulação Cardíaca Artificial/efeitos adversos , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Modelos Animais de Doenças , Masculino , Desenho de Prótese , Artéria Pulmonar/fisiopatologia , Fluxo Sanguíneo Regional , Suínos , Fatores de Tempo , Ultrassonografia , Vasodilatação , Função Ventricular Esquerda , Pressão Ventricular
15.
Europace ; 7 Suppl 2: 135-45, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16102511

RESUMO

AIMS: Contemporary ionic-based membrane models are computationally expensive and are not intended to match the properties of a given experimental preparation. The aim of this work was to use measured restitution properties of electrically remodelled atrial tissue to develop a simplified membrane model based on the Fenton-Karma (FK) equations amenable to large-scale simulation of chronic atrial fibrillation (CAF). METHODS: Two membrane models, the FK-CAF and FK-CNTRL parameter sets, were developed to match action potential duration (APD) and conduction velocity (CV) restitution properties of rapid-pacing-induced electrically remodelled sheep atria and healthy atria, respectively. The models were tested by inducing reentry in a two-dimensional anisotropic monodomain and comparing the resulting cycle lengths (CL) with measured CLs. RESULTS: Parameters for the FK models were obtained that reproduced APD and CV restitution properties measured in the CAF and healthy sheep atria. Using the FK-CAF parameters, reentry was sustained in a 2.5 by 2.5 cm sheet with a CL = 91.0 +/- 3.0 ms. Reentry (CL = 113.2 +/- 5.2 ms) could only be sustained in the FK-CNTRL model after the tissue was first activated at a fast rate (136.5 ms). CONCLUSIONS: The FK-CAF model is shown to approximate the restitution properties of remodelled sheep atria and can be used to simulate reentry with short CLs similar to those measured during AF episodes.


Assuntos
Fibrilação Atrial/fisiopatologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Anisotropia , Simulação por Computador , Condutividade Elétrica , Ovinos
16.
J Interv Card Electrophysiol ; 10(2): 131-8, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15014213

RESUMO

Well-tolerated internal atrial defibrillation shocks must be below the pain threshold, which has been estimated to be less than 1 Joule. Defibrillation of the atria with low energy is made possible by delivering shocks at the low end of the defibrillation dose-response curve. We studied low-energy defibrillation in sheep to test the hypothesis that the energy that defibrillates the atria 10% of the time (ED10) is less than 1 Joule. The ED10 was estimated in seven sheep with rapid pacing induced chronic atrial fibrillation (AF). Low-energy defibrillation shocks were delivered from coronary sinus (CS) to superior vena cava (SVC) and the ED10 and ED50 (energy that defibrillates the atria 50% of the time) were then calculated using logistic regression. The mean ratio of ED10 to ED50 was 0.50, indicating that on average, the ED10 was equal to half of the ED50. ED10 shocks had energies ranging from 1.2 to 5.8 Joules. These results suggest that painless single-shock low-energy defibrillation may not be feasible.


Assuntos
Fibrilação Atrial/terapia , Função Atrial , Cardioversão Elétrica/métodos , Animais , Limiar Diferencial , Modelos Animais de Doenças , Feminino , Modelos Logísticos , Masculino , Sensibilidade e Especificidade , Carneiro Doméstico
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