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PURPOSE: To investigate the impact of surgical timing on visual acuity outcomes in retinal detachments based on the preoperative foveal status. METHODS: A retrospective multicenter cohort study was conducted. Cases were stratified into fovea-on, fovea-split, and fovea-off groups. Days to surgery was defined as the time between the preoperative examination and surgery. The main outcome measure was the final postoperative visual acuity. RESULTS: 1,675 cases were studied. More than 80% of fovea-on/fovea-split and fovea-off cases had surgery within 1 and 3 days, respectively. The mean final postoperative visual acuity did not differ significantly between the fovea-on and fovea-split groups (Snellen equivalent [SE] 20/33 ± 20/49 and 20/32 ± 20/39, P = 1.000) and did not change significantly based on days to surgery in either group. The mean final postoperative visual acuity was lowest in the fovea-off group (Snellen equivalent = 20/56 ± 20/76, P < 0.001) and was significantly lower in cases where surgery was performed after two or more days when compared with cases performed within 1 day (Snellen equivalent 20/74 ± 20/89 vs. 20/46 ± 20/63, P < 0.001). CONCLUSION: Fovea-on and fovea-split retinal detachments demonstrated comparable visual outcomes. Fovea-off RDs demonstrated worse visual outcomes, which declined further when surgery was delayed by two or more days.
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Descolamento Retiniano , Humanos , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Estudos de Coortes , Estudos Retrospectivos , Fóvea Central , Fatores de Tempo , Vitrectomia , Recurvamento da EscleraRESUMO
PURPOSE: To assess the utility of pig head model as an oculoplastic surgical training tool. METHODS: Fresh pig head was availed for surgical workshop for entropion correction, eyelid margin repair, and evisceration with implant for oculoplastic surgery-naïve participants. Skill improvement, surgical understanding, and performance of the participants were evaluated both subjectively and objectively by trained oculoplastic surgeons. Subjective assessment was done by a standardized questionnaire based on Likert scale shared with the participants post training. Objective evaluation was done by the faculty based on a three-point scale and a competency-based surgical assessment rubric. RESULTS: There were 18 surgery-naïve participants in the workshop which comprised ophthalmology residents and comprehensive ophthalmologists. About 88.88% of the participants were able to perform the lid margin and sub-tarsal dissection in entropion surgery. While performing lid tear repair, 94.44% were correctly able to identify the grey line and anterior and posterior lamellae. About 83.33% of the participants were able to place an implant in the scleral shell or intraconal space. About 83.33% of the participants noted that texture and tissue maneuvering were similar to the human eye while performing surgical steps. About 94.44% of the participants reported better understanding, development of skill and additional confidence after training. The median score on objective assessment was 3. The performance on real patients resulted in a median score of 4 for entropion correction. CONCLUSION: Porcine orbital dissection is an available, affordable, and useful tool for oculoplastic surgical training. Training on porcine model can improve anatomical understanding, clinical judgement, and surgical efficiency in trainees.
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PURPOSE OF REVIEW: To discuss the drawbacks and propose recommendations for integrating physician extenders in ophthalmologic practice. RECENT FINDINGS: In this article, the role of utilizing physician extenders in ophthalmology is discussed. A role for physician extenders has been suggested as more and more patients will require ophthalmologic care. SUMMARY: Guidance is needed on how to best integrate physician extenders into eye care. However, quality of care is of the highest importance, and unless there is reliable and consistent training of extenders, using physician extenders to administer invasive procedures (e.g., intravitreal injection) should be avoided due to safety concerns.
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Oftalmologia , Assistentes Médicos , Humanos , Assistentes Médicos/legislação & jurisprudência , Oftalmologia/organização & administraçãoRESUMO
We describe the outcomes of oral mucous membrane grafting as a surgical technique for unilateral lid margin keratinization following radiotherapy. A 47-year- old woman presented with an 8-month history of a white spot in her right eye. She had a history of adenoid cystic carcinoma of the right spheno-ethmoid sinus, for which she underwent radiotherapy. Slit-lamp evaluation revealed lid margin keratinization of the right upper and lower eyelids and a keratin plaque on the corneal surface. We performed excision of the keratin plaque and lid margin keratinization, followed by oral mucous membrane grafting of the upper and lower eyelid margins. Histopathological evaluation of the excised lid margin revealed keratinized stratified squamous epithelium, consistent with lid margin keratinization. The corneal surface and lid margins showed no recurrent keratin deposition at the final follow-up, 11 months postoperatively.
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Pálpebras , Mucosa Bucal , Feminino , Humanos , Pessoa de Meia-Idade , Pálpebras/cirurgia , Pálpebras/patologia , Mucosa Bucal/transplante , QueratinasRESUMO
PURPOSE: The purpose of this article is to review the literature on nomenclature, natural history, clinical features, diagnosis, management, and prognosis of both macular microhole (MMH) and foveal red spot syndrome (FRS). METHODS: A PubMed primary literature search (February 1, 2020) utilizing the terms macular microhole, foveal red spot syndrome, and outer retinal hole was conducted. All chosen articles were case reports or case series. Articles qualified for inclusion if they documented symptoms, imaging findings, or followed patients longitudinally. RESULTS: A total of 14 studies from 1988 to 2019 that evaluated either MMH, FRS, or both were included in the review. No comparative study between the two defects was found. Studies often used the terms FRS and MMH interchangeably to reference both partial- and full-thickness lesions of the macula. Spectral-domain optical coherence tomography (SD-OCT) was most frequently able to identify these lesions and revealed an absence of all neural retinal layers from the inner limiting membrane (ILM) to the retinal pigment epithelium (RPE) in the full-thickness lesions while the partial-thickness lesions most often involved the photoreceptor layer (PRL) and less frequently the external limiting membrane (ELM). OCT revealed that vitreomacular traction (VMT) was involved in the natural history of both FRS and MMH for a significant subset of patients. CONCLUSION: The terms MMH and FRS have been used interchangeably in the literature. Advances in OCT have revealed that MMHs and FRSs are distinct but sometimes overlapping entities. We suggest that MMH and FRS are similar entities defined as one or more sharply defined lesions in the fovea of the eye < 150 µm in size. MMHs are a full-thickness defect of the entire neuroretina at the center of the foveola while FRSs are partial-thickness lesions. Current literature suggests that there may be subtle differences in the pathogenesis, clinical features, and diagnosis between MMH and FRS; however, prognosis and management for both are favorable. Lastly, we suggest that the terms outer lamellar macular microholes and full-thickness macular microholes may be the more appropriate terminologies to refer to FRS and MMH, respectively.
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Macula Lutea , Perfurações Retinianas , Fóvea Central , Humanos , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
PURPOSE: Acute retinal artery occlusion (RAO) is an urgent ophthalmic condition often indicative of future ischemic pathology. Patients diagnosed at an outpatient retina clinic must present to an emergency department (ED) or primary care clinic to obtain a systemic workup. We review the overall compliance and suspected delay in completing the required testing. DESIGN: Retrospective cohort study METHODS: Patients presenting with a symptomatic RAO from June 2009 to January 2019 at a vitreoretinal practice (The Retina Institute, St. Louis, MO) were included. Documentation of carotid vasculature and echocardiographic imaging was requested from the patient's primary care physician (PCP), cardiologist, or neurologist. Time to workup (TTW) from RAO diagnosis to receiving appropriate workup and site of workup (ED vs. outpatient setting) were recorded. RESULTS: One hundred forty-seven patients were included. A total of 132 (89.8%) patients were documented as having completed at least one type of cardiovascular or carotid imaging. Seventy-seven patients (52.3%) were documented to have completed both carotid and echocardiographic imaging. Following RAO diagnosis, 97 (66.0%) patients were referred to an outpatient facility while 35 (23.8%) were evaluated at an ED. Mean TTW through an ED setting vs. outpatient was 2.20 days (1.10 STDM, range 0-29) vs.13.6 days (2.23 STDM, range 0-149) respectively (p=0.003). CONCLUSION: Our study gives objective data to the delay suspected in referring patients with acute symptomatic RAO for outpatient workup. We recommend all outpatient ophthalmology and retina practices establish a relationship with a comprehensive or primary stroke center to facilitate urgent testing through an emergency department.
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Pacientes Ambulatoriais , Oclusão da Artéria Retiniana , Humanos , Retina , Oclusão da Artéria Retiniana/diagnóstico , Estudos Retrospectivos , UltrassonografiaRESUMO
PURPOSE: Anatomically similar rhegmatogenous retinal detachments (RRDs) can be treated with scleral buckle (SB), pars plana vitrectomy (PPV), or SB combined with PPV (PPV/SB). This study compares moderately complex phakic primary RRD treated with SB, PPV, or PPV/SB to review anatomic and visual outcomes. DESIGN: Multicenter, retrospective, interventional cohort study. PARTICIPANTS: Data were gathered on all patients from multiple retina practices in the United States with RRD in 2015 and >90 days of follow-up. The cohort of phakic patients with moderately complex RRD was analyzed. METHODS: A large and detailed database was generated. Eyes with findings that would bias toward PPV (vitreous hemorrhage, dense cataract, proliferative vitreoretinopathy, giant retinal tear, among others) were excluded. Age <40 years (bias toward SB) was excluded. Comparable cases of moderately complex RRD were then chosen naive to surgeon, surgery, and outcome for subgroup analysis. MAIN OUTCOME MEASURES: Single surgery anatomic success (SSAS), defined as retinal attachment with no other RRD surgery within 90 days, is the main outcome measure. Final visual acuity is the secondary outcome measure. Pearson's chi-square and analysis of variance were used to test treatment effect of surgery type on SSAS and vision. RESULTS: Single surgery anatomic success was noted in 155 of 169 SB cases (91.7%), 207 of 249 PPV cases (83.1%), and 271 of 297 PPV/SB cases (91.2%). Scleral buckle and PPV/SB were superior to PPV for SSAS (P = 0.0041). For macula-on or split cases, SB had significantly better visual outcomes than PPV or PPV/SB even after controlling for cataract (cases with minimal cataract at final follow-up or after cataract surgery) (P < 0.001). CONCLUSIONS: For phakic moderately complex primary RRDs in this study of PPV versus SB versus PPV/SB, SB had the best visual outcomes, and PPV had the worst SSAS outcomes.
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Descolamento Retiniano/cirurgia , Recurvamento da Esclera/métodos , Acuidade Visual , Vitrectomia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Descolamento Retiniano/diagnóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: This study evaluates outcomes of comparable pseudophakic rhegmatogenous retinal detachment (RRD) treated with pars plana vitrectomy (PPV) or PPV with scleral buckle (PPV-SB). DESIGN: Multicenter, retrospective, interventional cohort study. PARTICIPANTS: Data were gathered from patients from multiple retina practices in the United States with RRD in 2015. METHODS: A large detailed database was generated. Pseudophakic patients with RRD managed with PPV or PPV-SB were analyzed for anatomic and visual outcomes. Eyes with proliferative vitreoretinopathy, giant retinal tears, previous invasive glaucoma surgery, and ≤90 days of follow-up were excluded from outcomes analysis. Single surgery anatomic success (SSAS) was defined as retinal attachment without ongoing tamponade and with no other RRD surgery within 90 days. MAIN OUTCOME MEASURES: Single surgery anatomic success and final Snellen visual acuity (VA). RESULTS: A total of 1158 of 2620 eyes (44%) with primary RRD were pseudophakic. A total of 1018 eyes had greater than 90 days of follow-up. Eyes with proliferative vitreoretinopathy, previous glaucoma surgery, and giant retinal tears were excluded, leaving 893 pseudophakic eyes eligible for outcome analysis. A total of 461 (52%) were right eyes. A total of 606 patients (67%) were male, with a mean age of 65±11 years. Pars plana vitrectomy and PPV-SB as the first procedure were performed on 684 eyes (77%) and 209 eyes (23%), respectively. The mean follow-up was 388±161 days, and overall SSAS was achieved in 770 eyes (86%). Single surgery anatomic success was 84% (577/684) for PPV and 92% (193/209) for PPV-SB. The difference in SSAS between types of treatment was significant (P = 0.009). In eyes with macula-on RRD, SSAS was 88% in eyes treated with PPV and 100% in eyes treated with PPV-SB (P = 0.0088). In eyes with macula-off RRD, SSAS was 81% in eyes treated with PPV and 89% in eyes treated with PPV-SB (P = 0.029). Single surgery anatomic success was greater for PPV-SB than PPV for inferior (96% vs. 82%) and superior (90% vs. 82%) detachments. Mean final VA was similar for PPV (20/47) and PPV-SB (20/46; P = 0.805). CONCLUSIONS: In pseudophakic RRDs, SSAS was better in patients treated with PPV-SB compared with PPV alone, whereas visual outcomes were similar for both groups.
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Pseudofacia/complicações , Descolamento Retiniano/cirurgia , Recurvamento da Esclera/métodos , Acuidade Visual , Vitrectomia/métodos , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the efficacy of unilateral tarso-frontalis silicone sling without levator extirpation or disinsertion in dampening the jaw wink in patients with congenital ptosis associated with Marcus Gunn Jaw Winking synkinesis phenomenon. METHODS: Retrospective review of medical records of all patients of congenital ptosis with moderate to severe Marcus Gunn jaw winking synkinesis who underwent unilateral tarsofrontal silicone sling surgery without extirpation of the levator muscle were retrospectively reviewed. Data were collected about the pre- and the postoperative severity of the ptosis and the amount of Marcus Gunn jaw winking excursion. RESULTS: Twenty-three patients were included in the study. Mean postoperative follow up duration was 31.2 (range 6-208) weeks. The severity of the preoperative jaw wink was mild (<2 mm excursion) in 0 patient, moderate (2-5mm) in 15 (65%) patients, and severe (>5 mm eyelid excursion) in 8 (35%) patients. Postoperatively, 20 (87%) patients had mild residual jaw wink, 3 (13%) patients had moderate jaw wink and none of the patient had severe residual jaw wink. CONCLUSION: Unilateral tarsofrontal silicone sling without disinsertion or extirpation of the levator can reduce the severity of the jaw wink excursion in patients with congenital ptosis with moderate to severe preoperative Marcus Gunn jaw winking synkinesis.
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Blefaroptose , Sincinesia , Blefaroptose/cirurgia , Piscadela , Humanos , Músculos Oculomotores/cirurgia , Estudos Retrospectivos , SiliconesRESUMO
BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.
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Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Resultado do Tratamento , Estados UnidosAssuntos
Túnica Conjuntiva/irrigação sanguínea , Doenças Retinianas/diagnóstico , Esclera/irrigação sanguínea , Pressão Venosa/fisiologia , Transtornos da Visão/diagnóstico , Desequilíbrio Hidroeletrolítico/diagnóstico , Adulto , Corantes/administração & dosagem , Angiofluoresceinografia , Humanos , Verde de Indocianina/administração & dosagem , Masculino , Doenças Retinianas/fisiopatologia , Líquido Sub-Retiniano , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
PURPOSE: Retinoschisis and retinal detachments are primarily differentiated based on characteristic examination findings. In diagnostically challenging cases, noncontact wide-field infrared imaging can help diagnosis and visualize the extent/margins of retinoschisis, retinal detachment, or combined schisis detachments by comparing reflectivity patterns. METHODS: This is a retrospective, observational, descriptive case series of 14 eyes of 14 nonconsecutive patients, ranging from 28 to 89 years old (mean 61), diagnosed with retinoschisis, retinal detachment, or schisis detachment from May 5, 2014 to March 4, 2015. Patients with secondary retinoschisis and/or retinal detachment from other causes were not included in the study. Heidelberg Wide-Field Module lens and Heidelberg Spectralis HRA+OCT machine (Heidelberg Engineering, Heidelberg, Germany) were used to obtain noncontact, wide-field infrared images on each study eye. RESULTS: Seven eyes with retinal detachments, four with retinoschises, and three with schisis detachments were imaged using this novel wide-field infrared technique. Retinoschisis appears light and translucent with prominent vasculature, retinal detachments appear dark and opaque, and combined retinoschisis/retinal detachment exhibit mixed reflectivity patterns. CONCLUSION: Wide-field infrared imaging provides a quick, noncontact, noninvasive method to accurately diagnose and to monitor for progression of retinoschisis, retinal detachment, or combined schisis detachments.
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Técnicas de Diagnóstico Oftalmológico , Descolamento Retiniano/diagnóstico por imagem , Retinosquise/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Raios Infravermelhos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: The optimal management approach to retinal arterial macroaneurysms (RAM) is unknown. This paper compares long-term outcomes in RAM treated with laser therapy versus observation. METHODS: This is an IRB-approved retrospective study of patients with symptomatic RAM. Charts of patients with a diagnosis of RAM causing symptomatic visual loss were reviewed. Patients with less than 6 months follow up, other confounding diagnoses, or additional therapy beyond thermal laser were excluded. Statistical analysis was done using χ(2) or Student's t test as appropriate. RESULTS: Forty-eight patients with RAM were identified and 27 were included in the study (13 treated, 14 observed). Mean visual acuity in the observation group improved from 20/120 to 20/96 (p = 0.53) compared to 20/280 to 20/54 (p = 0.0003) in the treated group. Subgroup analysis showed that visual acuity in primarily hemorrhagic lesions treated with laser therapy improved by 1.21 logMAR compared to a loss of 0.11 logMAR (p = 0.002) in those that were observed. In primarily exudative lesions, both treated and observed lesions showed an improvement of 0.32 logMAR. No patients in the treatment group had a final visual acuity below 20/200 compared to four in the observation group. CONCLUSION: Treatment with direct laser photocoagulation was associated in this study with greater improvement in visual acuity and may decrease the risk of severe visual loss especially in primarily hemorrhagic RAM lesions. Compared to observation alone.
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Aneurisma/cirurgia , Coagulação com Plasma de Argônio/métodos , Artéria Retiniana/cirurgia , Doenças Retinianas/cirurgia , Idoso , Aneurisma/diagnóstico , Aneurisma/fisiopatologia , Anticoagulantes/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Estudos Observacionais como Assunto , Artéria Retiniana/patologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Estudos Retrospectivos , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: To report the presence of transient peripapillary serous detachments in multiple evanescent white dot syndrome. METHODS: Retrospective case series. RESULTS: Four eyes of four patients diagnosed with multiple evanescent white dot syndrome presented with peripapillary serous detachments. Diagnosis was based on clinical presentation, fundus findings, and angiographic findings. All 4 were female with age ranges between 24 and 40 years and presented with photopsias, an enlarged scotoma contiguous with the blind spot, and chorioretinal white dots in the posterior pole with characteristic angiographic features. All of the serous detachments resolved or were greatly reduced concomitantly with the resolution of the patient's other clinical symptoms and fundus findings. CONCLUSION: The authors report peripapillary serous detachments as a previously unreported manifestation of multiple evanescent white dot syndrome. These seem to be self limited with concurrent resolution with the rest of the patient's symptoms.
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Doenças Retinianas/diagnóstico , Epitélio Pigmentado da Retina/patologia , Escotoma/diagnóstico , Adulto , Corantes , Feminino , Angiofluoresceinografia , Humanos , Verde de Indocianina , Disco Óptico/patologia , Estudos Retrospectivos , Líquido Sub-Retiniano , Tomografia de Coerência Óptica , Acuidade Visual , Testes de Campo Visual , Campos Visuais , Adulto JovemRESUMO
We have developed an all-electronic digital microfluidic device for microscale chemical synthesis in organic solvents, operated by electrowetting-on-dielectric (EWOD). As an example of the principles, we demonstrate the multistep synthesis of [(18)F]FDG, the most common radiotracer for positron emission tomography (PET), with high and reliable radio-fluorination efficiency of [(18)F]FTAG (88 ± 7%, n = 11) and quantitative hydrolysis to [(18)F]FDG (> 95%, n = 11). We furthermore show that batches of purified [(18)F]FDG can successfully be used for PET imaging in mice and that they pass typical quality control requirements for human use (including radiochemical purity, residual solvents, Kryptofix, chemical purity, and pH). We report statistical repeatability of the radiosynthesis rather than best-case results, demonstrating the robustness of the EWOD microfluidic platform. Exhibiting high compatibility with organic solvents and the ability to carry out sophisticated actuation and sensing of reaction droplets, EWOD is a unique platform for performing diverse microscale chemical syntheses in small volumes, including multistep processes with intermediate solvent-exchange steps.
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Eletrônica/instrumentação , Microquímica/instrumentação , Microquímica/métodos , Técnicas Analíticas Microfluídicas , Sondas Moleculares/síntese química , Animais , Cromatografia em Camada Fina , Eletroumectação , Radioisótopos de Flúor , Fluordesoxiglucose F18/síntese química , Halogenação , Humanos , Linfoma/diagnóstico por imagem , Camundongos , Camundongos SCID , Tomografia por Emissão de Pósitrons , Controle de Qualidade , Distribuição Tecidual , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. RESULTS: 118 patients (median age 31·0 years; IQR 18·061·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 3153%]) for everolimus and 0% (0 of 39 [09%]) for placebo (response rate difference 42% [2458%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.
Assuntos
Angiomiolipoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Sirolimo/análogos & derivados , Adulto , Angiomiolipoma/complicações , Método Duplo-Cego , Everolimo , Feminino , Humanos , Linfangioleiomiomatose/complicações , Masculino , Estudos Prospectivos , Sirolimo/uso terapêutico , Esclerose Tuberosa/complicaçõesRESUMO
BACKGROUND: Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. FINDINGS: 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). INTERPRETATION: These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.