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In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.
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Cromatina , Epigênese Genética , Genótipo , Mutação , Análise de Célula Única , Animais , Feminino , Humanos , Masculino , Camundongos , Antígenos CD34/metabolismo , Diferenciação Celular/genética , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética/genética , Epigenoma/genética , Genoma Mitocondrial/genética , Técnicas de Genotipagem , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Inflamação/genética , Inflamação/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Membrana/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , RNA/genética , Células Clonais/metabolismoRESUMO
BACKGROUND: Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery. METHODS: We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major noncardiac surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery. RESULTS: A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to noncardiac surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, P<0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, P=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, P<0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]). CONCLUSIONS: Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before noncardiac surgery.
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Cálcio , Infarto do Miocárdio , Adulto , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X/métodos , Infarto do Miocárdio/etiologia , Medição de Risco/métodosRESUMO
BACKGROUND: Challenges in temporomandibular joint (TMJ) arthroscopy training include the cost of operating room time, surgical risks, and the accessibility of cadavers and high-fidelity simulators. A low-fidelity simulator (LFS) was developed for initial TMJ arthroscopy training. PURPOSE: The aim of this study was to evaluate improvement in TMJ arthroscopic skills after training with an LFS using the Arthroscopic Surgical Skill Evaluation Tool (ASSET) global rating scale. STUDY DESIGN, SETTING, SAMPLE: A prospective randomized controlled study was conducted. Subjects included Oral and Maxillofacial Surgery residents in postgraduate year 1-5 at Thomas Jefferson University. Chief residents actively performing TMJ arthroscopy were excluded. PREDICTOR VARIABLE: The predictor variable was participation in LFS training. Subjects were randomly assigned to the LFS training or no LFS training group. MAIN OUTCOME VARIABLES: The primary outcome variable was simulated surgical skill measured by total ASSET score (maximum score of 35). The secondary outcome variables were simulated surgical skill measured by each ASSET domain score and time to completion. COVARIATES: The covariates included sex, age, handedness, postgraduate year, endoscopic experience, open TMJ surgery experience, and experience with musical instruments and sports. ANALYSES: Data analyses included paired T-tests to determine changes in outcome variables after TMJ arthroscopy training between experimental groups, and ANOVA and χ2 tests to identify associations between covariates. Inter-rater reliability of the blinded examiners was evaluated using Cronbach's alpha correlation. A P-value < .05 was considered significant. RESULTS: The sample was composed of 10 residents: 5 (100%) males in the no LFS group, 3 (60%) males, and 2 (40%) females in the LFS group (P = .4). There was no significant difference between the groups in pre-TMJ arthroscopy training ASSET scores (P = .3). After training, the total ASSET score improved by 3.40 ± 6.87 in the no LFS group and by 6.27 ± 2.68 in the LFS group (P = .03). CONCLUSIONS AND RELEVANCE: Study results showed that low-fidelity simulation can improve fundamental arthroscopic skills. Future research should be conducted on a larger scale to further validate this model and show the transfer of skill improvements to cadaver and live patient settings.
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Aging affects almost all aspects of an organism-its morphology, its physiology, its behavior. Isolating which biological mechanisms are regulating these changes, however, has proven difficult, potentially due to our inability to characterize the full repertoire of an animal's behavior across the lifespan. Using data from fruit flies (D. melanogaster) we measure the full repertoire of behaviors as a function of age. We observe a sexually dimorphic pattern of changes in the behavioral repertoire during aging. Although the stereotypy of the behaviors and the complexity of the repertoire overall remains relatively unchanged, we find evidence that the observed alterations in behavior can be explained by changing the fly's overall energy budget, suggesting potential connections between metabolism, aging, and behavior.
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Drosophila melanogaster , Drosophila , Envelhecimento , Animais , Comportamento Animal , Drosophila/fisiologia , Drosophila melanogaster/fisiologia , LongevidadeRESUMO
Red cell rigidity is common in sickle cell disease (SCD). The contribution of oxidative stress on deformability remains unknown. This study investigated red blood cell (RBC) vitamin C concentrations in pediatric SCD (n=43) compared with healthy controls ( n =23) and developed a protocol to raise RBC vitamin C concentrations to measure the effect on deformability. Sickle cell RBC vitamin C concentrations seem low (20.5 µM, SD: 16.2 vs. 51.7 µM, SD: 15.8; P <0.0001). Vitamin C can be successfully loaded into sickle cell RBCs but seems to have minimal effect on deformability. Future studies are needed to understand the clinical implications of vitamin C deficiency in pediatric SCD.
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Anemia Falciforme , Ácido Ascórbico , Humanos , Criança , Ácido Ascórbico/farmacologia , Deformação Eritrocítica , Eritrócitos , Eritrócitos Anormais , VitaminasRESUMO
ABSTRACT: A 64-year-old man presented with painless sequential bilateral vision loss, consistent with optic neuropathy, over the span of months. The significant decline in his visual function was out of proportion to the appearance of the optic nerves (which were not pale) or changes in his retinal nerve fiber layer thickness on optical coherence tomography. Neuroimaging revealed only mild T2 signal abnormality and faint enhancement in the left optic nerve. Extensive workup for potential infectious, metabolic, inflammatory, and ischemic etiologies was unremarkable. Empiric treatment with intravenous steroids did not slow or ameliorate the vision loss. Ultimately, genetic analysis revealed a missense m.11778G>A mutation in mitochondrial MT-ND4 gene, consistent with Leber hereditary optic neuropathy. Initiation of multivitamin supplements and idebenone unfortunately did not result in recovery of vision.
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Atrofia Óptica Hereditária de Leber , DNA Mitocondrial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/complicações , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Nervo Óptico , Esteroides , Tomografia de Coerência Óptica , Transtornos da VisãoRESUMO
OBJECTIVES: Prior studies have shown that left ventricular diastolic dysfunction (DD) is associated with increased mortality after surgical aortic valve replacement but studies on transcatheter aortic valve replacement (TAVR) are limited and have not taken into account mitral annular calcification (MAC), which limits the use of mitral valve annular tissue Doppler imaging. We performed a single-center retrospective analysis to better evaluate the role of baseline DD on outcomes after TAVR. METHODS: After excluding patients with atrial fibrillation, mitral valve prostheses and significant mitral stenosis, 359 consecutive TAVR patients were included in the study. Moderate-to-severe MAC was present in 58% of the patients. We classified patients into severe versus nonsevere DD based on the evaluation of elevated left ventricular filling pressure. The outcome measure was all-cause mortality or heart failure hospitalization. RESULTS: Over a mean follow-up time of 13 months, severe DD was associated with an increased risk for the outcome measure (HR 2.02 [1.23-3.30], p = .005). However, this association was lost in a propensity-matched cohort. In multivariate analysis, STS score was the only independent predictor of all cause mortality of heart failure hospitalization (HR 1.1 [1.05-1.15], p < .001). CONCLUSIONS: We evaluated the role of baseline DD on outcomes after TAVR by taking into account the presence of MAC. Severe DD was associated with increased all-cause mortality or heart failure hospitalization but not independently of other structural parameters and known predictors of the outcome measure.
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Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/fisiopatologia , Calcinose/diagnóstico por imagem , Calcinose/fisiopatologia , Causas de Morte , Diástole , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Readmissão do Paciente , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/mortalidade , Pressão VentricularRESUMO
BACKGROUND: Vaccination recommendations for childhood cancer survivors are ambiguous. Limited data exist on vaccination rates and patient/caregiver knowledge of vaccination postchemotherapy. PROCEDURE: A single-institution study of childhood cancer survivors treated from 1996 to 2018. Study included a retrospective chart review assessing patient's vaccination status, survey of patient's/caregiver's knowledge/beliefs regarding vaccination postchemotherapy, and assessment of immunoglobulin titers. RESULTS: A total of 120 patient charts were included. Vaccination records were available for 82% (98/120) of patients, 57% (56/98) were up to date with vaccinations before chemotherapy, and 83% (81/98) received vaccinations after chemotherapy. Children who resumed vaccination postchemotherapy were younger at cancer diagnosis compared to those who did not resume vaccination (2 vs 4 years, P < .02). Median time since chemotherapy was higher in vaccinated versus unvaccinated patients (107 vs 60 months, P < .02). Immunoglobulin titers were assessed in 27 patients, and 74% (20/27) were not immune to one or more infections tested. Lack of immunity to pneumococcal strains was the most common. There was no difference in median age at diagnosis or time since chemotherapy completion in immune versus nonimmune patients. In 33 surveyed patients/caregivers, 33% (11/33) were not advised about resuming vaccinations postchemotherapy. Over one-third (12/33) of respondents were concerned about vaccination safety after chemotherapy, although 88% (29/33) agreed they would vaccinate if recommended by their pediatrician/pediatric oncologist. CONCLUSIONS: Most childhood cancer survivors resume vaccinations postchemotherapy. Considerable variability exists in vaccination timing after chemotherapy. Pediatric oncologists play a central role in educating patients/pediatricians about vaccination recommendations postchemotherapy.
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Sobreviventes de Câncer/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Neoplasias/imunologia , Neoplasias/prevenção & controle , Cooperação do Paciente/estatística & dados numéricos , Vacinação/métodos , Adolescente , Cuidadores/psicologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neoplasias/patologia , Neoplasias/psicologia , Pais/psicologia , Cooperação do Paciente/psicologia , Prognóstico , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Vacinação/psicologiaRESUMO
PURPOSE: Although temporomandibular joint (TMJ) arthroscopy outcomes have been well documented in the adult population, conclusive data are lacking for pediatric patients with TMJ disorders. The aim of the present study was to evaluate the early and late outcomes of TMJ arthroscopy in the pediatric population. PATIENTS AND METHODS: We performed a retrospective analysis to evaluate the short- (1-month) and long-term (1-year) improvements in the visual analog scale (VAS) scores for pain after pediatric TMJ arthroscopy from 2008 to 2016. The arthroscopic interventions varied according to the diagnostic findings and Wilkes classification. The primary outcome variable was the magnitude of VAS score for pain (0, no pain; 100, worst pain) at 1 year postoperatively. The secondary outcome variables were the short-term for the VAS score for pain and the short- and long-term outcomes for perceived jaw dysfunction (0, normal jaw function; 100, complete jaw dysfunction), mouth opening, joint loading (contralateral joint pain when biting on the canine), joint noise, and muscle pain. Univariate, bivariate, and multivariate statistical analyses were performed with the significance level set at P < .05. RESULTS: A total of 23 patients (37 joints), with a mean age of 14.1 years (range, 12.8 to 16.7 years) had undergone TMJ arthroscopic surgery with short- and long-term postoperative follow-up data available. The VAS scores for pain showed average improvements of 26% in the short-term (P < .0001) and 25% in the long-term (P < .0008). Perceived jaw dysfunction showed an average improvement of 23.8% in the short-term (P < .0001) and 19.2% in the long-term (P < .0008). The average mouth opening had improved by 5.4 mm in the short-term (P < .0016) and 8.2 mm in the long-term (P < .0001). Controlling for stage and diagnosis, the patients with Wilkes III showed the most benefit with statistically significant improvements in pain, jaw dysfunction, maximum interincisal opening, and joint loading pain. CONCLUSIONS: TMJ arthroscopy could be an effective and minimally invasive form of surgical intervention for treating Wilkes II, III, and IV TMJ disorders in the pediatric population.
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Luxações Articulares , Transtornos da Articulação Temporomandibular , Adolescente , Adulto , Artroscopia , Criança , Humanos , Medição da Dor , Amplitude de Movimento Articular , Estudos Retrospectivos , Articulação Temporomandibular , Resultado do TratamentoRESUMO
PURPOSE: Total joint replacement is the recommended treatment for end-stage temporomandibular joint (TMJ) disease. The goal of treatment is to help the return to acceptable function with improvement of the maximum incisal opening (MIO) and a reduction of pain. When a prosthetic joint shows late complications, surgical management includes an open approach, with debridement, cultures, and prosthetic replacement as options. The purpose of the present study was to evaluate the early outcomes of arthroscopic management of failing prosthetic TMJs (PTMJs). PATIENTS AND METHODS: The inclusion criteria were patients with custom or stock joints with complaints of limitation of mouth opening and pain, who had undergone arthroscopy. The exclusion criteria were patients with radiographic heterotopic bone formation, improvement with antibiotic treatment, and failed hardware found on imaging studies. RESULTS: A total of 9 patients were included in the present study (all women), with 5 unilateral and 4 bilateral PTMJs, for a total of 13 sides that underwent arthroscopy. Their mean age was 40 years (range, 23 to 65 years). The mean preoperative MIO was 25 mm, and the mean preoperative visual analog scale for pain and functional limitation scores were both 8 of 10. The corresponding scores were 4 of 10 and 3 of 10 at 3 months postoperatively. CONCLUSIONS: Arthroscopic management of prosthetic joints has been reported in orthopedic studies, with benefits shown in the diagnosis and management of synovial impingement and arthrofibrosis. The results from the present study demonstrated that the early clinical outcomes of arthroscopic management of PTMJs is promising for decreasing pain and increasing the MIO. Larger studies with longer follow-up are needed to further classify the different causes of prosthetic failure and advance the approaches to management.
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Artroplastia de Substituição , Prótese Articular , Transtornos da Articulação Temporomandibular/cirurgia , Adulto , Idoso , Artroscopia , Feminino , Humanos , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Articulação Temporomandibular/cirurgia , Resultado do Tratamento , Adulto JovemAssuntos
Infecções Oculares Bacterianas , Ceratite , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/microbiologia , Antibacterianos/uso terapêuticoRESUMO
INTRODUCTION: Subclinical atrial fibrillation (AF), in the form of cardiac implantable device-detected atrial high rate episodes (AHREs), has been associated with increased thromboembolism. An implantable cardioverter-defibrillator (ICD) lead with a floating atrial dipole may permit a single lead (DX) ICD system to detect AHREs. We sought to assess the utility of the DX ICD system for subclinical AF detection in patients, with a prospective multicenter, cohort-controlled trial. METHODS AND RESULTS: One hundred fifty patients without prior history of AF (age 59 ± 13 years; 108 [72%] male) were enrolled into the DX cohort and implanted with a Biotronik DX ICD system at eight centers. Age-, sex-, and left ventricular ejection fraction-matched single- and dual-chamber ICD cohorts were derived from a Cornell database and from the IMPACT trial, respectively. The primary endpoint were AHRE detection at 12 months. During median 12 months follow-up, AHREs were detected in 19 (13%) patients in the DX, 8 (5.3%) in the single-chamber, and 19 (13%) in the dual-chamber cohorts. The rate of AHRE detection was significantly higher in the DX cohort compared to the single-chamber cohort (P = .026), but not significantly different compared to the dual-chamber cohort. There were no inappropriate ICD therapies in the DX cohort. At 12 months, only 3.0% of patients in the DX cohort had sensed atrial amplitudes less than 1.0 mV. CONCLUSION: Use of a DX ICD lead allows subclinical AF detection with a single lead DX system that is superior to that of a conventional single-chamber ICD system.
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Fibrilação Atrial/diagnóstico , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Técnicas Eletrofisiológicas Cardíacas/instrumentação , Tecnologia de Sensoriamento Remoto/instrumentação , Potenciais de Ação , Adulto , Idoso , Doenças Assintomáticas , Fibrilação Atrial/fisiopatologia , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Estados UnidosRESUMO
BACKGROUND: Ablation of atrial tachycardia (AT) that occurs after cardiac surgery or prior ablation often requires complex lesion sets. In combination with the pre-existing atrial scar, these lesion sets may result in inadvertent intra-atrial conduction block. This study reports the phenomenon of incidental isolation of right atrial (RA) regions that occurs secondary to AT ablation, which in some cases results in profound bradycardia due to sinus exit block. METHODS AND RESULTS: Intracardiac electrograms were examined in consecutive patients who underwent AT ablation in the RA. Cases of localized isolation of the RA were defined as areas that developed electrical dissociation during ablation. Of 132 patients having ablation in both the RA free wall and the cavotricuspid isthmus (CTI), 10 (7.6%) developed unintentional isolation of the lateral RA. Five of these patients had prior mitral valve surgery, comprising 12.2% of all 41 patients with mitral surgery who underwent ablation in the CTI and the RA free wall. All patients with regional isolation had a pre-existing scar in the lateral wall of the RA. In six patients, isolation of the lateral RA resulted in profound bradycardia due to exit block from the peri-sinus node myocardium. CONCLUSIONS: Complex ablation lesions in patients with prior valve surgery, prior ablation, or atrial myopathy may result in unintended localized conduction block in the RA. In some cases, isolation of the lateral RA can result in complete sinus exit block with profound bradycardia requiring pacemaker implantation.
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Flutter Atrial/cirurgia , Função do Átrio Direito , Bradicardia/etiologia , Ablação por Cateter/efeitos adversos , Átrios do Coração/cirurgia , Frequência Cardíaca , Taquicardia Supraventricular/cirurgia , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Flutter Atrial/diagnóstico , Flutter Atrial/fisiopatologia , Bradicardia/diagnóstico , Bradicardia/fisiopatologia , Bradicardia/terapia , Estimulação Cardíaca Artificial , Feminino , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
We propose a new class of carbon allotropes obtained by combining linear sp carbon chains with sp3 bulk carbon. The structure of these crystalline carbon allotropes consists of sp chains inserted in cylindrical cavities periodically arranged in hexagonal diamond (lonsdaleite). We carry out a detailed computational analysis of the structural, electronic, and vibrational properties of a simple form in this class: a single C6 strand embedded in a nm-sized cavity. We obtain a metallic allotrope exhibiting characteristic high-frequency vibrations associated with the sp chain stretching modes, and characterized by long-time room-temperature stability. In addition, we suggest how numerous similar allotropes could be constructed within this class, that we call zayedenes, all characterized by comparable metallicity and high-frequency vibrations.
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We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established.