RESUMEN
Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA-damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress and has been implicated as a potential biomarker to predict sensitivity to DNA-damaging agents (DDA). SLFN11 expression was quantified in 220 children with solid tumors using IHC. Sensitivity to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN) was assessed in sarcoma cell lines, including SLFN11 knock-out (KO) and overexpression models, and a patient-derived orthotopic xenograft model (PDOX). SLFN11 was expressed in 69% of pediatric sarcoma sampled, including 90% and 100% of Ewing sarcoma and desmoplastic small round-cell tumors, respectively, although the magnitude of expression varied widely. In sarcoma cell lines, protein expression strongly correlated with response to TAL and IRN, with SLFN11 KO resulting in significant loss of sensitivity in vitro and in vivo Surprisingly, retrospective analysis of children with sarcoma found no association between SLFN11 levels and favorable outcome. Subsequently, high SLFN11 expression was confirmed in a PDOX model derived from a patient with recurrent Ewing sarcoma who failed to respond to treatment with TAL + IRN. Selective inhibition of BCL-xL increased sensitivity to TAL + IRN in SLFN11-positive resistant tumor cells. Although SLFN11 appears to drive sensitivity to replicative stress in pediatric sarcomas, its potential to act as a biomarker may be limited to certain tumor backgrounds or contexts. Impaired apoptotic response may be one mechanism of resistance to DDA-induced replicative stress.
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Daño del ADN/genética , Genómica/métodos , Proteínas Nucleares/metabolismo , Sarcoma de Ewing/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Ratones Desnudos , Adulto JovenRESUMEN
Morphogens function in concentration-dependent manners to instruct cell fate during tissue patterning. The cytoneme morphogen transport model posits that specialized filopodia extend between morphogen-sending and responding cells to ensure that appropriate signaling thresholds are achieved. How morphogens are transported along and deployed from cytonemes, how quickly a cytoneme-delivered, receptor-dependent signal is initiated, and whether these processes are conserved across phyla are not known. Herein, we reveal that the actin motor Myosin 10 promotes vesicular transport of Sonic Hedgehog (SHH) morphogen in mouse cell cytonemes, and that SHH morphogen gradient organization is altered in neural tubes of Myo10-/- mice. We demonstrate that cytoneme-mediated deposition of SHH onto receiving cells induces a rapid, receptor-dependent signal response that occurs within seconds of ligand delivery. This activity is dependent upon a novel Dispatched (DISP)-BOC/CDON co-receptor complex that functions in ligand-producing cells to promote cytoneme occurrence and facilitate ligand delivery for signal activation.
During development, cells must work together and talk to each other to build the organs and tissues of the growing embryo. To communicate precisely with long-distance targets, cells can project a series of thin finger-like structures known as cytonemes. Cells use these miniature highways to exchange cargo and signals, such as the protein sonic hedgehog (SHH for short). Alterations to the way SHH is exchanged during development predispose to cancer and lead to disorders of the nervous system. Yet, the mechanisms by which cytonemes work in mammals remain to be fully elucidated. In particular, it is still unclear how the structures start to form, and how the proteins are loaded and transported from one end to another. A 'molecular motor' called myosin 10, which can carry cargo along the internal skeleton of cells, may be involved in these processes. To find out, Hall et al. used fluorescent probes to track both myosin 10 and SHH in mouse cells, showing that myosin 10 carries SHH from the core of the signal-producing cell to the tips of cytonemes. There, the protein is passed to the target cell upon contact, triggering a quick response. SHH also appeared to be more than just passive cargo, interacting with another group of proteins in the signal-emitting cell before reaching its target. This mechanism then encourages the signalling cells to produce more cytonemes towards their neighbours. SHH is crucial during development, but also after birth: in fact, changes to SHH transport in adulthood can also disrupt tissue balance and hinder healing. Understanding how healthy tissues send this signal may reveal why and how disease emerges.
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Moléculas de Adhesión Celular/genética , Proteínas Hedgehog/genética , Inmunoglobulina G/genética , Proteínas de la Membrana/genética , Miosinas/genética , Receptores de Superficie Celular/genética , Animales , Transporte Biológico , Moléculas de Adhesión Celular/metabolismo , Proteínas Hedgehog/metabolismo , Inmunoglobulina G/metabolismo , Ligandos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Miosinas/metabolismo , Receptores de Superficie Celular/metabolismoRESUMEN
BACKGROUND: Evaluate the efficacy of two courses of vincristine and topotecan (VT) neoadjuvant intravenous chemotherapy in reducing retinoblastoma tumor volumes. METHODS: Twenty-seven patients with previously untreated, bilateral advanced retinoblastoma who were enrolled on a prospective treatment protocol (NCT00186888). Patients underwent high-resolution ophthalmic imaging at diagnosis and were reimaged following treatment with two cycles of VT. Tumor height and diameter were measured before and after treatment, and tumor volumes were calculated. Statistical methods for dependent samples were used. RESULTS: Imaging was completed for 75 tumors in 23 patients (43 eyes). After two cycles of VT, median decrease in tumor height was 47% and median decrease in tumor diameter was 22%. Median decrease in estimated tumor volume was 74%. Sixty-one of 75 tumors demonstrated >50% reduction in tumor volume. Distance from the optic nerve (=0 vs >0), age (<4 vs >4 months), macular location (within vs outside), and time (pre- and posttreatment) were found significantly associated with log-transformed tumor volume adjusting for the repeated effect of patient eye using generalized estimating equations to estimate the parameters of a generalized linear model (P < .0001 [ ß : 1.95, CI: 1.53-2.36], P = .0031 [ ß : 1.49, CI: 0.57-2.41], P < .0001 [ ß : .94, CI: 0.54-1.35], and P < .0001 [ ß : 1.43, CI: 1.15-1.71]). CONCLUSION: Chemoreduction was achieved in all patients and most retinoblastoma tumors following two cycles of VT. Reduction in tumor dimensions was comparable to that reported with platinum-based chemotherapy. Tumor location, distance from the optic nerve, and age at diagnosis were significant predictors of treatment response.
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Antineoplásicos/uso terapéutico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Topotecan/uso terapéutico , Vincristina/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias de la Retina/patología , Retinoblastoma/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosAsunto(s)
Anestesiología , Neoplasias , Anestesiólogos , Niño , Humanos , Estudios Retrospectivos , Sociedades Médicas , Estados UnidosRESUMEN
Chimeric antigen receptor (CAR) T cells targeting CD123, an acute myeloid leukemia (AML) antigen, hold the promise of improving outcomes for patients with refractory/recurrent disease. We generated five lentiviral vectors encoding CD20, which may serve as a target for CAR T cell depletion, and 2nd or 3rd generation CD123-CARs since the benefit of two costimulatory domains is model dependent. Four CARs were based on the CD123-specific single-chain variable fragment (scFv) 26292 (292) and one CAR on the CD123-specific scFv 26716 (716), respectively. We designed CARs with different hinge/transmembrane (H/TM) domains and costimulatory domains, in combination with the zeta (z) signaling domain: 292.CD8aH/TM.41BBz (8.41BBz), 292.CD8aH/TM.CD28z (8.28z), 716.CD8aH/TM.CD28z (716.8.28z), 292.CD28H/TM. CD28z (28.28z), and 292.CD28H/TM.CD28.41BBz (28.28.41BBz). Transduction efficiency, expansion, phenotype, and target cell recognition of the generated CD123-CAR T cells did not significantly differ. CAR constructs were eliminated for the following reasons: (1) 8.41BBz CARs induced significant baseline signaling, (2) 716.8.28z CAR T cells had decreased anti-AML activity, and (3) CD28.41BBz CAR T cells had no improved effector function in comparison to CD28z CAR T cells. We selected the 28.28z CAR since CAR expression on the cell surface of transduced T cells was higher in comparison to 8.28z CARs. The clinical study (NCT04318678) evaluating 28.28z CAR T cells is now open for patient accrual.
RESUMEN
BACKGROUND: Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. PATIENTS AND METHODS: Cohorts of 3-6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1-6, and intravenous irinotecan and oral temozolomide were administered on days 2-6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. RESULTS: Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. CONCLUSIONS: The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Irinotecán/uso terapéutico , Neoplasias/tratamiento farmacológico , Ftalazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Temozolomida/uso terapéutico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Niño , Preescolar , Femenino , Humanos , Irinotecán/farmacología , Masculino , Neoplasias/patología , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Temozolomida/farmacología , Adulto JovenRESUMEN
PURPOSE: Several studies describe sleep-wake disturbances in pediatric craniopharyngioma, but none have determined the prevalence or associated predictors of excessive sleepiness in this group after diagnosis and prior to post-operative observation or adjuvant radiotherapy. In this study, we report sleep-wake disturbances in children and adolescents with craniopharyngioma and associated clinical and treatment variables. METHODS: After surgery and prior to radiotherapy or observation, pediatric patients (n = 110) with craniopharyngioma ≥ 3 years old completed a baseline sleep clinic evaluation by a pediatric sleep specialist, polysomnography (PSG) and next-day multiple sleep latency test (MSLT). MSLT was limited to those ≥ 6 years old. Logistic regression models were used to determine the relationship between patient characteristics and the presence and type of hypersomnia. RESULTS: Amongst patients completing PSG and MSLT, 80% had polygraphic evidence of excessive daytime sleepiness. Hypersomnia due to medical condition was diagnosed in 45% and narcolepsy in 35%. Overweight or obese patients were more likely to be diagnosed with hypersomnia (P = 0.012) or narcolepsy (P = 0.009). Grade 2 hypothalamic involvement (HI) at diagnosis was associated with the diagnosis of narcolepsy (P = 0.0008). CONCLUSIONS: This study describes the prevalence and associated predictors of hypersomnia for patients with craniopharyngioma after surgical resection. HI was predictive of narcolepsy diagnosis, and a higher body mass index z-score was associated with hypersomnia due to medical condition and narcolepsy. We recommend that sleep assessment and intervention begin after surgical resection, especially in overweight or obese patients and those with extensive tumors.
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Craneofaringioma/complicaciones , Trastornos de Somnolencia Excesiva/diagnóstico , Narcolepsia/diagnóstico , Neoplasias Hipofisarias/complicaciones , Adolescente , Niño , Preescolar , Trastornos de Somnolencia Excesiva/etiología , Femenino , Humanos , Lactante , Masculino , Narcolepsia/etiologíaRESUMEN
BACKGROUND: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied. METHODS: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy. RESULTS: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56bright NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses. CONCLUSION: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56bright expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance. TRIAL REGISTRATION NUMBER: NCT01857934.
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Inmunoterapia/métodos , Células Asesinas Naturales/metabolismo , Neuroblastoma/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Cinética , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. RESULTS: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031). CONCLUSIONS: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Quimioterapia de Inducción/mortalidad , Neoplasias Pulmonares/mortalidad , Sarcoma de Ewing/mortalidad , Adolescente , Adulto , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Sarcoma de Ewing/patología , Sarcoma de Ewing/terapia , Tasa de Supervivencia , Trasplante Autólogo , Adulto JovenRESUMEN
BACKGROUND: The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. METHODS: In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. RESULTS: Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. CONCLUSIONS: The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Everolimus/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Pronóstico , Supervivencia sin ProgresiónRESUMEN
PURPOSE: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma. PATIENTS AND METHODS: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction. RESULTS: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3). CONCLUSIONS: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Supervivencia sin Enfermedad , Femenino , Gangliósidos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Quimioterapia de Inducción/efectos adversos , Estimación de Kaplan-Meier , Células Asesinas Naturales/efectos de los fármacos , Masculino , Neuroblastoma/patología , Supervivencia sin Progresión , Estudios Prospectivos , Adulto JovenRESUMEN
STUDY OBJECTIVES: Children with craniopharyngioma are at risk for excessive daytime sleepiness (EDS). Multiple Sleep Latency Testing (MSLT) is the gold standard for objective evaluation of EDS; however, it is time and resource intensive. We compared the reliability, sensitivity, and specificity of the modified Epworth Sleepiness Scale (M-ESS) and MSLT in monitoring EDS in children with craniopharyngioma. METHODS: Seventy patients (ages 6 to 20 years) with craniopharyngioma completed the M-ESS and were evaluated by polysomnography and MSLT. Evaluations were made after surgery, if performed, and before proton therapy. RESULTS: MSLT revealed that 66 participants (81.8%) had EDS, as defined by a mean sleep latency (MSL) < 10 minutes, with only 28.8% reporting EDS on the M-ESS by using a cutoff score of 10. The M-ESS demonstrated adequate internal consistency and specificity (91.7%) but poor sensitivity (33.3%) with the established cutoff score of 10. A cutoff score of 6 improved the sensitivity to 64.8% but decreased the specificity to 66.7%. CONCLUSIONS: Patients with craniopharyngioma are at high risk for EDS, as documented objectively on the MSLT, but they frequently do not recognize or accurately report their sleepiness. Future sleep studies should investigate whether specific items or alternative self- and parent-reported measures of sleepiness may have greater clinical utility in monitoring sleepiness in this population.
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Craneofaringioma/complicaciones , Trastornos de Somnolencia Excesiva/complicaciones , Trastornos de Somnolencia Excesiva/diagnóstico , Neoplasias Hipofisarias/complicaciones , Adolescente , Adulto , Niño , Craneofaringioma/fisiopatología , Trastornos de Somnolencia Excesiva/fisiopatología , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/fisiopatología , Polisomnografía/estadística & datos numéricos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Latencia del Sueño/fisiología , Somnolencia , Adulto JovenRESUMEN
OBJECTIVES: To develop an evidence-based compassion fatigue program and evaluate its impact on nurse-reported burnout, secondary traumatic stress, and compassion satisfaction, as well as correlated factors of resilience and coping behaviors. SAMPLE & SETTING: The quality improvement pilot program was conducted with 59 nurses on a 20-bed subspecialty pediatric oncology unit at the St. Jude Children's Research Hospital in Memphis, Tennessee. METHODS & VARIABLES: Validated measures of compassion fatigue and satisfaction (Professional Quality of Life Scale V [ProQOLV]), coping (Brief COPE), and resilience (Connor-Davidson Resilience Scale-2) were evaluated preprogram and at two, four, and six months postprogram, with resilience and coping style measured at baseline and at six months postprogram. RESULTS: Secondary traumatic stress scores significantly improved from baseline to four months. Select coping characteristics were significantly correlated with ProQOLV subscale scores. IMPLICATIONS FOR NURSING: Ongoing organizational support and intervention can reduce compassion fatigue and foster compassion satisfaction among pediatric oncology nurses.
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Agotamiento Profesional/prevención & control , Desgaste por Empatía/prevención & control , Enfermeras Pediátricas/psicología , Enfermería Oncológica , Enfermería Pediátrica , Adaptación Psicológica , Adulto , Aflicción , Agotamiento Profesional/etiología , Agotamiento Profesional/psicología , Desgaste por Empatía/etiología , Depresión/etiología , Educación Continua en Enfermería , Femenino , Estudios de Seguimiento , Pesar , Conductas Relacionadas con la Salud , Humanos , Satisfacción en el Trabajo , Masculino , Relaciones Enfermero-Paciente , Enfermeras Pediátricas/educación , Apoyo Nutricional , Proyectos Piloto , Resiliencia Psicológica , Adulto JovenRESUMEN
BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.
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Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Células Germinativas , Consentimiento Informado/psicología , Competencia Mental/psicología , Neoplasias/genética , Padres/educación , Adolescente , Adulto , Anciano , Niño , Femenino , Mutación de Línea Germinal , Humanos , Conocimiento , Masculino , Persona de Mediana Edad , Autoinforme , Adulto JovenRESUMEN
BACKGROUND: High-quality oncology care is marked by skillful communication, yet little is known about patient and family communication perceptions or content preferences. Our study sought to elicit pediatric oncology patient and parent perceptions of early cancer communication to establish whether informational needs were met and identify opportunities for enhanced communication throughout cancer care. METHOD: An original survey instrument was developed, pretested, and administered to 129 patients, age 10-18 years, and their parents at 3 cancer centers between 2011 and 2015. Statistical analysis of survey items about perceived communication, related associations, and patient/parent concordance was performed. RESULTS: A greater percentage of participants reported "a lot" of discussion about the physical impact of cancer (patients, 58.1% [n = 75]; parents, 69.8% [n = 90]) compared with impact on quality of life (QOL) (patients, 44.2% [n = 57]; parents, 55.8% [n = 72]) or emotional impact (patients, 31.8% [n = 41]; parents, 43.4% [n = 56]). One fifth of patients (20.9% [n = 27]) reported they had no up-front discussion about the emotional impact of cancer treatment. Parents indicated a desire for increased discussion regarding impact on family life (27.9% [n = 36]), long-term QOL (27.9% [n = 36]), and daily activities (20.2% [n = 26]). Patients more frequently than parents indicated a desire for increased physician/patient discussion around the impact on daily activities (patients, 40.3% [n = 52]; parents, 21.7% [n = 28]; P < .001), long-term QOL (patients, 34.9% [n = 45]; parents, 16.3% [n = 21]; P < .001), pain management (patients, 23.3% [n = 30]; parents, 7% [n = 9]; P < .001), physical symptom management (patients, 24% [n = 31]; parents, 7.8% [n = 10]; P < .001), short-term QOL (patients, 23.3% [n = 30]; parents, 9.3% [n = 12]; P = .001), and curative potential (patients, 21.7% [n = 28]; parents, 8.5% [n = 11]; P = .002, P values calculated using McNemar's test). CONCLUSION: Oncologists may not be meeting the informational needs of many patients and some parents/caregivers. Communication could be enhanced through increased direct physician-patient communication, as well as proactive discussion of emotional symptoms and impact of cancer on QOL.
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Comunicación , Necesidades y Demandas de Servicios de Salud , Oncología Médica , Neoplasias/terapia , Pediatría , Adolescente , Adulto , Anciano , Cuidadores/psicología , Cuidadores/estadística & datos numéricos , Niño , Familia/psicología , Femenino , Necesidades y Demandas de Servicios de Salud/normas , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Humanos , Masculino , Oncología Médica/normas , Oncología Médica/estadística & datos numéricos , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/psicología , Educación del Paciente como Asunto/métodos , Educación del Paciente como Asunto/normas , Educación del Paciente como Asunto/estadística & datos numéricos , Pediatría/normas , Pediatría/estadística & datos numéricos , Relaciones Médico-Paciente , Médicos/psicología , Médicos/normas , Médicos/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND:: Education and training for interdisciplinary pediatric providers requires training in principles of palliative and end-of-life (EOL) care. The experiences of bereaved parents can inform and enhance palliative care educational curricula in uniquely powerful and valuable ways. The objective of this study is to present an innovative palliative care educational program facilitated by trained bereaved parents who serve as volunteer educators in local and national palliative care educational forums and to describe how incorporation of bereaved parents in these educational forums affects participant comfort with communication and management of children at the EOL. METHODS:: Parent educators underwent both general and session-specific training and participated in debriefings following each session. Survey tools were developed or adapted to determine how bereaved parent educators affected participant experiences in 3 different educational forums. Pre- and postsession surveys with incorporation of retrospective preprogram assessment items to control for response shift were used in the evaluation of institutional seminars on pediatric palliative and EOL care and role-play-based communication training sessions. Results from feedback surveys sent to attendees were used to appraise the participants' experience at the international oncology symposium. RESULTS:: Involvement of trained parent educators across diverse, interdisciplinary educational forums improved attendee comfort in communicating with, and caring for, patients and families with serious illness. Importantly, parent educators also derive benefit from involvement in educational sessions with interdisciplinary clinicians. CONCLUSIONS:: Integration of bereaved parents into palliative and EOL care education is an innovative and effective model that benefits both interdisciplinary clinicians and bereaved parents.
Asunto(s)
Docentes/organización & administración , Medicina Paliativa/educación , Padres , Pediatría/educación , Cuidado Terminal , Comunicación , Humanos , Calidad de Vida , Estudios RetrospectivosRESUMEN
OBJECTIVES: To describe the clinical characteristics of children and adolescents undergoing hematopoietic cell transplantation (HCT) who develop oral mucositis. SAMPLE & SETTING: 45 patients who underwent HCT from July 2015 to May 2016 at St. Jude Children's Research Hospital in Memphis, Tennessee. METHODS & VARIABLES: Clinical factors were described as transplantation type, mucositis severity or grade, mucositis duration, days to engraftment, total parenteral nutrition (TPN) support, IV opioid pain management use during mucositis, positive blood or oral cultures, and length of hospitalization, then compared across mucositis grade. RESULTS: 24 patients had grade 3 or greater mucositis onset from day -3 to day 9 of transplantation; of these, 23 required IV opioid medication to treat mucosal pain. Patients with mucositis grade 3 or greater were more likely to have undergone an allogeneic transplantation, receive TPN, have documented positive blood or oral cultures, and have longer hospitalizations than those with low-grade mucositis. IMPLICATIONS FOR NURSING: Nurses are in a unique position to propose and administer interventions to prevent and alleviate symptoms of mucositis.
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Analgésicos Opioides/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Manejo del Dolor/métodos , Dolor/tratamiento farmacológico , Estomatitis/tratamiento farmacológico , Estomatitis/etiología , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Tennessee , Adulto JovenRESUMEN
BACKGROUND: In the U.S., more children die from cancer than from any other disease, and more than one third die in the hospital setting. These data have been replicated even in subpopulations of children with cancer enrolled on a palliative care service. Children with cancer who die in high-acuity inpatient settings often experience suffering at the end of life, with increased psychosocial morbidities seen in their bereaved parents. Strategies to preemptively identify children with cancer who are more likely to die in high-acuity inpatient settings have not been explored. MATERIALS AND METHODS: A standardized tool was used to gather demographic, disease, treatment, and end-of-life variables for 321 pediatric palliative oncology (PPO) patients treated at an academic pediatric cancer center who died between 2011 and 2015. Multinomial logistic regression was used to predict patient subgroups at increased risk for pediatric intensive care unit (PICU) death. RESULTS: Higher odds of dying in the PICU were found in patients with Hispanic ethnicity (odds ratio [OR], 4.02; p = .002), hematologic malignancy (OR, 7.42; p < .0001), history of hematopoietic stem cell transplant (OR, 4.52; p < .0001), total number of PICU hospitalizations (OR, 1.98; p < .0001), receipt of cancer-directed therapy during the last month of life (OR, 2.96; p = .002), and palliative care involvement occurring less than 30 days before death (OR, 4.7; p < .0001). Conversely, lower odds of dying in the PICU were found in patients with hospice involvement (OR, 0.02; p < .0001) and documentation of advance directives at the time of death (OR, 0.37; p = .033). CONCLUSION: Certain variables may predict PICU death for PPO patients, including delayed palliative care involvement. Preemptive identification of patients at risk for PICU death affords opportunities to study the effects of earlier palliative care integration and increased discussions around preferred location of death on end-of-life outcomes for children with cancer and their families. IMPLICATIONS FOR PRACTICE: Children with cancer who die in high-acuity inpatient settings often experience a high burden of intensive therapy at the end of life. Strategies to identify patients at higher risk of dying in the pediatric intensive care unit (PICU) have not been explored previously. This study finds that certain variables may predict PICU death for pediatric palliative oncology patients, including delayed palliative care involvement. Preemptive identification of patients at risk for PICU death affords opportunities to study the effects of earlier palliative care integration and increased discussions around preferred location of death on end-of-life outcomes for children with cancer and their families.
Asunto(s)
Muerte , Neoplasias/mortalidad , Cuidados Paliativos/métodos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Neoadjuvant chemotherapy is given to children with unresectable hepatoblastoma to increase the rate and safety of curative complete surgical resection. Elevated levels of serum alpha-fetoprotein (sAFP) decline with tumor shrinkage. In this single-institution retrospective study, we determined early dynamic changes of sAFP levels and tumor volume in children during therapy for unresectable hepatoblastoma. METHODS: We correlated early dynamic changes of sAFP levels and tumor volume and the sum of the longest primary tumor and measurable metastatic disease diameters as per RECIST 1.1 criteria with patient outcome. RESULTS: There were 34 patients, 7 of whom died of disease. Patients with ≥ 90% (≥ 1 log10) decrease in sAFP levels after two chemotherapy courses had a better event-free survival (P = 0.039) and overall survival (OS; P = 0.045) than those with < 90% decrease. During this treatment interval, average tumor volume decreased from 481 mL (± 254 mL) to 268 mL (± 258 mL; P < 0.001) which was associated with OS (P = 0.029). Relative change in sAFP levels or tumor volume in between course 2 and pre-surgery or response as per RECIST 1.1 was not associated with OS. CONCLUSION: Early decline of sAFP levels and tumor volume, but not response as per RECIST 1.1 may predict survival in children with unresectable hepatoblastoma. This finding could be useful to identify therapy non-responders for whom alternative interventions may be required for cure. Confirmation of the finding using larger patient cohorts will be necessary before this strategy is incorporated into prospective trials.
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Biomarcadores de Tumor/sangre , Hepatoblastoma/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , alfa-Fetoproteínas/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Hepatoblastoma/mortalidad , Hepatoblastoma/patología , Humanos , Lactante , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Terapia Neoadyuvante , Estudios Retrospectivos , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Evaluation of energy requirements is an important part of the nutrition assessment of pediatric oncology patients. Adequate provision of energy in this population is of extreme importance because of the prevalence of malnutrition and its effect on growth, development, quality of life, morbidity, and mortality. Numerous methods are used in clinical practice for estimating the resting energy expenditures (REE), specifically indirect calorimetry and predictive equations. A relatively new instrument used to assess REE is the hand-held indirect calorimeter. The purpose of this quality improvement project was to compare the accuracy of REE measurements taken by a hand-held indirect calorimeter and predictive equations to that of a standard indirect calorimeter metabolic cart. METHODS: Patients receiving therapy for pediatric cancer, aged 7-18 years, and having a weight ≥15 kg and scheduled for a REE nutrition assessment were eligible. Sequentially, the patient's REE was assessed with the cart and the hand-held indirect calorimeter along with the predictive equation calculation. RESULTS: Post hoc pairwise comparisons revealed that all 3 methods were significantly different from one another (P < .0001). When compared with the cart, the portable hand-held calorimeter was found to underestimate REE by 11.9%, whereas predictive equations overestimated REE by 12.4%. CONCLUSION: Our quality improvement project suggests that the hand-held indirect calorimeter underestimated REE, and predictive equations overestimated REE in pediatric oncology nutrition assessment. Therefore, we recommend that these limitations in assessment be considered when assessing REE using a hand-held indirect calorimeter or predictive equations.