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PURPOSE: To compare the incidence of sustained ocular hypertension (OHT) after intravitreal injections of prepackaged versus freshly prepared bevacizumab monotherapy for the treatment of neovascular age-related macular degeneration. METHODS: Charts of 1,216 patients with neovascular age-related macular degeneration receiving intravitreal bevacizumab monotherapy at 2 retina practices using different preparations of bevacizumab between January 1, 2009, and December 31, 2011, were reviewed. Primary outcome was incidence of sustained OHT, defined as intraocular pressure > 25 mmHg with an increase ≥ 6 from baseline on ≥ 2 consecutive visits or requiring treatment. RESULTS: A total of 6,479 injections in 740 eyes of 634 patients were included and 14 eyes (0.81% incidence per eye-year) developed sustained OHT. For eyes receiving prepackaged bevacizumab, 10 of 339 eyes (1.39% incidence per eye-year) developed sustained OHT compared with 4 of 401 eyes (0.39% incidence per eye-year) receiving freshly prepared bevacizumab, giving an incidence rate ratio of 3.55 (95% confidence interval, 0.93-13.49; P = 0.063). All eyes that developed sustained OHT achieved intraocular pressure control with observation or topical therapy alone. CONCLUSION: Incidence of sustained OHT after intravitreal bevacizumab is low. We found a trend toward higher rates of sustained OHT with prepackaged bevacizumab although this difference was not statistically or clinically significant.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Composición de Medicamentos , Embalaje de Medicamentos , Hipertensión Ocular/epidemiología , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/química , Bevacizumab/efectos adversos , Bevacizumab/química , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Presión Intraocular/efectos de los fármacos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Hipertensión Ocular/inducido químicamente , Factores de Riesgo , Tonometría Ocular , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
OBJECTIVE: This study was designed to determine whether the volume and type of fluid administered for pancreaticoduodenectomy impacts postoperative outcomes. BACKGROUND: Three percent hypertonic saline (HYS) has been suggested as a means of reducing the volume of fluid required to sustain tissue perfusion in the perioperative period. METHODS: Between May 2011 and November 2013, patients undergoing pancreaticoduodenectomy were enrolled in an institutional review board-approved, single-center, prospective, parallel, randomized controlled trial (NCT 01428050), comparing lactated Ringers (LAR) (15 mL/kg/hr LAR intraoperation, 2 mL/kg/hr LAR postoperation) with HYS (9 mL/kg/hr LAR and 1 mL/kg/hr HYS intraoperation, 1 mL/kg/hr HYS postoperation). RESULTS: A total of 264 patients were randomized. Demographic variables between groups were similar. The HYS patients had a significantly reduced net fluid balance (65 vs 91 mL/kg, P = 0.02). The overall complication rate was reduced in the HYS group (43% vs 54%), with a relative risk of 0.79 [95% confidence interval (CI), 0.62-1.02; P = 0.073], factoring stratification for pancreas texture. After adjustment for age and weight, the relative risk was 0.75 [95% CI (0.58-0.96); P = 0.023]. The total number of complications was significantly reduced in the HYS group (93 vs 123), with an incidence rate ratio of 0.74 [95% CI (0.56-0.97); P = 0.027]. After adjustment for age and weight, the incidence rate ratio was 0.69 [95% CI (0.52-0.90); P = 0.0068]. Reoperations, length of stay, readmissions, and 90-day mortality were similar between groups. CONCLUSIONS: A moderately restrictive fluid regimen with HYS resulted in a statistically significant 25% reduction in complications when adjusted for age, weight, and pancreatic texture.
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Soluciones Isotónicas/administración & dosificación , Pancreaticoduodenectomía , Complicaciones Posoperatorias/prevención & control , Solución Salina Hipertónica/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Pérdida de Sangre Quirúrgica , Vías Clínicas , Femenino , Fluidoterapia/métodos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/prevención & control , Pancreaticoduodenectomía/estadística & datos numéricos , Cuidados Posoperatorios/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Lactato de RingerRESUMEN
AIM: To investigate whether patients with metabolic syndrome (MetS) undergoing total hip or knee replacement have an increased risk for pulmonary embolism (PE). METHODS: We studied patients undergoing total hip or total knee replacement from January 2001 to April 2006. The diagnosis of PE was based on a positive finding with a chest CT or a lung scan. Components of MetS were defined as 1) BMI≥30 kg/m(2) , 2) non-fasting preadmission glucose ≥11.1 mmol/L or diagnosis of diabetes, 3) hypertension, and 4) dyslipidemia. MetS was diagnosed if at least three of these components were present. RESULTS: Of 7282 patients, 107 (1.47%) were diagnosed with PE. The incidence of PE in patients with 0, 1, 2, 3, and 4 MetS components was respectively 0.85% (16/1888; 95% confidence interval [CI] 0.5%-1.4%), 1.24% (31/2500; 95% CI 0.9%-1.8%), 1.76% (34/1936; 95% CI 1.2%-2.5%), 2.64% (21/796; 95% CI 1.7%-4.1%), and 3.09% (5/162; 95% CI 1.1%-7.4%). The independent risk factors for PE were age ≥70, knee as opposite to hip replacement, bilateral knee surgery, congestive heart failure, and MetS or the number of MetS components. The odds of PE independently increased 1.6 times (95% CI 1.01-2.56; P=0.043) for patients with MetS and 1.23 times (95% CI 1.02-1.48; P=0.028) per each additional MetS component. CONCLUSION: Patients with MetS are at increased risk for PE after total joint arthroplasty. The increasing number of MetS components significantly increased the incidence of PE.
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Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Síndrome Metabólico/complicaciones , Embolia Pulmonar/etiología , Adulto , Femenino , Articulación de la Cadera/cirugía , Humanos , Incidencia , Articulación de la Rodilla/cirugía , Masculino , Síndrome Metabólico/cirugía , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico por imagen , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome. METHODS: Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models. RESULTS: Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome. CONCLUSIONS: Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Factor de Transcripción STAT5/metabolismo , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Núcleo Celular/metabolismo , Terapia Combinada , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Fosforilación , Pronóstico , Transporte de Proteínas , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce. METHODS: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS). RESULTS: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively). Similar results were obtained for DFS. CONCLUSIONS: RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Estudios de Cohortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleósido Difosfato Reductasa , Análisis de Supervivencia , GemcitabinaRESUMEN
In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
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Leucemia Linfocítica Crónica de Células B , Humanos , Antígenos CD19 , Supervivencia sin Enfermedad , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Estudios Prospectivos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Linfocitos TRESUMEN
PURPOSE: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
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Antígenos CD19/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Proyectos Piloto , Adulto JovenRESUMEN
PURPOSE: Temporal lobectomy is a well-established treatment for refractory temporal lobe epilepsy, yet many patients experience at least one seizure postoperatively. Little is known about the prognostic significance of the time from surgery to first seizure relapse in predicting long-term outcome. METHODS: In a retrospective analysis of patients who reported at least one complex partial seizure (CPS) or generalized tonicclonic seizure (GTCS) after anterior temporal lobectomy (n = 268), we used a nominal response logistic model to predict the odds ratio (OR) of a seizure outcome based on length of the latency period from surgery to first postoperative seizure. A modified Engel outcome class scheme was used. We controlled for factors known to influence postoperative outcome, including history of tonicclonic seizures, intelligence quotient (IQ), preoperative seizure frequency, magnetic resonance imaging (MRI) findings, and history of febrile convulsions. RESULTS: In the univariate analysis, the latency from surgery to the first postoperative disabling seizure was significantly associated with long-term outcome. Longer latency was associated with higher odds of being seizure-free or improved (modified Engel's classes 1, 2, and 3) relative to the unimproved state (class 4) (p < 0.001, 0.001 and 0.004, respectively). Conversely, a shorter latency increased the likelihood of achieving the worst prognosis (class 4) relative to class 1 (p < 0.001). Multivariate analysis yielded similar results. DISCUSSION: Latency to the first postoperative seizure predicts long-term outcome, with short latencies portending poor prognosis and long latencies portending a good prognosis. This information can be used for patient counseling and may influence decisions regarding reoperation.
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Lobectomía Temporal Anterior/métodos , Epilepsia del Lóbulo Temporal/cirugía , Adulto , Supervivencia sin Enfermedad , Epilepsia del Lóbulo Temporal/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Probabilidad , Pronóstico , Recurrencia , Inducción de Remisión , Proyectos de Investigación , Estudios Retrospectivos , Convulsiones/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
We investigate whether preadmission hyperglycemia is a risk factor for developing in-hospital symptomatic pulmonary embolism after major orthopedic surgery. Medical records of patients undergoing total hip or total knee arthroplasty from January 2001 to April 2006 were reviewed. The incidence of PE was 1.47% (107/7282 patients). Multivariate analysis showed that preadmission blood glucose (BG) of at least 200 mg/dL independently increased the risk of pulmonary embolism by 3.19 times (P = .015), when compared with patients with BG of less than 110 mg/dL. Other significant risks factors were age (>or=70 years old), body mass index of more than 30 kg/m(2), and congestive heart failure. Total knee had 2.19 times (P = .002) more risk than total hip arthroplasty and bilateral procedure increased the risk by 2.13 times (P = .015). Sex, American Society of Anesthesiologists status, duration of surgery, malignancy, pulmonary disease, hypertension, diabetes mellitus, dyslipidemia, sleep apnea, and stroke were not found to be significant risk factors for pulmonary embolism.
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Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Hiperglucemia/complicaciones , Embolia Pulmonar/etiología , Anciano , Anciano de 80 o más Años , Femenino , Mortalidad Hospitalaria , Humanos , Hiperglucemia/diagnóstico , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Factores de RiesgoRESUMEN
PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
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Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Anciano , Antígenos CD19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Receptores Quiméricos de Antígenos/inmunología , Recurrencia , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/trasplanteRESUMEN
PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
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Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Adulto JovenRESUMEN
Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1ß were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1ß was associated with sepsis. This combination of IFNγ and IL1ß was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepsis , Niño , Enfermedad Crítica , Síndrome de Liberación de Citoquinas , Humanos , Receptores de Antígenos de Linfocitos T , Sepsis/diagnósticoRESUMEN
OBJECTIVE: The objective of the study was to identify maternal variables predicting length of treatment for neonatal abstinence syndrome (NAS). STUDY DESIGN: This was a retrospective cohort study of infants treated for NAS during 2000-2006 whose mothers were on methadone maintenance at delivery. Mixed-effects linear regression was used to examine the interaction of maternal and neonatal variables with length of treatment. RESULTS: Of 204 neonates born to methadone exposed mothers, the average dose at delivery was 127 mg daily (25-340 mg) with median length of treatment 32 days (1-122 days). Trimester of initial exposure (P = .33), methadone dose at delivery (P = .198), body mass index (P = .31), antidepressant use (P = .40), cigarette use (P = .76), race (P = .78), and maternal age (P = .84) did not predict length of treatment. In the multivariate analysis, gestational age at delivery and benzodiazepine use were significant predictors of length of treatment. CONCLUSION: Later gestational age and concomitant benzodiazepine use were associated with longer treatment.
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Analgésicos Opioides/administración & dosificación , Metadona/administración & dosificación , Síndrome de Abstinencia Neonatal/terapia , Trastornos Relacionados con Opioides/rehabilitación , Benzodiazepinas , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Análisis Multivariante , Factores de TiempoRESUMEN
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.
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Antígenos CD19/metabolismo , Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Receptores Quiméricos de Antígenos/metabolismo , Animales , Femenino , Interleucina-6/metabolismo , Masculino , Ratones , Factor de Transcripción STAT3/metabolismo , Transcripción Genética , Resultado del TratamientoRESUMEN
To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.
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Antieméticos/farmacología , Citocromo P-450 CYP2D6/metabolismo , Indoles/farmacocinética , Morfolinas/farmacología , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Adulto , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Aprepitant , Estudios Cruzados , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Electrocardiografía , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Femenino , Genotipo , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Morfolinas/efectos adversos , Quinolizinas/administración & dosificación , Quinolizinas/efectos adversos , Valores de Referencia , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/efectos adversosRESUMEN
In various studies of sporadic breast cancers, 40-70% were strongly positive for fragile histidine triad (Fhit) protein expression, whereas only 18% of BRCA2 mutant breast cancers demonstrated strong Fhit expression, suggesting that the BRCA2 repair function may be necessary to retain intact fragile common chromosome fragile site 3B(FRA3B)/FHITloci. In the current study, 22 breast tumors with deleterious BRCA1 mutations were analyzed for Fhit expression by immunohistochemistry in a case-control matched pair analysis. Loss of Fhit expression was significantly more frequent in the BRCA1 cancers compared with sporadic breast tumors (9% Fhit positive versus 68% Fhit positive), suggesting that the BRCA1 pathway is also important in protecting the FRA3B/FHIT locus from damage. To investigate the relationship between repair gene deficiencies and induction of chromosome fragile sites in vitro, we have analyzed the frequency of aphidicolin induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient cell lines. Each of the repair-deficient cell lines showed elevated expression of chromosome gaps and breaks, consistent with the proposal that proteins involved in mismatch and double-strand break repair are important in maintaining the integrity of common fragile regions. Correspondingly, genes at common fragile sites may sustain elevated levels of DNA damage in cells with deficient DNA repair proteins such as those mutated in several familial cancer syndromes.
Asunto(s)
Ácido Anhídrido Hidrolasas , Proteína BRCA1/deficiencia , Neoplasias de la Mama/genética , Reparación del ADN/genética , Proteínas de Neoplasias/genética , Animales , Afidicolina/farmacología , Aberraciones Cromosómicas , Rotura Cromosómica , Silenciador del Gen , Genes BRCA1 , Humanos , Ratones , Proteínas de Neoplasias/biosíntesis , Células Tumorales CultivadasRESUMEN
PURPOSE: To describe the outcomes of eyes that have undergone a second glaucoma drainage implant (GDI) surgery. METHODS: A retrospective review of eyes that underwent a second GDI surgery from 2006 to 2013 was conducted. Primary outcome measures included intraocular pressure (IOP) reduction and success rates. Secondary outcome measures included glaucoma medication use, visual acuity, and number of reoperations. Success was defined as 6 ≤ IOP ≤ 21 with at least 20% IOP reduction, and no increase in the number of glaucoma medications from baseline at 3 months of follow-up or more. RESULTS: Sixty-five eyes (63 patients) had a mean follow-up of 22.4 ± 19.9 months. The most frequently placed second GDIs were an Ahmed FP7 (49%) or a Baerveldt 250 (26%) in the inferotemporal (46%) or inferonasal (35%) quadrant. At 3-year follow-up, IOP was reduced from 25.8 ± 7.7 to 17.4 ± 9.9 mm Hg (P = 0.004) and the number of glaucoma medications decreased from 3.6 ± 1.2 to 2.5 ± 1.4 (P = 0.01) compared with baseline. The median time to failure was 24.7 ± 5.8 months. There was no significant difference in failure rates for type of sequential GDI (P = 0.80) or plate location (P = 0.34). There was no significant difference in visual acuity between baseline and 3-year follow-up (P = 1.0). The most common postoperative complication was corneal edema (n = 9, 14%). CONCLUSIONS: Most eyes undergoing a second GDI achieve adequate IOP control with fewer antiglaucoma medications. Failure rates were similar regardless of quadrant selection or GDI type.
Asunto(s)
Implantes de Drenaje de Glaucoma , Glaucoma/cirugía , Presión Intraocular/fisiología , Implantación de Prótesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Glaucoma/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Hipotensión Ocular/cirugía , Complicaciones Posoperatorias , Reoperación , Estudios Retrospectivos , Resultado del Tratamiento , Agudeza Visual/fisiologíaRESUMEN
T cells expressing a CD19-specific chimeric antigen receptor (CAR19) are demonstrating remarkable efficacy in hematologic malignancies. Treatment is often associated with life-threatening cytokine release syndrome (CRS) which can be effectively treated with cytokine blockade using the antibodies, Siltuximab or Tocilizumab respectively targeting IL-6 or the IL-6 receptor. As IL-6 blockade is moving into the clinic for the treatment of CRS as well as IL-6-driven rheumatologic and malignant diseases, clinicians are utilizing serum cytokine panels more frequently to assess the effects of IL-6 inhibitors. It is paramount to ascertain whether levels obtained are accurate, especially as certain drugs may, in theory, affect quantification. We report the comparative quantification of IL-6 and sIL-6R using Luminex-based immunoassay kits from two vendors. Our results indicate good agreement of the commercial immunoassays in measurement of IL-6 but disagreement in quantitation of sIL-6R. We found that both Siltuximab and Tocilizumab can interfere with the measurement of their respective ligands using reagents from one vendor but not the second. This has significant implications for the analysis of IL-6 and sIL-6R pharmacokinetics analysis in Siltuximab or Tocilizumab-treated patients. We found that high levels of IL-6 can falsely reduce the measured levels of sIL-6R and high levels of sIL-6R can reduce levels of IL-6 when measured with some commercial assays. These data demonstrate the importance of assessing the impact of cytokine-blocking agents on accuracy of clinical biomarker assays in other diseases, as drugs targeting TNF-alpha, IL1B, and IL5 are being used more frequently in a large number of diseases.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Interleucina-6/sangre , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Interleucina-6/sangre , Humanos , Leucemia/terapia , Linfoma/terapia , Terapia Molecular Dirigida , Pennsylvania , Transducción de SeñalRESUMEN
UNLABELLED: Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill. SIGNIFICANCE: CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664-79. ©2016 AACR.See related commentary by Rouce and Heslop, p. 579This article is highlighted in the In This Issue feature, p. 561.