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BACKGROUND: Gastrointestinal (GI) complications in lung transplant recipients can occur any time during the post-operative period, leading to prolonged morbidity and mortality. Despite the negative association between GI complications and patient outcomes, little is known about their incidence and risk factors for their development in pediatric lung transplant recipients. METHODS: We performed a retrospective chart review at one pediatric tertiary center to describe the frequency of GI complications in lung transplant recipients. We identified potential risk factors for the diagnosis of gastroparesis, gastroesophageal reflux disease (GERD) and aspiration in the post-transplant period. Lastly, we investigated the association of these complications with mortality and graft survival. RESULTS: 84.3% of lung transplant recipients experienced at least one GI complication in the post-transplant period. Gastroparesis (52.9%), GERD (41.2%), and oropharyngeal dysphagia/laryngeal penetration (33.3%) were the most common complications diagnosed. Post-operative opioid exposure was a risk factor for gastroparesis, with the odds increasing 3.0% each day a patient was prescribed opioids (p = .021). The risk of death or retransplant in individuals who experienced gastroparesis was 2.7 times higher than those not diagnosed with gastroparesis (p = .027). CONCLUSION: Exposure to opioids in the post-operative period is a risk factor for gastroparesis and a prolonged hospitalization placed patients at risk for aspiration. Gastroparesis was associated with increased patient mortality and graft failure, while aspiration and GERD had no effect on long term outcomes. Future prospective studies investigating the relationship between opioid use and the development of a gastroparesis are necessary to improve patient outcomes.
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Reflujo Gastroesofágico , Enfermedades Gastrointestinales , Gastroparesia , Trasplante de Pulmón , Humanos , Niño , Gastroparesia/etiología , Gastroparesia/complicaciones , Estudios Retrospectivos , Incidencia , Estudios Prospectivos , Analgésicos Opioides , Receptores de Trasplantes , Enfermedades Gastrointestinales/epidemiología , Enfermedades Gastrointestinales/etiología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Factores de Riesgo , Trasplante de Pulmón/efectos adversos , PulmónRESUMEN
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
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Regulación Neoplásica de la Expresión Génica/genética , Genoma Humano/genética , Genómica , Leucemia Mieloide Aguda/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Conjuntos de Datos como Asunto , Exoma/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Nucleofosmina , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Análisis de Secuencia de ARN , Factores de Empalme Serina-Arginina/genéticaRESUMEN
Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.
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Antineoplásicos , Mesilato de Imatinib , Imidazoles , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Imidazoles/uso terapéutico , Imidazoles/efectos adversos , Imidazoles/administración & dosificación , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/uso terapéutico , Piridazinas/efectos adversos , Inducción de Remisión , AdolescenteRESUMEN
Blinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome-positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies.
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Anticuerpos Biespecíficos/farmacología , Antineoplásicos/farmacología , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Linfocitos T/inmunología , Familia-src Quinasas/antagonistas & inhibidores , Linfocitos B , Dasatinib/farmacología , Humanos , Mesilato de Imatinib/farmacología , Imidazoles/farmacología , Ensayos de Liberación de Interferón gamma , Células Jurkat , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Mutación Missense , Proteínas de Neoplasias/fisiología , Fosforilación/efectos de los fármacos , Mutación Puntual , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas c-abl/genética , Piridazinas/farmacología , Pirimidinas/farmacología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/enzimología , Linfocitos T/metabolismo , Células Tumorales Cultivadas , Familia-src Quinasas/fisiologíaRESUMEN
INTRODUCTION: Implementation of programs that increase both psychiatric patient education and their involvement in treatment programming can lead to positive outcomes postdischarge. Patients involved in programs focusing on skills, recovery, and that are individualized show a reduction in symptoms as well as an increase in engagement, treatment, and recovery posthospitalization. AIMS: This quality improvement project examines (1) the effectiveness of a safety planning group on an inpatient psychiatric unit for developing individualized safety plans, (2) the usefulness of the safety plans upon discharge, and (3) how helpful the patient found them. METHODS: A standardized safety plan was presented during 1-hour groups on an adult inpatient unit. Completed safety plans scored using a rubric to determine how patients individualized the content. One week postdischarge, patients were contacted to determine location and use of the safety plan since discharge. RESULTS: Patient's (n = 124) safety plans were relatively individualized when compared to the standardized safety plan (mean [SD] = 32.85 [8.27] on a 44-point rating). Of those patients who were contacted postdischarge (n = 76), 73 (96.1%) had a copy of their safety plan 1-week postdischarge while 28 (36.8%) reported using their safety plan since discharge. Many of the patients who used their safety plan reported that it was helpful (n = 19; 67.9%). CONCLUSIONS: Developing a safety plan can be a helpful tool for individuals admitted to a psychiatric inpatient unit.
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Pacientes Internos , Alta del Paciente , Adulto , Humanos , Pacientes Internos/psicología , Cuidados Posteriores , Mejoramiento de la CalidadRESUMEN
Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.
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Enfermedad Injerto contra Huésped , Trasplante de Hígado , Linfohistiocitosis Hemofagocítica , Trastornos de Fallo de la Médula Ósea , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/genética , Humanos , Trasplante de Hígado/efectos adversos , Linfohistiocitosis Hemofagocítica/genética , Mutación/genéticaRESUMEN
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, â¼30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, â¼40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next-generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.
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ADN (Citosina-5-)-Metiltransferasas/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/mortalidad , Proteínas Nucleares/genética , Adulto , Anciano , ADN Metiltransferasa 3A , Bases de Datos Genéticas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Nucleofosmina , Análisis de SupervivenciaAsunto(s)
Aurora Quinasa A , Leucemia-Linfoma Linfoblástico de Células Precursoras , Aurora Quinasa A/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Humanos , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación GenéticaRESUMEN
To examine ownership and protection status of forests with high-biomass stores (>200 Mg/ha) in the Pacific Northwest (PNW) region of the United States, we used the latest versions of publicly available datasets. Overlay, aggregation, and GIS-based computation of forest area in broad biomass classes in the PNW showed that the National Forests contained the largest area of high-biomass forests (48.4 % of regional total), but the area of high-biomass forest on private lands was important as well (22.8 %). Between 2000 and 2008, the loss of high-biomass forests to fire on the National Forests was 7.6 % (236,000 ha), while the loss of high-biomass forest to logging on private lands (364,000 ha) exceeded the losses to fire across all ownerships. Many remaining high-biomass forest stands are vulnerable to future harvest as only 20 % are strictly protected from logging, while 26 % are not protected at all. The level of protection for high-biomass forests varies by state, for example, 31 % of all high-biomass federal forests in Washington are in high-protection status compared to only 9 % in Oregon. Across the conterminous US, high-biomass forest covers <3 % of all forest land and the PNW region holds 56.8 % of this area or 5.87 million ha. Forests with high-biomass stores are important to document and monitor as they are scarce, often threatened by harvest and development, and their disturbance including timber harvest results in net C losses to the atmosphere that can take a new generation of trees many decades or centuries to offset.
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Conservación de los Recursos Naturales/métodos , Árboles/crecimiento & desarrollo , Biomasa , Incendios , Agricultura Forestal/legislación & jurisprudencia , Sistemas de Información Geográfica , Oregon , Propiedad/clasificación , Árboles/clasificación , WashingtónRESUMEN
PURPOSE OF REVIEW: Acute lymphoblastic leukemia (ALL) is a widely heterogeneous disease in terms of genomic alterations, treatment options, and prognosis. While ALL is considered largely curable in children, adults tend to have higher risk disease subtypes and do not respond as favorably to conventional chemotherapy. Identifying genomic drivers of leukemogenesis and applying targeted therapies in an effort to improve disease outcomes is an exciting focus of current ALL research. Here, we review recent updates in ALL targeted therapy and present promising opportunities for future research. RECENT FINDINGS: With the utilization of next-generation sequencing techniques, the genomic landscape of ALL has greatly expanded to encompass novel subtypes characterized by recurrent chromosomal rearrangements, gene fusions, sequence mutations, and distinct gene expression profiles. The evolution of small molecule inhibitors and immunotherapies, and the exploration of unique therapy combinations are some examples of recent advancements in the field. Targeted therapies are becoming increasingly important in the treatment landscape of ALL to improve outcomes and minimize toxicity. Significant recent advancements have been made in the detection of susceptible genomic drivers and the use of novel therapies to target them.
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Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Niño , Humanos , Leucemia Mieloide Aguda/diagnóstico , Pronóstico , Mutación , Biomarcadores de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
BACKGROUND: The 2009 cystic fibrosis (CF) infant care guidelines recommend breastmilk as the initial feeding but do not address if/when it should be fortified or supplemented with formula to promote optimal growth and pulmonary health. METHODS: We conducted a prospective multi-center cohort study in breastfed and formula-fed infants that included 172 infants with CF who were born during 2012-17, enrolled after newborn screening at age 1.9 ± 1.0 months, and evaluated growth and lung disease manifestations in the first 3 years of life. RESULTS: Seventy-two percent of our study cohort was breastfed at birth, but 64 % transitioned to receiving fortified feedings (breastmilk, formula, or a combination) by 6 months of age to reverse the downward trajectory of their growth curves. Fortified feedings accelerated catch-up growth to normal weight-for-age (0.12 ± 0.80 z-score) and near normal height-for-age (-0.13 ± 0.90 z-score) at 3 years of age. Within the fortified group, breastmilk and formula were similarly effective in promoting catch-up growth, but proportionately fewer infants with CF fed predominantly breastmilk (30 %) experienced severe or moderate early-onset lung disease compared to those fed predominantly formula (62 %), p = 0.02. CONCLUSIONS: Most infants with CF require fortified feedings to recuperate from growth faltering and achieve normal growth at 3 years of age. For these infants, the proactive/preventive strategy of fortified breastmilk feedings starting soon after CF diagnosis, an alternative to the reactive/monitoring approach, can minimize the risk of prolonged postnatal growth faltering, accelerate the potential of attaining catch-up growth, and decrease the likelihood of experiencing more severe early-onset lung disease.
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PURPOSE: To describe a patient with a history of pre-B-cell acute lymphoblastic leukemia in remission, who developed recurrent alternating intraocular leukemia manifesting with pseudohypopyon, uveal mass, and serous retinal detachment. In multiple instances, this constellation of ocular findings preceded systemic leukemia recurrence. METHOD: Case report. RESULTS: A 29-year-old man with a history of pre-B-cell acute lymphoblastic leukemia, in remission after a hematopoietic stem cell transplant, presented with pseudohypopyon, uveal lesions, and serous retinal detachment of the right eye. Comprehensive workup for infectious and inflammatory etiologies was unremarkable, and a bone marrow biopsy revealed systemic recurrence of leukemia. One year later, while again in remission, the patient developed a pseudohypopyon, uveal mass, and serous retinal detachment of the other eye. Repeat bone marrow biopsy showed impending leukemia relapse, which occurred 1 month later. Orbital radiation resulted in complete ocular resolution. CONCLUSION: The constellation of pseudohypopyon, serous retinal detachment, and uveal mass (pseudopanuveitis) should be recognized as a harbinger for systemic pre-B ALL recurrence.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Desprendimiento de Retina , Neoplasias de la Úvea , Masculino , Humanos , Adulto , Desprendimiento de Retina/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Ojo , Enfermedad Aguda , RecurrenciaRESUMEN
In this review, we discuss the use of measurable residual disease (MRD) in AML, ALL, and chronic myeloid leukemia (CML). Our aims were to review the different methodologies for MRD assessment; describe the clinical relevance and medical decision making on the basis of MRD; compare and contrast the usage of MRD across AML, ALL, and CML; and discuss what patients need to know about MRD as it relates to their disease status and treatment. Finally, we discuss ongoing challenges and future directions with the goal of optimizing MRD usage in leukemia management.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide Aguda , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Toma de Decisiones Clínicas , Relevancia Clínica , Neoplasia ResidualRESUMEN
BACKGROUND: Maintaining a healthy weight is a focus of Cystic Fibrosis (CF) care. With the increased use of highly effective CFTR modulators, many people with CF are gaining weight more easily, which may affect eating habits and body image. This study investigates providers' understanding and current practices surrounding body image disturbance and disordered eating in people with CF. METHODS: We distributed a one-time web-based survey to United States (U.S.)-based CF healthcare providers via CF Foundation list servs. The survey investigated providers' understanding and perceived importance of issues surrounding disordered eating and body image disturbance in adolescent and young adults (AYA) with CF as well as current screening practices. We used descriptive statistics to analyze participants' characteristics and practices. RESULTS: A total of 232 healthcare providers completed the survey. While most participants felt that screening for both body image disturbance and disordered eating should be standardized in CF care (79% and 82%, respectively), fewer than one third felt comfortable screening, and only one quarter actually screened for various eating disordered behaviors in daily practice. Only 2.7% reported using a formal screening tool. Participants reported provider assessment tools (86%), standardized partnerships with eating disorder specialists (80%), and CFF or national guidelines (79%) would be helpful to improve screening and counseling. CONCLUSION: While most CF providers believe that body image disturbance and disordered eating are important topics in AYA with CF, few address these topics with their patients. The development of educational sessions and national guidelines may improve screening and counseling practices.
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Fibrosis Quística , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Adolescente , Adulto Joven , Imagen Corporal , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/psicología , Conducta Alimentaria/psicología , Encuestas y Cuestionarios , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/etiologíaRESUMEN
Measurable residual disease (MRD) is an adverse prognostic factor in adult patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic cell transplant (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT, patients aged ≥18 years with ALL who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014 and April 2021 and were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed before HCT (MRDpre) and up to 1 year after HCT (MRDpost). Patients were followed up for leukemia relapse and survival for up to 2 years after HCT. In total, 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10-4 (hazard ratio [HR], 3.56; 95% confidence interval [95% CI], 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR, 4.60; 95% CI, 3.01-7.02). In exploratory analyses limited to patients with B-cell ALL, the detection of post-HCT immunoglobulin H (IgH) MRD clonotypes, rather than non-IgH MRD clonotypes, was associated with relapse. In this analysis across 2 large transplant centers, we found that the detection of MRD by NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Adolescente , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Trasplante Homólogo , Neoplasia Residual/diagnóstico , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Factores de Riesgo , Mutación , Citogenética , Quimioterapia de InducciónRESUMEN
Measurable residual disease (MRD) is an established component of acute lymphoblastic leukemia (ALL) management in both children and adults. Society guidelines and expert consensus documents include assessment of MRD as the standard of care following induction therapy, consolidation therapy, and at additional time points, depending on the treatment regimen administered. Further, the approval of blinatumomab for MRD+ B-ALL has advanced the concept of MRD response as a clinical endpoint in ALL. Although the utility of MRD in ALL has been well defined over the last decades, several questions remain. In this review we focus on areas of ongoing controversy and exploration in ALL MRD, including the following: (1) Does increasing the depth of MRD assessment add prognostic value? (2) Is there a role for ongoing MRD monitoring once patients achieve MRD response? (3) Can MRD assessment of the peripheral blood be substituted for bone marrow? (4) Should MRD assays be applied to the analysis of the central nervous system (CNS)? Ongoing studies should answer the majority of these questions in the coming years.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Adulto , Humanos , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Médula Ósea , Enfermedad Aguda , Citometría de FlujoRESUMEN
INTRODUCTION: There is evidence for increased risk of eating disorders in individuals with diet-treated chronic illnesses, however, data in patients with cystic fibrosis (CF) is less clear. No studies have evaluated avoidant/restrictive food intake disorder (ARFID) in the CF population. We investigated the prevalence of eating disorders, including ARFID, in adolescents and young adults with CF. METHODS: Patients with CF aged 14-35 years were recruited to complete three validated surveys: (1) Eating Disorder Examination Questionnaire (EDE-Q), (2) Nine-Item Avoidant/Restrictive Food Intake Disorder Scale (NIAS), and (3) Cystic Fibrosis Questionnaire-Revised (CFQ-R). Univariate linear regression analysis identified baseline risk factors associated with these survey scores. Variables with univariate p < 0.20 were considered for inclusion in a multivariable linear regression model. Backwards stepwise linear regression was used to identify the final model. RESULTS: A total of 52 patients enrolled. The prevalence of a positive screen on the EDE-Q was 9.6%, and on the NIAS was 13.5%. The CFQ-R eating and weight subscales were associated with scores on the EDE-Q, and CFQ-R eating subscale and being dF508 homozygous were correlated with the NIAS total score. DISCUSSION: A clinically significant number of participants screened positive for eating disorders on the EDE-Q and NIAS. Scores on the eating and weight scales of the CFQ-R were associated with the scores on these surveys. Further work is needed to better understand the optimal way to use such tools to screen and treat for eating disorders in individuals with CF.
Asunto(s)
Fibrosis Quística , Trastornos de Alimentación y de la Ingestión de Alimentos , Adolescente , Enfermedad Crónica , Fibrosis Quística/complicaciones , Fibrosis Quística/epidemiología , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Humanos , Calidad de Vida , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.