RESUMEN
BACKGROUND: Sacrectomy remains a technically complex procedure for resection of malignant pelvic neoplasia. Commonly, postoperative complications include permanent neurological deficits. Only a few studies have reported the long-term functional outcomes of patients who had undergone sacrectomy. CASE PRESENTATION: We previously reported on the utilization of complete sacrectomy and lumbopelvic reconstruction for the management of primary myofibroblastic sarcoma of the sacrum and ilium in a 15-year-old female patient. In this report, we update her postoperative course with an additional 5 years of follow-up and Health-Related Quality of Life (HRQoL) outcomes. During this time period, she gave birth to two healthy full-term babies. CONCLUSION: To the best of our knowledge, this is the first report of pregnancy after total sacrectomy and lumbopelvic reconstruction. We outline some of the challenges in the obstetrical management of this patient.
Asunto(s)
Vértebras Lumbares/cirugía , Procedimientos Ortopédicos/efectos adversos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones del Embarazo/etiología , Sacro/cirugía , Adolescente , Femenino , Estudios de Seguimiento , Humanos , Ilion , Nacimiento Vivo , Miosarcoma/cirugía , Procedimientos Ortopédicos/métodos , Periodo Posoperatorio , Embarazo , Procedimientos de Cirugía Plástica/métodos , Neoplasias de la Columna Vertebral/cirugía , TiempoRESUMEN
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here, we employ a clinical next generation sequencing (NGS) workflow to achieve high sequencing depth and detect ultra-low frequency variants across exons of genes associated with cancer, all exons, and genome wide. In three separate primary human hematopoietic stem and progenitor cell (HSPC) donors assessed in technical triplicates, we electroporated high-fidelity Cas9 protein targeted to three loci (AAVS1, HBB, and ZFPM2) and harvested genomic DNA at days 4 and 10. Our results demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants and that even a single SNP in a gRNA spacer sequence is sufficient to eliminate Cas9 off-target activity in primary, repair-competent human HSPCs.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Células Madre Hematopoyéticas/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , ARN Guía de Kinetoplastida/genéticaRESUMEN
PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.