RESUMEN
PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.
RESUMEN
Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.
RESUMEN
Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.
RESUMEN
PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.
Asunto(s)
Bacteriemia , Infecciones Bacterianas , Infecciones , Neoplasias , Sepsis , Humanos , Niño , Estudios Prospectivos , Bacteriemia/diagnóstico , Bacteriemia/epidemiología , Bacteriemia/microbiología , Fiebre/diagnóstico , Fiebre/etiología , Neoplasias/complicaciones , Sepsis/diagnóstico , Antibacterianos/uso terapéuticoRESUMEN
OBJECTIVE: To analyze the impact of the early COVID-19 pandemic on the diagnosis and initiation of treatment for patients with gynecologic cancer. METHODS: Patients diagnosed with gynecologic cancer in the National Cancer Database during 2017-2020 were included. For the first aim, incidence rate ratios were calculated to compare gynecologic cancer diagnosis in the first year of the COVID-19 pandemic to the three years prior, and factors associated with a reduction in diagnosis were identified. For the second aim, patients who experienced an 8-week delay in cancer treatment were compared to those who did not. Multivariate logistic regression was used to identify factors associated with treatment delay. Propensity score analysis was utilized to compare the rate of cancer treatment delay in patients who were diagnosed with COVID-19 to those who were not. RESULTS: The incidence rate ratio of being diagnosed with gynecologic cancer in 2020 versus 2017-2019 was 0.90 (95%CI 0.90-0.91). Factors associated with increased risk of missed or delayed diagnosis in 2020 included cervical cancer, earlier cancer stage, younger age, lower levels of medical comorbidity, and lack of health insurance. In 2020, factors associated with treatment delay included COVID-19 diagnosis (aOR 1.50, 95%CI 1.35-1.67), in addition to race and ethnicity, insurance type, comorbidity, cancer stage, and primary site. The risk of treatment delay remained significantly elevated in patients diagnosed with COVID-19 after propensity-score matching. CONCLUSIONS: Gynecologic cancer diagnosis and timely provision of care were negatively impacted during the first year of the COVID-19 pandemic, with certain subgroups at elevated risk.
Asunto(s)
COVID-19 , Neoplasias de los Genitales Femeninos , Neoplasias del Cuello Uterino , Humanos , Femenino , COVID-19/epidemiología , Pandemias , Prueba de COVID-19 , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/terapia , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/terapiaRESUMEN
PURPOSE: Soft tissue sarcomas (STS) are rare mesenchymal neoplasms that frequently show complex chromosomal aberrations such as amplifications or deletions of DNA sequences or even whole chromosomes. We recently found that gain of chromosome (chr) 8 is associated with worse overall survival (OS) in STS as a group. We therefore aimed to investigate the overall copy number profile of rhabdomyosarcoma (RMS) to evaluate for prognostic signatures. METHODS: Fluorescence in situ hybridization (FISH) testing was performed on a cohort of STS to assess for chr8 gain. Copy number variation (CNV) data from the National Cancer Institute were analyzed to assess for prognostically significant CNV aberrations in FOXO1 fusion-negative (FN)- versus fusion-positive (FP)-RMS. FISH testing was performed on a cohort of FN-RMS to assess for chr3q loss and correlate with outcomes. RESULTS: Chr8 gain is a highly prevalent CNV in embryonal RMS and shows slightly improved prognosis. Meanwhile, loss of chr3q was associated with worse outcome in FN-RMS compared with FP-RMS. CONCLUSION: The pathogenesis of STS including FN-RMS remains poorly understood, emphasizing the need for new therapeutic advances and adequate risk stratification. Our data demonstrate that loss of chr3q is associated with poor OS in FN-RMS, supporting it as an important tool for risk stratification.
Asunto(s)
Variaciones en el Número de Copia de ADN , Rabdomiosarcoma , Humanos , Hibridación Fluorescente in Situ , Pronóstico , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/genética , CromosomasRESUMEN
Understanding the molecular landscape of papillary thyroid carcinoma (PTC), the most common thyroid cancer in children, creates additional therapeutic approaches. RET gene rearrangements are observed in pediatric PTC, and selective inhibition of RET is now possible with specific tyrosine kinase inhibitors designed to target diverse RET -activating alterations. We present a 13-year-old female with metastatic PTC, clinically resistant to radioactive iodine, and found to harbor a NCOA4-RET fusion. She responded to selpercatinib treatment with the elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and biomarker decline. The response was maintained despite 2 dose reductions for possibly related weight gain.
Asunto(s)
Neoplasias de la Tiroides , Adolescente , Femenino , Humanos , Reordenamiento Génico , Radioisótopos de Yodo/uso terapéutico , Coactivadores de Receptor Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Cáncer Papilar Tiroideo/tratamiento farmacológico , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Factores de Transcripción/genéticaRESUMEN
Introduction: The purpose of this descriptive study is to examine a learning health system (LHS) continuous improvement and learning approach as a case for increased quality, standardized processes, redesigned workflows, and better resource utilization. Hospital acquired pressure injuries (HAPI) commonly occur in the hospitalized patient and are costly and preventable. This study examines the effect of a LHS approach to reducing HAPI within a large academic medical center. Methods: Our learning health center implemented a 6-year series of iterative improvements that included both process and technology changes, with robust data and analytical reforms. In this descriptive, observational study, we retrospectively examined longitudinal data from April 1, 2018 to March 31, 2022, examining the variables of total number of all-stage HAPI counts and average length of stay (ALOS). We also analyzed patient characteristics observed/expected mortality ratios, as well as total patient days, and the case-mix index to determine whether these factors varied over the study period. We used the Agency for Healthcare Research and Quality cost estimates to identify the estimated financial benefit of HAPI reductions on an annualized basis. Results: HAPI per 1000 patient days for FY 20 (October 1-September 30) and FY 21, decreased from 2.30 to 1.30 and annualized event AHRQ cost estimates for HAPI decreased by $4 786 980 from FY 20 to FY 21. A strong, statistically significant, negative and seemingly counterintuitive correlation was found (r = -.524, P = .003) between HAPI and ALOS. Conclusions: The LHS efforts directed toward HAPI reduction led to sustained improvements during the study period. These results demonstrate the benefits of a holistic approach to quality improvement offered by the LHS model. The LHS model goes beyond a problem-based approach to process improvement. Rather than targeting a specific problem to solve, the LHS system creates structures that yield process improvement benefits over a continued time period.
RESUMEN
Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.
Asunto(s)
Neurofibroma Plexiforme , Neurofibromatosis 1 , Niño , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibroma Plexiforme/tratamiento farmacológico , Calidad de Vida , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.
Asunto(s)
Neoplasias Renales , Tumor de Wilms , Humanos , Neoplasias Renales/patología , Estadificación de Neoplasias , Tumor de Wilms/patología , Pronóstico , RecurrenciaRESUMEN
High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.
Asunto(s)
Proteína BRCA1 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína Fosfatasa 2/genética , Proteína BRCA2/genética , Daño del ADN , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Recombinación Homóloga , Muerte CelularRESUMEN
Sclerosing epithelioid fibrosarcoma (SEF) is a rare but aggressive sarcoma. We report the first case of hepatic SEF in pediatric patient, which is also the second case in literature. A 17-year-old previously healthy female presented with a liver mass measuring 13.7 cm in greatest dimension and mild elevation of liver enzymes and cancer antigen 19-9. Needle biopsy revealed multiple cores of liver parenchyma mostly replaced by densely hyalinized fibrotic tissue and areas of small-to-medium sized epithelioid cells with eosinophilic and clear cytoplasm. Immunohistochemistry (IHC) demonstrated diffuse strong cytoplasmic staining of MUC4, suggesting a working diagnosis of sclerosing epithelioid fibrosarcoma (SEF)/low-grade fibromyxoid sarcoma (LGFMS). Liver explant demonstrated a well-circumscribed, nodular mass with firm, gray-white cut surface, and similar histopathology as seen in needle biopsy with no convincing evidence suggesting LGFMS. Sequencing panel revealed EWSR1::CREB3L1 gene fusion and confirmed the diagnosis of SEF. Post-operative cancer antigen 19-9 normalized 3 months after transplant; follow-up 3 and 6 months post-transplant imaging at that time showed no concern for disease recurrence.
Asunto(s)
Fibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Femenino , Niño , Adolescente , Recurrencia Local de Neoplasia , Fibrosarcoma/diagnóstico , Fibrosarcoma/genética , Fibrosarcoma/patología , Sarcoma/genética , Neoplasias de los Tejidos Blandos/patología , Hígado/patologíaRESUMEN
ABSTRACT: Hospital-acquired pressure injuries (HAPIs) continue to increase in comparison to other hospital-acquired conditions, despite advancements in prevention and wound care practices. In 2017, an interprofessional skin team (IST) was formed at an academic medical center to improve patient care and reduce HAPIs. Intentional wound, ostomy, continence (WOC) nurse rounding coupled with IST efforts steadily decreased HAPIs in the organization by 39%. In an effort to continue to improve care, a root cause analysis (RCA) of HAPIs was initiated in two intensive care units (ICUs) in October 2019. Using the Plan-Do-Study-Act model, two WOC nurses and a nursing professional development specialist from the IST developed the HAPIs RCA process. Rapid cycle process improvement demonstrated the need to transition from a paper form to an electronic process to increase accessibility for all nursing units and patients to benefit. In May 2020, an electronic reporting system for RCAs for HAPIs began. After implementation, there has been a 53.5% reduction in HAPIs over 2 years. The standardized, electronic RCA process has resulted in improvement, dissemination of best practices, and fostering nonpunitive accountability for each unit's HAPIs.
Asunto(s)
Úlcera por Presión , Humanos , Úlcera por Presión/prevención & control , Análisis de Causa Raíz , Unidades de Cuidados Intensivos , HospitalesRESUMEN
Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.
Asunto(s)
Neoplasias Renales , Tumor de Wilms , Humanos , Neoplasias Renales/patología , Estadificación de Neoplasias , Tumor de Wilms/patología , Pronóstico , RecurrenciaRESUMEN
BACKGROUND: Malignant bowel obstruction (MBO) is a sequela of advanced intraabdominal cancer and has a profound impact on quality of life. Common therapy is endoscopic decompressive gastrostomy tube placement. Standard gastrostomy tubes are poorly designed to completely evacuate the dependent portions of the stomach due to their location on the anterior gastric wall. In our institution we have begun placing the ASPIRE Assist gastrostomy tube (ASPIRE Bariatrics, Exton, PA) which includes a 15 cm long, 30Fr fenestrated gastric tube extension for enhanced gastric decompression. This tube is FDA indicated for gastric decompression and marketed for endoscopic weight loss. The purpose of this study is to review our experience managing MBO utilizing the ASPIRE Assist tube. METHODS: This is a retrospective analysis of outcomes at a single institution. All decompressive endoscopic gastrostomy tubes placed by two surgeons between November 2019 and July 2021 were reviewed. Endoscopic placement was performed utilizing standard safe tract and Ponsky pull techniques. RESULTS: Fourteen patients were identified (10F:4 M), mean age 70 (range 35-89). Primary cancer diagnoses included gynecologic (8), colorectal (3), bladder (1), small bowel (1), peritoneal serous (1). During the 12 months before decompressive gastrostomy tube placement, mean number of hospital admissions for MBO was 1.6 (range 1-3). Following tube placement, twelve patients had no further hospital admissions for MBO over their lifespan of mean 270 days (range 8-679 days). One patient had 1 admission for MBO in the 12 months before tube placement and 3 admissions in the 4 months after placement. A second patient had 2 admissions in the 12 months before tube placement and 1 admission in their 54-day lifespan after placement. There were no major complications. CONCLUSIONS: Endoscopic placement of the ASPIRE Assist gastrostomy tube is safe for palliation of MBO and may improve gastric decompression compared with standard endoscopic gastrostomy tubes. Enhanced gastric decompression can better manage symptoms, reduce hospital encounters, and improve quality of life. Further study is needed, however, our initial data appears promising.
Asunto(s)
Obstrucción Intestinal , Neoplasias , Humanos , Femenino , Anciano , Estudios Retrospectivos , Calidad de Vida , Estómago/cirugía , Gastrostomía/métodos , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Descompresión/efectos adversosRESUMEN
INTRODUCTION: The neurofibromatoses comprise three different genetic conditions causing considerable morbidity and mortality: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). This review summarizes recent and ongoing clinical trials involving patients with neurofibromatoses to better understand the current state of clinical trial research centered around these conditions and inform areas of need. METHODS: A search was conducted using the Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases. Inclusion and exclusion criteria were designed to identify clinical trials focused on patients with NF1, NF2, or SWN completed in or after 2010 and in process as of December 31, 2021. Information was collected using standardized guidelines. RESULTS: A total of 134 clinical trials were included, with 75 (56%) completed and 59 (44%) in process. For completed trials, 74% (n = 56) involved patients with NF1, and of those based on specific tumors (n = 26, 46%), the majority focused on plexiform neurofibromas (PNs) (n = 12, 46%). For ongoing trials, 79% (n = 47) involve patients with NF1, and of those based on specific tumors (n = 29, 61%), the majority are focused on PNs (n = 13, 45%). CONCLUSION: Both recent and ongoing clinical trials have primarily focused on patients with NF1 and the treatment of PNs. This research has led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality. Trials evaluating comorbid psychiatric conditions and quality of life among patients with any of the neurofibromatoses appear less common. These areas may warrant focus in future studies to improve clinical management.
Asunto(s)
Neurilemoma , Neurofibroma Plexiforme , Neurofibromatosis , Neurofibromatosis 1 , Neurofibromatosis 2 , Humanos , Neurilemoma/terapia , Neurofibromatosis/terapia , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/terapia , Neurofibromatosis 2/genética , Calidad de Vida , Neoplasias CutáneasRESUMEN
BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Benzamidas , Niño , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Adulto JovenRESUMEN
We explored the psychometric properties of the Hebrew version of the Fear of COVID-19 (FCV-19S) scale among health care workers in a large medical center in Israel. Participants (N = 705) completed the FCV-19S scale, as well as resilience, subjective well-being, and meaning in life using validated scales. Results showed a two-factor structural model accounting for 79.33% of the total variance. Both factors were negatively associated with resilience and satisfaction with life. Results suggest the FCV-19S has good psychometric properties among health care workers and may be used to assess the effects of the pandemic in this population.
Asunto(s)
COVID-19 , Miedo , Personal de Salud , Humanos , Israel , Psicometría/métodos , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve sheath tumors seen in 30-50% of patients with NF1. These tumors may cause significant pain and disfigurement or may compromise organ function. Given the morbidity associated with these tumors, therapeutic options for patients with NF1-related PN are necessary. AREAS COVERED: We searched the www.clinicaltrials.gov database for 'plexiform neurofibroma.' This article summarizes completed and ongoing trials involving systemic therapies for PN. EXPERT OPINION: Surgery is the mainstay treatment; however, complete resection is not possible in many cases. Numerous systemic therapies have been evaluated in patients with NF1, with MEK inhibitors (MEKi) showing the greatest efficacy for volumetric reduction and improvement in functional and patient-reported outcomes. The MEKi selumetinib is now FDA approved for the treatment of inoperable, symptomatic PN in pediatric NF1 patients. Questions remain regarding the use of this drug class in terms of when to initiate therapy, overall duration, reduced dosing schedules, and side effect management. Future studies are needed to fully understand the clinical application of MEKi and to evaluate other potential therapies through appropriate trial designs for this potentially devastating, manifestation in NF1.