RESUMEN
Germline variants have a rich history of being studied in the context of cancer risk. Emerging studies now suggest that germline variants contribute not only to cancer risk but to tumor progression as well. In this opinion article, we discuss the initial discoveries associating germline variants with patient outcome and the mechanisms by which germline variants affect molecular pathways. Germline variants affect molecular pathways through amino acid changes, alteration of splicing patterns or expression of genes, influencing the selection for somatic mutations, and causing genome-wide mutational enrichment. These molecular alterations can lead to tumor phenotypes that become clinically apparent such as metastasis, alterations to the immune microenvironment, and modulation of therapeutic response. Overall, the growing body of evidence suggests that germline variants play a larger role in tumor progression than has been previously appreciated and that germline variation holds substantial potential for improving personalized medicine and patient outcomes.
Asunto(s)
Mutación de Línea Germinal , Neoplasias/genética , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Resultado del TratamientoRESUMEN
PURPOSE: Outcomes of patients with non-functioning pituitary adenomas categorized using the 2004 and 2017 WHO classification systems are understudied. We report outcomes from the University of Virginia of patients with non-functioning pituitary adenomas categorized using both systems. METHODS: We constructed a database from all 239 patients who underwent resection of a non-functioning pituitary adenoma between 2003 and 2015 and had at least 5 years of follow-up. Pathologic diagnosis was determined under both the 2004 and 2017 WHO classification systems. We compared the rates of recurrence and progression between subtypes using univariate and multivariate Cox regression analyses. RESULTS: Nearly 30% of the tumors in our database were classified as null cell adenomas under the 2004 classification system, whereas only 10% of the tumors were classified as null cell adenomas using the 2017 classification system. Most of these tumors were reclassified as either corticotroph or gonadotroph adenomas. Despite our relatively large cohort and average follow-up of nearly 9 years, we did not detect a significant difference in recurrence and progression between subtypes. CONCLUSIONS: The majority of null cell adenomas diagnosed under the 2004 WHO classification system are reclassified as gonadotroph or corticotroph adenomas under the 2017 WHO classification system. Rates of progression and recurrence between subtypes are not as different as previously believed at our institution and require a larger cohort to further investigate.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH , Adenoma , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Adenoma/cirugía , Adenoma/patología , Adenoma Hipofisario Secretor de ACTH/patología , Organización Mundial de la SaludRESUMEN
Ribosomal protein (RP) genes encode structural components of ribosomes, the cellular machinery for protein synthesis. A single functional copy has been maintained in most of 78-80 RP families in animals due to evolutionary constraints imposed by gene dosage balance. Some fungal species have maintained duplicate copies in most RP families. The mechanisms by which the RP genes were duplicated and maintained and their functional significance are poorly understood. To address these questions, we identified all RP genes from 295 fungi and inferred the timing and nature of gene duplication events for all RP families. We found that massive duplications of RP genes have independently occurred by different mechanisms in three distantly related lineages: budding yeasts, fission yeasts, and Mucoromycota. The RP gene duplicates in budding yeasts and Mucoromycota were mainly created by whole genome duplication events. However, duplicate RP genes in fission yeasts were likely generated by retroposition, which is unexpected considering their dosage sensitivity. The sequences of most RP paralogs have been homogenized by repeated gene conversion in each species, demonstrating parallel concerted evolution, which might have facilitated the retention of their duplicates. Transcriptomic data suggest that the duplication and retention of RP genes increased their transcript abundance. Physiological data indicate that increased ribosome biogenesis allowed these organisms to rapidly consume sugars through fermentation while maintaining high growth rates, providing selective advantages to these species in sugar-rich environments.
Asunto(s)
Hongos/metabolismo , Duplicación de Gen , Proteínas Ribosómicas/genética , Evolución Molecular , Proteínas Fúngicas/genética , Hongos/clasificación , Hongos/genética , Conversión Génica , Dosificación de Gen , Filogenia , Especificidad de la EspecieRESUMEN
OBJECTIVE: Innovations in genomics, epigenomics, and transcriptomics now lay the groundwork for therapeutic interventions against neoplastic disease. In the past 30 years, the molecular pathogenesis of pituitary adenomas has been characterized. This enhanced understanding of the biology of pituitary tumors has potential to impact current treatment paradigms, and there exists significant translational potential for these results. In this review the authors summarize the results of genomics and molecular biology investigations into pituitary adenoma pathogenesis and behavior and discuss opportunities to translate basic science findings into clinical benefit. METHODS: The authors searched the PubMed and MEDLINE databases by using combinations of the keywords "pituitary adenoma," "genomics," "pathogenesis," and "epigenomics." From the initial search, additional articles were individually evaluated and selected. RESULTS: Pituitary adenoma growth is primarily driven by unrestrained cell cycle progression, deregulation of growth and proliferation pathways, and abnormal epigenetic regulation of gene expression. These pathways may be amenable to therapeutic intervention. A significant number of studies have attempted to establish links between gene mutations and tumor progression, but a thorough mechanistic understanding remains elusive. CONCLUSIONS: Although not currently a prominent aspect in the clinical management of pituitary adenomas, genomics and epigenomic studies may become essential in refining patient care and developing novel pharmacological agents. Future basic science investigations should aim at elucidating mechanistic understandings unique to each pituitary adenoma subtype, which will facilitate rational drug design.
Asunto(s)
Adenoma/genética , Desarrollo de Medicamentos/tendencias , Epigénesis Genética/genética , Genómica/tendencias , Neoplasias Hipofisarias/genética , Investigación Biomédica Traslacional/tendencias , Adenoma/diagnóstico , Adenoma/terapia , Desarrollo de Medicamentos/métodos , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Humanos , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/terapia , Investigación Biomédica Traslacional/métodosRESUMEN
PURPOSE: To review the natural history of asymptomatic and symptomatic pediatric Chiari I malformations with and without syringomyelia. MATERIALS AND METHODS: We reviewed the literature for case reports and case series describing the natural history of asymptomatic and symptomatic children with Chiari I malformations with and without syringomyelia. Our review included approximately 700 asymptomatic children without syringomyelia, 100 symptomatic children without syringomyelia, 22 asymptomatic children with syringomyelia, and 11 symptomatic children with syringomyelia. Symptomatic and imaging outcomes at the point of last reported follow-up were noted to describe the natural history of Chiari I malformations in children. RESULTS: Our review of about 700 asymptomatic children with CM-I without syrinx revealed that most children do not exhibit new-onset symptoms (5-6%) or syrinx (2-3%). The nearly 100 published cases of symptomatic CM-I without syrinx suggest that about half of children report symptomatic improvement (48%) and few report symptomatic worsening (7%). New-onset syrinx is rarely observed (2%). Few cases have been published about asymptomatic and symptomatic CM-I with syrinx as syringomyelia are generally regarded to be an indication for surgical intervention. Nevertheless, all 22 children with asymptomatic CM-I with syringomyelia included in this study were asymptomatic at follow-up, with syrinx resolution observed in 18 children and tonsillar herniation improvement observed in 16 children. Overall, our review of asymptomatic pediatric CM-I with or without syringomyelia suggests that its natural history is much more favorable than previously acknowledged and that the literature generally favors conservative management of these cases. CONCLUSION: Our review of asymptomatic pediatric CM-I with or without syringomyelia suggests that its natural history is much more favorable than previously acknowledged and that the literature generally favors conservative management of these cases. Further study of symptomatic pediatric CM-I is necessary to better understand its natural history.
Asunto(s)
Malformación de Arnold-Chiari/diagnóstico por imagen , Malformación de Arnold-Chiari/cirugía , Procedimientos Neuroquirúrgicos/tendencias , Siringomielia/diagnóstico por imagen , Siringomielia/cirugía , Niño , Estudios de Cohortes , Estudios de Seguimiento , HumanosRESUMEN
The pathogenesis of intracranial aneurysms remains complex and multifactorial. While vascular, genetic, and epidemiological factors play a role, nascent aneurysm formation is believed to be induced by hemodynamic forces. Hemodynamic stresses and vascular insults lead to additional aneurysm and vessel remodeling. Advanced imaging techniques allow us to better define the roles of aneurysm and vessel morphology and hemodynamic parameters, such as wall shear stress, oscillatory shear index, and patterns of flow on aneurysm formation, growth, and rupture. While a complete understanding of the interplay between these hemodynamic variables remains elusive, the authors review the efforts that have been made over the past several decades in an attempt to elucidate the physical and biological interactions that govern aneurysm pathophysiology. Furthermore, the current clinical utility of hemodynamics in predicting aneurysm rupture is discussed.
Asunto(s)
Aneurisma Roto/fisiopatología , Biofisica , Hemodinámica , Aneurisma Intracraneal/fisiopatología , Animales , Progresión de la Enfermedad , Humanos , Estrés FisiológicoRESUMEN
BACKGROUND: Gangliogliomas are low-grade neoplasms that typically affect patients under the age of 30 and present with epilepsy and symptoms of mass effect. Here, we report a case of an intraventricular ganglioglioma involving the septum pellucidum in a pediatric patient with history of optic glioma. Only one other pediatric intraventricular ganglioglioma arising from the septum pellucidum has been reported previously. CASE REPORT: The patient initially presented at 9 months of age with a pilocytic astrocytoma centered on the optic chiasm, treated with chemotherapy and radiation at 3 years of age. Routine follow-up imaging at 13 years of age revealed the development of a mass in the septum pellucidum, which was subtotally resected endoscopically because of its proximity to the fornices. Pathology confirmed a ganglioglioma positive for the BRAF V600E mutation. The tumor residual progressed and was treated with stereotactic radiosurgery. The patient was asymptomatic at her 6-month follow-up visit and the size of the nodule remained stable. LITERATURE REVIEW: Our review of the 25 previously reported intraventricular gangliogliomas found that their pre-surgical diagnoses were often incorrect, reflecting the difficulty of making the diagnosis with signs, symptoms, and imaging alone. Patients can be reassured that the prognosis is generally favorable following uncomplicated neurosurgical resection.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Ganglioglioma/diagnóstico por imagen , Recurrencia Local de Neoplasia/diagnóstico por imagen , Radiocirugia/tendencias , Tabique Pelúcido/diagnóstico por imagen , Adolescente , Neoplasias Encefálicas/radioterapia , Femenino , Ganglioglioma/radioterapia , Humanos , Recurrencia Local de Neoplasia/radioterapia , Radiocirugia/métodosRESUMEN
INTRODUCTION: Stereotactic radiosurgery (SRS) is a common treatment modality among patients with brain metastases, particularly from malignant melanoma. Our objective was to investigate the difference in local control, toxicity, and survival among patients with hemorrhagic and solid melanoma brain metastases. METHODS: We collected demographic, treatment, local control, toxicity, and survival for 134 patients with a total of 936 intracranial melanoma metastases who underwent SRS between 1998 and 2015. Pre-radiosurgical diagnostic imaging was reviewed for evidence of hemorrhage (melanin-containing or clearly hemorrhagic). RESULTS: The cohort consisted of 92 men and 42 women with a mea age of 61.7 years (range 21.2-84.9) at the time of radiosurgery. Overall survival of patients with brain metastases from malignant melanoma was 42, 31, 12% at 12, 24, and 72 months from date of first SRS. At 6 months, 43% of the patients with hemorrhagic metastases had local tumor control compared to 83% of solid melanoma metastases (p < 0.001). No significant difference in toxicity was noted between the two groups. Factors that were significantly associated with time to local tumor progression on multivariate analysis include prior WBRT (HR 1.62, p = 0.003), prior chemotherapy (HR 0.69, p = 0.011), margin dose (HR 0.88, p < 0.001) and radiographic features of melanin deposition (HR 3.73, p < 0.001), or clear hemorrhage (HR 2.20, p < 0.001). CONCLUSIONS: Our findings demonstrate that hemorrhagic intracranial melanoma metastases are associated with inferior local tumor control when treated with SRS, as compared to solid tumors. These results highlight the importance of early radiosurgery among patients with melanoma brain metastases before hemorrhage occurs.
Asunto(s)
Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/secundario , Hemorragias Intracraneales/etiología , Melanoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Femenino , Humanos , Estado de Ejecución de Karnofsky , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiocirugia/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has been adopted as an alternative technique to hasten recovery and minimize postoperative morbidity. Advances in instrumentation technologies and operative techniques have evolved to maximize patient outcomes as well as radiographic results. The development of expandable interbody devices allows a surgeon to perform MIS-TLIF with minimal tissue disruption. However, sagittal segmental and pelvic radiographic outcomes after MIS-TLIF with expandable interbody devices are not well characterized. The object of this study is to evaluate the radiographic sagittal lumbar segmental and pelvic parameter outcomes of MIS-TLIF performed using an expandable interbody device. METHODS A retrospective review of MIS-TLIFs performed between 2014 and 2016 at a high-volume center was performed. Radiographic measurements were performed on lateral radiographs before and after MIS-TLIF with static or expandable interbody devices. Radiographic measurements included disc height, foraminal height, fused disc angle, lumbar lordosis, pelvic incidence, sacral slope, and pelvic tilt. Mismatch between pelvic incidence and lumbar lordosis were calculated for each radiograph. RESULTS A total of 48 MIS-TLIFs were performed, predominantly at the L4-5 level, in 44 patients. MIS-TLIF with an expandable interbody device led to a greater and more sustained increase in disc height when compared with static interbody devices. Foraminal height increased after MIS-TLIF with expandable but not with static interbody devices. MIS-TLIF with expandable interbody devices increased index-level segmental lordosis more than with static interbody devices. The increase in segmental lordosis was sustained in the patients with expandable interbody devices but not in patients with static interbody devices. For patients with a collapsed disc space, MIS-TLIF with an expandable interbody device provided superior and longer-lasting increases in disc height, foraminal height, and index-level segmental lordosis than in comparison with patients with static interbody devices. Using an expandable interbody device improved the Oswestry Disability Index scores more than using a static interbody device, and both disc height and segmental lordosis were correlated with improved clinical outcome. Lumbar MIS-TLIF with expandable or static interbody devices had no effect on overall lumbar lordosis, pelvic parameters, or pelvic incidence-lumbar lordosis mismatch. CONCLUSIONS Performing MIS-TLIF with an expandable interbody device led to a greater and longer-lasting restoration of disc height, foraminal height, and index-level segmental lordosis than MIS-TLIF with a static interbody device, especially for patients with a collapsed disc space. However, neither technique had any effect on radiographic pelvic parameters.
Asunto(s)
Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Huesos Pélvicos/cirugía , Diseño de Prótesis , Fusión Vertebral/métodos , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Disco Intervertebral/diagnóstico por imagen , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Huesos Pélvicos/diagnóstico por imagen , Estudios Retrospectivos , Fusión Vertebral/instrumentaciónRESUMEN
Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, non-neoplastic, slow-growing tumors that can present anywhere throughout the central nervous system. While the etiology of these lesions remains unknown, the mainstay of treatment is surgical excision. We describe a case of CAPNON at our institution in a 66 year-old female patient who presented with 5 months of pain and burning sensation in her thigh. On MRI, an intradural extramedullary lesion was identified at the level of T11-T12. The mass was surgically excised and the patient reported resolution of her symptoms by her six week follow-up appointment. We reviewed 79 spinal CAPNON cases, covering all cases reported in the literature thus far. In summary, we find that spinal CAPNON are most commonly lumbar and extradural in location, with pain as the most common presenting symptom. Lesions are well-defined and hypointense on T1 and T2 MRI sequence. The majority of cases had favorable surgical outcomes with near complete resolution of pain and associated symptoms.
RESUMEN
OBJECTIVE: The authors sought to determine the time to recurrence after achieving gross-total resection of nonfunctioning pituitary adenoma (NFPA) in adult patients. The authors also sought to determine the rate of recurrence after increasing years of recurrence-free imaging. METHODS: The authors performed a retrospective chart review of all adult patients who underwent gross-total resection of NFPA between September 2004 and January 2018 by the senior surgeon. The primary outcome of the study was time to recurrence, defined by imaging and/or clinical criteria. RESULTS: The median follow-up time of the 148 patients who met the inclusion criteria was 91 months; 12 of these patients (8.1%) had recurrence. The median time to recurrence was 80 months. The range of time for these recurrences was 36-156 months. The probabilities of remaining recurrence free at 180 months after gross-total resection of NFPA and 12, 36, 60, 84, or 120 months of recurrence-free imaging were 82%, 84%, 86%, 88%, and 93%, respectively. The year-over-year odds of a recurrence increased linearly by 1.07%. There was no difference in recurrence-free imaging when patients were stratified by Knosp grade or tumor subtype. None of the patients with recurrence underwent repeat resection. When identified, patients were managed either conservatively or with radiosurgery. CONCLUSIONS: Increased intervals of recurrence-free imaging were not associated with a decrease in risk of recurrence, which suggests that patients require life-long periodic imaging. If followed with periodic imaging, recurrence can be discovered before clinically symptomatic and successfully treated without repeat surgery.
RESUMEN
Germline Variants (GVs) are effective in predicting cancer risk and may be relevant in predicting patient outcomes. Here we provide a bioinformatic pipeline to identify GVs from the TCGA lower grade glioma cohort in Genomics Data Commons. We integrate paired whole exome sequences from normal and tumor samples and RNA sequences from tumor samples to determine a patient's GV status. We then identify the subset of GVs that are predictive of patient outcomes by Cox regression. For complete details on the use and execution of this protocol, please refer to Chatrath et al. (2019) and Chatrath et al. (2020).
Asunto(s)
Exoma , Glioma , Biología Computacional , Exoma/genética , Glioma/genética , Humanos , Secuenciación del ExomaRESUMEN
We present a data integration framework that uses non-negative matrix factorization of patient-similarity networks to integrate continuous multi-omics datasets for molecular subtyping. It is demonstrated to have the capability to handle missing data without using imputation and to be consistently among the best in detecting subtypes with differential prognosis and enrichment of clinical associations in a large number of cancers. When applying the approach to data from individuals with lower-grade gliomas, we identify a subtype with a significantly worse prognosis. Tumors assigned to this subtype are hypomethylated genome wide with a gain of AP-1 occupancy in demethylated distal enhancers. The tumors are also enriched for somatic chromosome 7 (chr7) gain, chr10 loss, and other molecular events that have been suggested as diagnostic markers for "IDH wild type, with molecular features of glioblastoma" by the cIMPACT-NOW consortium but have yet to be included in the World Health Organization (WHO) guidelines.
Asunto(s)
Glioblastoma , Glioma , Humanos , Multiómica , Glioma/diagnóstico , Glioblastoma/diagnóstico , Pronóstico , Aberraciones CromosómicasRESUMEN
OBJECTIVE: Primary spinal cord astrocytomas are rare, fatal, and poorly studied. METHODS: This study included a 2-center, retrospective analysis of primary spinal cord astrocytoma patients from 1997 to 2020. Patients with drop metastases or without at least one follow-up were excluded. RESULTS: Seven World Health Organization grade I, 6 grade II, 7 grade III, and 4 grade IV astrocytoma patients were included. Older patients had higher grades (median 20 years in grade I vs. 36.5 in grade IV). The median follow-up was 15 months. Thirteen patients were discharged to rehabilitation. Eight patients demonstrated radiographic progression. Adjuvant therapy was utilized more in higher grades (5 of 13 grades III vs. all 11 grades IIIIV). Six patients died (1 death in grades III vs. 5 in grades IIIIV). Ten patients had worsened symptoms at the last follow-up. The median progression-free survival in grade I, II, III, and IV tumors was 116, 36, 8, and 8.5 months, respectively. The median overall survival in grade I, II, III, and IV tumors was 142, 69, 19, and 12 months, respectively. Thrombotic complications occurred in 2 patients, one with isocitrate dehydrogenasewild type glioblastoma. CONCLUSIONS: Outcomes worsen with higher grades and lead to difficult postoperative periods. Clinicians should be vigilant for thromboembolic complications. Further research is needed to understand these rare tumors.
Asunto(s)
Astrocitoma , Neoplasias de la Médula Espinal , Humanos , Estudios Retrospectivos , Astrocitoma/diagnóstico por imagen , Astrocitoma/terapia , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/cirugía , Neoplasias de la Médula Espinal/patología , Terapia CombinadaRESUMEN
High tumor mutational burden (TMB) is associated with response to checkpoint blockade in several cancers. We identify pathogenic germline variants associated with increased TMB (GVITMB). GVITMB were found in 7 genes using a pan-cancer approach (APC, FANCL, SLC25A13, ERCC3, MSH6, PMS2, and TP53) and 38 gene sets (e.g., those involved in DNA repair and programmed cell death). GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant. In a validation cohort of 140 patients with cutaneous melanoma, we found that patients with GVITMB had prolonged progression-free survival (p = 0.0349, hazard ratio = 0.688) and responded favorably (p = 0.0341, odds = 1.842) when treated with immune checkpoint inhibitors. Our results suggest that germline variants can influence the molecular phenotypes of tumors and predict the response to immune checkpoint inhibitors.
RESUMEN
BACKGROUND: Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE: To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS: An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS: A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION: AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.
Asunto(s)
Meningioma/cirugía , Radiocirugia , Humanos , Meningioma/mortalidad , Complicaciones Posoperatorias/epidemiología , Traumatismos por Radiación/epidemiología , Radiocirugia/efectos adversos , Radiocirugia/métodos , Radiocirugia/mortalidad , Reoperación/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
DRAIC is a 1.7 kb spliced long noncoding RNA downregulated in castration-resistant advanced prostate cancer. Decreased DRAIC expression predicts poor patient outcome in prostate and seven other cancers, while increased DRAIC represses growth of xenografted tumors. Here, we show that cancers with decreased DRAIC expression have increased NF-κB target gene expression. DRAIC downregulation increased cell invasion and soft agar colony formation; this was dependent on NF-κB activation. DRAIC interacted with subunits of the IκB kinase (IKK) complex to inhibit their interaction with each other, the phosphorylation of IκBα, and the activation of NF-κB. These functions of DRAIC mapped to the same fragment containing bases 701-905. Thus, DRAIC lncRNA inhibits prostate cancer progression through suppression of NF-κB activation by interfering with IKK activity. SIGNIFICANCE: A cytoplasmic tumor-suppressive lncRNA interacts with and inhibits a major kinase that activates an oncogenic transcription factor in prostate cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/5/950/F1.large.jpg.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Quinasa I-kappa B/genética , FN-kappa B/metabolismo , Neoplasias de la Próstata/genética , ARN Largo no Codificante/metabolismo , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Masculino , Ratones , Fosforilación/genética , Próstata/patología , Neoplasias de la Próstata/patología , ARN Largo no Codificante/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.
Asunto(s)
Secuenciación de Inmunoprecipitación de Cromatina , Neoplasias , Línea Celular , ADN/genética , Variaciones en el Número de Copia de ADN , ADN Circular/genética , HumanosRESUMEN
BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a debilitating disease process accounting for 5% of strokes. Although improvements in care have reduced the case-fatality rates, patients have an increased risk of neurological and medical complications after discharge. Additionally, the readmission rates have been increasingly used as a metric for patient care quality. METHODS: In the present study, we reviewed the medical records of 206 patients who had been treated for aSAH at the University of Virginia from 2011 to 2018 to identify the causes and predictors of readmission. RESULTS: The all-cause readmission rate was 9.8%, 15.3%, and 21.3% within 30, 60, and 180 days, respectively. The readmission rate for neurologic causes was 7.7%, 12.6%, and 18.0% within 30, 60, and 180 days, respectively. The neurologic causes of readmission included aneurysm retreatment, cranioplasty, a fall, hydrocephalus, stroke symptoms, and syncope. Surgical treatment (odds ratio [OR], 4.11-6.30) and endovascular treatment (OR, 3.79-8.33) of vasospasm were associated with an increased risk of all-cause readmission. Endovascular aneurysm treatment (OR, 0.22) was associated with a decreased risk of all-cause readmission. The average interval to the first follow-up appointment at our institution was 55.3 ± 63.3 days. Of the patients who had been readmitted from the emergency room, 65% had not had follow-up contact with physicians at our institution until their readmission. CONCLUSIONS: To the best of our knowledge, the present study is the first to have examined the readmission rates for subarachnoid hemorrhage >90 days after treatment. Our results have suggested that the readmission rates >90 days after treatment could still be predicted by the hospital and treatment course during admission and that follow-up appointments with patients earlier in the clinic could identify those patients with a greater risk of readmission.
Asunto(s)
Procedimientos Endovasculares/tendencias , Procedimientos Neuroquirúrgicos/tendencias , Readmisión del Paciente/tendencias , Hemorragia Subaracnoidea/cirugía , Adulto , Anciano , Procedimientos Endovasculares/efectos adversos , Femenino , Estudios de Seguimiento , Predicción , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/epidemiología , Resultado del TratamientoRESUMEN
OBJECTIVE: Syringogenesis in Chiari malformation type I (CM-I) is thought to occur secondary to impaction of the cerebellar tonsils within the foramen magnum (FM). However, the correlation between the CSF area and syringogenesis has yet to be elucidated. The authors sought to determine whether the diminution in subarachnoid space is associated with syringogenesis. Further, the authors sought to determine if syrinx resolution was associated with the degree of expansion of subarachnoid spaces after surgery. METHODS: The authors performed a retrospective review of all patients undergoing posterior fossa decompression for CM-I from 2004 to 2016 at the University of Virginia Health System. The subarachnoid spaces at the FM and at the level of the most severe stenosis were measured before and after surgery by manual delineation of the canal and neural tissue area on MRI and verified through automated CSF intensity measurements. Imaging and clinical outcomes were then compared. RESULTS: Of 68 patients, 26 had a syrinx at presentation. Syrinx patients had significantly less subarachnoid space at the FM (13% vs 19%, p = 0.0070) compared to those without syrinx. Following matching based on degree of tonsillar herniation and age, the subarachnoid space was significantly smaller in patients with a syrinx (12% vs 19%, p = 0.0015). Syrinx resolution was associated with an increase in patients' subarachnoid space after surgery compared with those patients without resolution (23% vs 10%, p = 0.0323). CONCLUSIONS: Syrinx development in CM-I patients is correlated with the degree to which the subarachnoid CSF spaces are diminished at the cranial outlet. Successful syrinx reduction is associated with the degree to which the subarachnoid spaces are increased following surgery.