RESUMEN
BACKGROUD: Neurofibromatosis type 1 (NF1) is a heterogeneous neurocutaneous disorder. Spinal neurofibromatosis (SNF) is a distinct clinical entity of NF1, characterized by bilateral neurofibromas involving all spinal nerve roots. Although both forms are caused by intragenic heterozygous variants of NF1, missense variants have been associated with SNF, according to a dominant inheritance model causing haploinsufficiency. Most patients carry pathogenic variants in one of the NF1 alleles; nevertheless, patients with both NF1-mutated copies have been described. Interestingly, all NF1 variants carried by the known SNF compound heterozygotes were missense/splicing variants or in-frame insertion-deletions. AIMS: To investigate whether there is a differential expression of NF1 variant alleles in an NF1 compound heterozygous SNF patient possibly contributing to clinical phenotype. MATERIALS & METHODS: We performed an allele-specific expression study, by chip-based digital PCR, in an SNF family carrying two NF1 missense variants. We evaluated the expression levels of the two NF1-mutated alleles both carried by the compound heterozygous SNF patient and his relatives. RESULTS: Both alleles were expressed at comparable levels in the patient and hyper-expressed compared to the wild-type alleles of healthy controls. DISCUSSION: Here we provide new insights into expression studies of NF1-mutated transcripts suggesting that a novel pathogenetic mechanism, caused by gain-of-function variants, could be associated with SNF. CONCLUSIONS: Further studies should be performed in larger cohorts, opening new perspectives in the NF1 pathogenesis comprehension.
Asunto(s)
Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Alelos , Fenotipo , Mutación Missense , Reacción en Cadena de la Polimerasa , Genes de Neurofibromatosis 1RESUMEN
NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two "likely pathogenic" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients' follow-up.
Asunto(s)
Deleción Cromosómica , Epigénesis Genética , Haploinsuficiencia , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Femenino , Masculino , Neurofibromina 1/genética , Cromosomas Humanos Par 17/genética , Fenotipo , Niño , Regiones Promotoras GenéticasRESUMEN
PURPOSE OF REVIEW: In recent years emerging evidence suggests that some tumor types, extremely rare in general population and understudied, can be observed in NF1 and neoplasms related with this condition harbor peculiar genetic and epigenetic features. The aim of this review is to summarize recent advances that, delving into the tumor complexity, have identified new diagnostic tools and potential tumor subtype that may have been associated with clinical implications. RECENT FINDINGS: The available data confirmed the presence of peculiar molecular signatures in those tumors, different from those observed in sporadic neoplasms and suggest that a specific reference to NF1 associated neoplasms would deserve to be mentioned in tumor WHO classification. Comprehensive multiomic analysis shows that the histologic assessment does not always match the methylation group assignment and facilitates tumor subclassification into categories predictive of clinical behavior. The non-invasive assessment of tumor genetic profiles by the analysis of plasma ctDNA is representative of tumor features, may help differential diagnosis and may identify malignant transformation, sparing the patient from repeated biopsies. SUMMARY: A better knowledge of NF1 associated tumors at the molecular level may suggest changes in the clinical management of the disease and open new frontiers of personalized treatment.
Asunto(s)
Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genética , Transformación Celular Neoplásica , Sistema Nervioso Periférico/patologíaRESUMEN
Familial periodic paralyses (PPs) are inherited disorders of skeletal muscle characterized by recurrent episodes of flaccid muscle weakness. PPs are classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. HypoPP is an autosomal dominant disease caused by mutations in the CACNA1S gene, encoding for Cav1.1 channel (HypoPP-1), or SCN4A gene, encoding for Nav1.4 channel (HypoPP-2). In the present study, we included 60 patients with a clinical diagnosis of HypoPP. Fifty-one (85%) patients were tested using the direct sequencing (Sanger method) of all reported HypoPP mutations in CACNA1S and SCN4A genes; the remaining 9 (15%) patients were analyzed through a next-generation sequencing (NGS) panel, including the whole CACNA1S and SCN4A genes, plus other genes rarely associated to PPs. Fifty patients resulted mutated: 38 (76%) cases showed p.R528H and p.R1239G/H CACNA1S mutations and 12 (24%) displayed p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H SCN4A mutations. Forty-one mutated cases were identified among the 51 patients managed with Sanger sequencing, while all the 9 cases directly analyzed with the NGS panel showed mutations in the hotspot regions of SCN4A and CACNA1S. Ten out of the 51 patients unresolved through the Sanger sequencing were further analyzed with the NGS panel, without the detection of any mutation. Hence, our data suggest that in HypoPP patients, the extension of genetic analysis from the hotspot regions using the Sanger method to the NGS sequencing of the entire CACNA1S and SCN4A genes does not lead to the identification of new pathological mutations.
Asunto(s)
Parálisis Periódica Hipopotasémica , Canales de Calcio Tipo L/genética , Pruebas Genéticas , Humanos , Parálisis Periódica Hipopotasémica/genética , Parálisis Periódica Hipopotasémica/patología , Músculo Esquelético/patología , Mutación , Canal de Sodio Activado por Voltaje NAV1.4/genéticaRESUMEN
Neurofibromatosis type 2 is an autosomal dominant tumor-prone disorder mainly caused by NF2 point mutations or intragenic deletions. Few individuals with a complex phenotype and 22q12 microdeletions have been described. The 22q12 microdeletions' pathogenic effects at the genetic and epigenetic levels are currently unknown. We here report on 22q12 microdeletions' characterization in three NF2 patients with different phenotype complexities. A possible effect of the position was investigated by in silico analysis of 22q12 topologically associated domains (TADs) and regulatory elements, and by expression analysis of 12 genes flanking patients' deletions. A 147 Kb microdeletion was identified in the patient with the mildest phenotype, while two large deletions of 561 Kb and 1.8 Mb were found in the other two patients, showing a more severe symptomatology. The last two patients displayed intellectual disability, possibly related to AP1B1 gene deletion. The microdeletions change from one to five TADs, and the 22q12 chromatin regulatory landscape, according to the altered expression levels of four deletion-flanking genes, including PIK3IP1, are likely associated with an early ischemic event occurring in the patient with the largest deletion. Our results suggest that the identification of the deletion extent can provide prognostic markers, predictive of NF2 phenotypes, and potential therapeutic targets, thus overall improving patient management.
Asunto(s)
Discapacidad Intelectual , Neurofibromatosis 2 , Complejo 1 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora , Humanos , Discapacidad Intelectual/genética , Neurofibromatosis 2/genética , FenotipoRESUMEN
Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect â¼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
Asunto(s)
Codón/genética , Estudios de Asociación Genética , Mutación Missense/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adolescente , Secuencia de Aminoácidos , Niño , Estudios de Cohortes , Simulación por Computador , Demografía , Femenino , Heterocigoto , Humanos , Masculino , Neurofibromina 1/química , Fenotipo , Adulto JovenRESUMEN
Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.
Asunto(s)
Biomarcadores de Tumor , Neoplasias del Sistema Nervioso Central , Interleucina-10/líquido cefalorraquídeo , Linfoma , Mutación Missense , Factor 88 de Diferenciación Mieloide/genética , Proteínas de Neoplasias , Adulto , Anciano , Sustitución de Aminoácidos , Biomarcadores de Tumor/líquido cefalorraquídeo , Biomarcadores de Tumor/genética , Biopsia , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Interleucina-10/genética , Linfoma/líquido cefalorraquídeo , Linfoma/genética , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/líquido cefalorraquídeo , Proteínas de Neoplasias/líquido cefalorraquídeo , Proteínas de Neoplasias/genéticaRESUMEN
BACKGROUND: Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. METHODS: A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. RESULTS: High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. CONCLUSIONS: Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Glioblastoma/patología , Mutación , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Biopsia , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Terapia Combinada , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/terapia , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunohistoquímica , Imagen por Resonancia Magnética , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia , Neuroimagen , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Retratamiento , Linfocitos T/efectos de los fármacos , Resultado del Tratamiento , Secuenciación del ExomaRESUMEN
BACKGROUND: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. METHODS: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. RESULTS: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. CONCLUSIONS: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
Asunto(s)
COVID-19 , Telemedicina , Adulto , Niño , Humanos , Italia/epidemiología , Pandemias , Derivación y Consulta , SARS-CoV-2RESUMEN
Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior of some PNSTs compared to others are not precisely known. Considering that lipid homeostasis plays a crucial role in fibrotic/inflammatory processes and in several cancers, we hypothesized that the lipid asset was also unbalanced in this group of nerve tumors. Through untargeted lipidomics, NFs presented a significant increase in ceramide, phosphatidylcholine, and Vitamin A ester. PNFs displayed a marked decrease in 34 out of 50 lipid class analyzed. An increased level of ether- and oxidized-triacylglycerols was observed; phosphatidylcholines were reduced. After sphingolipidomic analysis, we observed six sphingolipid classes. Ceramide and dihydroceramides were statistically increased in NFs. All the glycosylated species appeared reduced in NFs, but increased in PNFs. Our findings suggested that different subtypes of PNSTs presented a specific modulation in the lipidic profile. The untargeted and targeted lipidomic approaches, which were not applied until now, contribute to better clarifying bioactive lipid roles in PNS natural history to highlight disease molecular features and pathogenesis.
Asunto(s)
Lípidos/fisiología , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/patología , Adulto , Anciano , Femenino , Homeostasis/fisiología , Humanos , Lipidómica/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: Gliomatosis cerebri (GC), defined until 2016 as a distinct astrocytic glioma entity, has been removed from the 2016 World Health Organization classification of tumors of the central nervous system. However, its identity is still debated. MATERIALS AND METHODS: We retrospectively present 122 patients, including a subgroup with histology confirmation (n = 75, cohort b). RESULTS: Radiological features showed extension limited to 3 lobes in 31%; bilateral, midline, and basal ganglia and subtentorial involvement in 95%, 52%, 84%, and 60%, respectively; and contrast enhancement in 59.5%. Perioperative mortality occurred in 4%. Histology concluded for grades II, III, and IV, respectively, in 31%, 35%, and 22% (not specified in 12%). Thirty-one percent had isocitrate dehydrogenase (IDH) 1 mutation. Treatments included radiotherapy in 51.2% and chemotherapy in 74.5%. Median overall survival was 17 months. Negative prognostic factors for survival were older age, poorer Karnofsky Performance Scale (KPS), subtentorial, midline and disseminated disease, and lack of chemotherapy, at univariate analysis. At multivariate analysis, KPS ≥ 80, chemotherapy, and subtentorial and disseminated disease remained prognostic (p < 0.0001). For cohort b, same prognostic factors were confirmed, except for midline location, at univariate analysis; at multivariate analysis, only KPS ≥ 80 and chemotherapy remained prognostic (p < 0.0001). CONCLUSION: We described clinical, neuroimaging, management, and histomolecular features of one of the largest GC series. We identified KPS ≥ 80, radiological pattern as subtentorial localization and dissemination, and chemotherapy as prognostic factors, at multivariate analysis. Planning prospective study, associated to focused genetic assays, could help to clarify if GC has specific features that may result in the identification as a separate entity from other gliomas.
Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Neuroepiteliales , Anciano , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Humanos , Neoplasias Neuroepiteliales/diagnóstico por imagen , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/terapia , Pronóstico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are often detected in lower-grade gliomas (LGG) and result into 2-hydroxyglutarate (2HG) synthesis. Prior studies showed that 2HG can be detected in vivo using magnetic resonance spectroscopy (MRS), but its accuracy and translational impact are still under investigation. PURPOSE: To investigate the clinical feasibility of MRS for in vivo detection and quantification of 2HG on consecutive treatment-naïve suspect LGG patients and to compare MRS accuracy with tissue IDH1/2 analysis. METHODS: MRS spectra at 3 T were acquired with 1H-MRS single-voxel PRESS 2HG-tailored sequences with TE 30 (group 1) or TE 97 (groups 2A and B). Voxel sizes were 1.5 × 1.5 × 1.5 cm3 for group 1 (n = 13) and group 2A (n = 14) and 2 × 2 × 2 cm3 for group 2B (n = 32). Multiple metabolites' concentrations were analyzed with LCModel. Tumors were assessed for IDH status and main molecular markers. 2HG levels in urine/blood were measured by liquid chromatography-mass spectrometry. RESULTS: The larger voxel TE 97 sequence resulted in highest specificity (100%), sensitivity (79%), and accuracy (87%). Urine and blood 2HG did not result predictive. CONCLUSION: Our data confirm that 2 × 2 × 2-cm3 voxel TE 97 MRS shows high accuracy for 2HG detection, with good sensitivity and 100% specificity in distinguishing IDH mutant gliomas. Main limits of the technique are small tumor volume and low cellularity. Integrating 2HG-MRS with other metabolites may help non-invasive diagnosis of glioma, prognostic assessment, and treatment planning in clinical setting.
Asunto(s)
Glioma/tratamiento farmacológico , Glioma/patología , Glutaratos/farmacología , Espectroscopía de Protones por Resonancia Magnética , Biomarcadores/análisis , Estudios de Factibilidad , Femenino , Humanos , Isocitrato Deshidrogenasa/genética , Espectroscopía de Resonancia Magnética/métodos , Masculino , Pronóstico , Espectroscopía de Protones por Resonancia Magnética/métodosRESUMEN
BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. FUNDING: Veneto Institute of Oncology and Bayer Italy.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Glioblastoma/tratamiento farmacológico , Lomustina/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Lomustina/administración & dosificación , Lomustina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Recurrencia , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: The current review summarizes recent advances on three important issues in neurofibromatosis type 1 (NF1) management: the identification of specific NF1 gene mutations predicting the risk for developing neurological malignancies; the molecular features of NF1-associated tumors and their differences from sporadic neoplasms; genetic, epigenetic, or microenviromental factors leading benign tumors to a malignant transformation in NF1. RECENT FINDINGS: The association between the risk of developing optic pathway glioma and specific germiline NF1 mutations is still debated and further studies are needed with large, new cohorts of patients. The available evidences suggest that gliomas and malignant peripheral nerve sheath tumors (MPNSTs) in NF1 have a distinct genetic signatures, different from those observed in sporadic neoplasms. Some neoplasms, very rare in general population, such as subependymal giant cell astrocytoma, can be observed in NF1. A subgroup of low-grade NF1-gliomas, some MPNSTs and plexiform neurofibromas contain abundant T lymphocyte infiltrates suggesting that immunotherapy could be a potential therapeutic approach. SUMMARY: These data support the notion that next-generation sequencing efforts are helpful in the genetic characterization of NF1-associated malignancies A better knowledge of those tumors at the genomic level, is essential for addressing new treatments and may contribute to a deeper comprehension of NF1/RAS signaling also in sporadic cancers.
Asunto(s)
Neurofibromatosis 1/patología , Glioma del Nervio Óptico/patología , Animales , Transformación Celular Neoplásica , Mutación de Línea Germinal , Humanos , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Glioma del Nervio Óptico/genéticaRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. METHODS: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. RESULTS: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases). CONCLUSIONS: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Amplificación de Genes , Glioblastoma/genética , Tamizaje Masivo/normas , Selección de Paciente , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Método Doble Ciego , Receptores ErbB/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , PronósticoRESUMEN
Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.
Asunto(s)
Neoplasias Encefálicas/complicaciones , Epilepsia/etiología , Epilepsia/terapia , HumanosRESUMEN
Recently, we found that temozolomide (TMZ) can upregulate the expression of the multidrug-resistance protein ABCC3 in NK cells from both glioma-bearing mice and glioblastoma patients treated with dendritic cell immunotherapy combined with TMZ, allowing NK cells to escape apoptosis and favoring their role as antitumor effector cells. Here, we demonstrate that CD56dim NK cells expressing CD16+ are predominant in patients surviving more than 12 months after surgery without disease progression. CD56dim CD16+ NK cells co-expressed high levels of ABCC3 and IFN-ï§. Notably, not only basal but also TMZ-induced ABCC3 expression was related to a strong, long-term NK cell response and a better prognosis of patients. The identification of the single nucleotide polymorphism (SNP) rs35467079 with the deletion of a cytosine (-897DelC) in the promoter region of the ABCC3 gene resulted associated with a better patient outcome. ABCC3 expression in patients carrying DelC compared to patients with reference haplotype was higher and modulated by TMZ. The transcription factor NRF2, involved in ABCC3 induction, was phosphorylated in CD56dim CD16+ NK cells expressing ABCC3 under TMZ treatment. Thus, ABCC3 protein and the SNP -897DelC can play a predictive role in patients affected by GBM, and possibly other cancers, treated with dendritic cell immunotherapy combined with chemotherapy.
Asunto(s)
Células Dendríticas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células Asesinas Naturales/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Receptores de IgG/metabolismo , Adulto , Anciano , Citotoxicidad Inmunológica/fisiología , Femenino , Glioblastoma/terapia , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Adulto JovenRESUMEN
The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.
Asunto(s)
Cromosomas Humanos Par 2 , Trastornos Mentales/genética , ARN Largo no Codificante/genética , ARN no Traducido/genética , Adolescente , Adulto , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/genética , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Trastornos Mentales/metabolismo , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Moléculas de Adhesión de Célula Nerviosa , Fenotipo , ARN Largo no Codificante/metabolismo , ARN no Traducido/metabolismoRESUMEN
Glioblastoma (GBM) are high-grade gliomas that severely impact on overall survival (OS). GBM cell motility and the breakdown of the blood-brain barrier could favor GBM cell communication with the systemic circulation. In spite of this, extracranial GBM metastases are rare. Here, we describe two YKL-40-positive GBM patients with extra-CNS (central nervous system) metastases, and we present a meta-analysis of 94 cases. The analysis concluded that extra-CNS metastases occurred 8.5 months after first GBM diagnosis and OS was 12 months; surgical GBM excision was associated at a longer interval to extra-CNS metastasis than biopsy only, and even longer if followed by radiotherapy and chemotherapy. Both our case reports were adult males who developed extra-CNS, YKL-40-positive metastases at lymph nodes, lung and subcutaneous sites, after 86 and 24 months from initial diagnosis of GBM. At first GBM local recurrence, they were treated with bevacizumab (BV), an anti-vascular endothelial growth factor antibody. They died after 4 and 1 month from the occurrence of metastases. Both cases expressed YKL-40 and lacked EGFR amplification, suggesting a mesenchymal phenotype, and maintained such profile at extra-CNS recurrence; they did not show MGMT promoter methylation, IDH1/2 mutations, or c-Met upregulation. Our two cases and the meta-analysis support the idea that prolonged survival of GBM patients increases the probability of GBM cells shedding to lymphatic and hematic system. Interestingly, the present two cases showed the features of mesenchymal profile, usually related with worst prognosis that was maintained in extracranial metastases.
Asunto(s)
Adipoquinas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/secundario , Glioblastoma/genética , Glioblastoma/patología , Lectinas/genética , Adipoquinas/metabolismo , Adulto , Neoplasias Encefálicas/cirugía , Neoplasias del Sistema Nervioso Central/cirugía , Proteína 1 Similar a Quitinasa-3 , Terapia Combinada , Resultado Fatal , Glioblastoma/cirugía , Humanos , Lectinas/metabolismo , Masculino , Procedimientos Neuroquirúrgicos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.