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BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used to assess patients' perioperative health. The PROM Information System 29 (PROMIS-29) is a well-validated global health assessment instrument for patient physical health, though its utility in cranial neurosurgery is unclear. OBJECTIVE: To investigate the utility of preoperative PROMIS-29 physical health (PH) summary scores in predicting postoperative outcomes in brain tumor patients. METHODS: Adult brain tumor patients undergoing resection at a single institution (January 2018-December 2021) were identified and prospectively received PROMIS-29 surveys during pre-operative visits. PH summary scores were constructed and optimum prediction thresholds for length of stay (LOS), discharge disposition (DD), and 30-day readmission were approximated by finding the Youden index of the associated receiver operating characteristic curves. Bivariate analyses were used to study the distribution of low (z-score≤-1) versus high (z-score>-1) PH scores according to baseline characteristics. Logistic regression models quantified the association between preoperative PH summary scores and post-operative outcomes. RESULTS: A total of 157 brain tumor patients were identified (mean age 55.4±15.4 years; 58.0% female; mean PH score 45.5+10.5). Outcomes included prolonged LOS (24.8%), non-routine discharge disposition (37.6%), and 30-day readmission (19.1%). On bivariate analysis, patients with low PH scores were significantly more likely to be diagnosed with a high-grade tumor (69.6% vs 38.85%, p=0.010) and less likely to have elective surgery (34.8% vs 70.9%, p=0.002). Low PH score was associated with prolonged LOS (26.1% vs 22%, p<0.001), nonroutine discharge (73.9% vs 31.3%, p<0.001) and 30-day readmission (43.5% vs 14.9%, p=0.003). In multivariate analysis, low PH scores predicted greater LOS (odds ratio [OR]=6.09, p=0.003), nonroutine discharge (OR=4.25, p=0.020), and 30-day readmission (OR=3.93, p=0.020). CONCLUSION: The PROMIS-29 PH summary score predicts short-term postoperative outcomes in brain tumor patients and may be incorporated into prospective clinical workflows.
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Neoplasias Encefálicas , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Feminino , Masculino , Neoplasias Encefálicas/cirurgia , Pessoa de Meia-Idade , Tempo de Internação/estatística & dados numéricos , Procedimentos Neurocirúrgicos , Estudos Prospectivos , Idoso , Adulto , Readmissão do Paciente/estatística & dados numéricos , Período Pré-Operatório , Prognóstico , Complicações Pós-Operatórias/epidemiologia , SeguimentosRESUMO
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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Neoplasias Cerebelares/genética , Meduloblastoma/genética , Adolescente , Adulto , Biomarcadores Tumorais/genética , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Intervalo Livre de Progressão , Fatores de Risco , Adulto JovemAssuntos
Neoplasias do Sistema Nervoso Central , Histonas , Proteínas Repressoras , Humanos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Histonas/metabolismo , Histonas/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
PURPOSE: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. METHODS: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. RESULTS: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03). CONCLUSIONS: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.
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Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Glioma/epidemiologia , Glioma/patologia , Histonas/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Estudos de Coortes , Feminino , Glioma/genética , Glioma/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sobrevida , Adulto JovemRESUMO
OBJECTIVES: Ketogenic diets (KDs) have long been used to treat epilepsy and are being explored in a variety of diseases. Preclinical data suggest KDs affect inflammation and cytokine release. It is unknown whether KDs affect white blood cell (WBC) counts over time. This is particularly important in clinical populations who may be immune-suppressed at baseline, such as those with cancer or autoimmune disorders. METHODS: A retrospective review of 125 consecutive adults seen at the Adult Epilepsy Diet Center (AEDC) was conducted. Clinical data regarding compliance, laboratory data, weights, and diet records were collected. A control cohort consisted of patients evaluated at the AEDC who elected not to complete a prescribed KD. RESULTS: In 52 adults on KDs, there was a small but statistically significant decrease in WBC and absolute neutrophil counts at 6 and 12 months into KD therapy. There was no effect on lymphocyte counts. This pattern was also seen in a small population of patients with gliomas (n = 10) on KDs, most (n = 8) of whom had also received chemotherapy and radiation, putting them at risk for bone marrow suppression. Across both glioma and non-glioma groups, patients with pre-existing lymphopenia did not have further worsening of their counts on the KD. CONCLUSIONS: In this retrospective case-control study, a small but significant decrease in total WBC and neutrophil counts was observed in patients with epilepsy treated with the KDs. These patterns are similar in patients with and without gliomas suggesting baseline immunosuppression does not worsen with KD. These findings provide data for prospective confirmatory studies.
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Dieta Cetogênica , Epilepsia/sangue , Epilepsia/dietoterapia , Contagem de Leucócitos , Adulto , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/dietoterapia , Neoplasias Encefálicas/imunologia , Estudos de Casos e Controles , Epilepsia/imunologia , Feminino , Glioma/sangue , Glioma/dietoterapia , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.
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Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Neoplasias Encefálicas/diagnóstico , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Resultado do Tratamento , Adulto JovemRESUMO
Temozolomide has been available to oncologists for over 30 years. During this time, it has become an integral part of standard therapy in patients with high-grade gliomas. Given its ability to traverse the blood-brain barrier, temozolomide has also been evaluated in other cancers that involve the central nervous system (CNS). We review its role in the management of patients with primary brain tumors, brain metastases, leptomeningeal carcinomatosis, and other selected CNS cancers. There is strong evidence that temozolomide is effective in patients with high-grade astrocytomas and oligodendrogliomas. Modest evidence supports its activity in primary CNS lymphomas and aggressive pituitary adenomas. Temozolomide, however, has minimal efficacy in a wide variety of systemic cancers. Given that concentrations of temozolomide in the CNS are only 20% of those in the blood, it is not surprising that it is generally inactive in patients with CNS metastases from solid tumors.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Temozolomida/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Temozolomida/efeitos adversos , Temozolomida/farmacocinética , Resultado do TratamentoRESUMO
Individuals with neurofibromatosis type 1 (NF-1), an autosomal dominant neurogenetic and tumor predisposition syndrome, are susceptible to developing low-grade glioma (LGG) and, less commonly, high-grade glioma (HGG). These gliomas exhibit loss of the neurofibromin gene (NF1), and 10-15% of sporadic HGG have somatic NF1 alterations. Loss of NF1 leads to hyperactive RAS signaling, creating opportunity given the established efficacy of MEK inhibitors (MEKi) in plexiform neurofibromas and some individuals with LGG. We observed that NF1-deficient glioblastoma neurospheres were sensitive to the combination of a MEKi (mirdametinib) with irradiation, as evidenced by synergistic inhibition of cell growth, colony formation, and increased cell death. In contrast, NF1-intact neurospheres were not sensitive to the combination, despite complete ERK pathway inhibition. No neurosphere lines exhibited enhanced sensitivity to temozolomide combined with mirdametinib. Mirdametinib decreased transcription of homologous recombination genes and RAD51 foci, associated with DNA damage repair, in sensitive models. Heterotopic xenograft models displayed synergistic growth inhibition to mirdametinib combined with irradiation in NF1-deficient glioma xenografts, but not those with intact NF1. In sensitive models, benefits were observed at least three weeks beyond the completion of treatment, including sustained phosphor-ERK inhibition on immunoblot and decreased Ki-67 expression. These observations demonstrate synergistic activity between mirdametinib and irradiation in NF1-deficient glioma models and may have clinical implications for patients with gliomas that harbor germline or somatic NF1 alterations.
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Advanced molecular testing has increasingly become an integral component for accurate diagnosis of central nervous system (CNS) tumors. We sought to establish the current state of molecular testing availability and approaches for the diagnosis of CNS tumors in US hospitals that conduct high volumes of CNS tumor resections. We distributed a 16-item survey inquiring about molecular testing approaches for CNS tumors to 115 neuropathologists at US hospitals with neurosurgery residency programs. Thirty-five neuropathologists (30.4%) responded to the survey, all of whom indicated their institutions perform molecular testing on CNS tumor tissue. The most commonly offered tests were MGMT methylation profiling and next-generation sequencing. Fourteen respondents (40%) indicated that their institution is able to test for and report all of the molecular alterations included in our survey. Nine (25.7%) respondents indicated that molecular testing is performed as standard of care for all patients with resected CNS tumors. Our results suggest that even in academic hospitals with a high volume of CNS tumor resections, molecular testing for these tumors is limited. Continued initiatives are necessary to expand the availability of molecular testing for CNS tumors to ensure diagnostic accuracy and guide targeted therapy.
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Neoplasias do Sistema Nervoso Central , Humanos , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/diagnóstico , Estados Unidos , Hospitais , Inquéritos e QuestionáriosRESUMO
Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.
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Neoplasias Encefálicas , Glioma , Isocitrato Desidrogenase , Gradação de Tumores , Humanos , Glioma/genética , Glioma/terapia , Glioma/tratamento farmacológico , Glioma/patologia , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Gerenciamento Clínico , Mutação , Terapia de Alvo MolecularRESUMO
PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Neoplasias Encefálicas , Carbamatos , Glioma , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Idoso , Resultado do Tratamento , Gradação de TumoresRESUMO
BACKGROUND AND OBJECTIVES: Oligodendrogliomas are defined by IDH1/2 mutation and codeletion of chromosome arms 1p/19q. Although previous studies identified CIC, FUBP1, and TERTp as frequently altered in oligodendrogliomas, the clinical relevance of these molecular signatures is unclear. Moreover, previous studies predominantly used research panels that are not readily available to providers and patients. Accordingly, we explore genomic alterations in molecularly defined oligodendrogliomas using clinically standardized next-generation sequencing (NGS) panels. METHODS: A retrospective single-center study evaluated adults with pathologically confirmed IDH-mutant, 1p/19q-codeleted oligodendrogliomas diagnosed between 2005 and 2021. Genetic data from formalin-fixed, paraffin-embedded specimens were analyzed with the NGS Solid Tumor Panel at the Johns Hopkins Medical Laboratories, which tests more than 400 cancer-related genes. Kaplan-Meier plots and log-rank tests compared progression-free survival (PFS) and overall survival by variant status. χ2 tests, t-tests, and Wilcoxon rank-sum tests were used to compare clinical characteristics between genomic variant status in the 10 most frequently altered genes. RESULTS: Two hundred and seventy-seven patients with molecularly defined oligodendrogliomas were identified, of which 95 patients had available NGS reports. Ten genes had 9 or more patients with a genomic alteration, with CIC, FUBP1, and TERTp being the most frequently altered genes (n = 60, 23, and 22, respectively). Kaplan-Meier curves showed that most genes were not associated with differences in PFS or overall survival. At earlier time points (PFS <100 months), CIC alterations conferred a reduction in PFS in patients (P = .038). CONCLUSION: Our study confirms the elevated frequency of CIC, FUBP1, and TERTp alterations in molecularly defined oligodendrogliomas and suggests a potential relationship of CIC alteration to PFS at earlier time points. Understanding these genomic variants may inform prognosis or therapeutic recommendations as NGS becomes routine.
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BRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF-mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF-mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAFV600E (Class I) and BRAF fusions in pediatric tumors. BRAFV600E alterations were associated with improved survival in adults with glioma overall, though not in glioblastoma. Other genomic alterations observed within functional classes were consistent with the putative roles of those BRAF mutation classes in glioma pathogenesis. In our adult cohort, BRAFV600E alterations conferred sensitivity to targeted therapies. Overall, this large cohort of BRAF-altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and survival.
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Background: Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Methods: Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Results: Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). Conclusion: While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.
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New or enlarged lesions in malignant gliomas after surgery and chemoradiation can be associated with tumor recurrence or treatment effect. Due to similar radiographic characteristics, conventional-and even some advanced MRI techniques-are limited in distinguishing these two pathologies. Amide proton transfer-weighted (APTw) MRI, a protein-based molecular imaging technique that does not require the administration of any exogenous contrast agent, was recently introduced into the clinical setting. In this study, we evaluated and compared the diagnostic performances of APTw MRI with several non-contrast-enhanced MRI sequences, such as diffusion-weighted imaging, susceptibility-weighted imaging, and pseudo-continuous arterial spin labeling. Thirty-nine scans from 28 glioma patients were obtained on a 3 T MRI scanner. A histogram analysis approach was employed to extract parameters from each tumor area. Statistically significant parameters (P < 0.05) were selected to train multivariate logistic regression models to evaluate the performance of MRI sequences. Multiple histogram parameters, particularly from APTw and pseudo-continuous arterial spin labeling images, demonstrated significant differences between treatment effect and recurrent tumor. The regression model trained on the combination of all significant histogram parameters achieved the best result (area under the curve = 0.89). We found that APTw images added value to other advanced MR images for the differentiation of treatment effect and tumor recurrence.
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Neoplasias Encefálicas , Glioma , Humanos , Prótons , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Amidas , Recidiva Local de Neoplasia/diagnóstico por imagem , Glioma/diagnóstico por imagem , Glioma/terapia , Imageamento por Ressonância Magnética/métodosRESUMO
It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.
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Neoplasias do Sistema Nervoso Central , Humanos , Reação em Cadeia da Polimerase/métodos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Técnicas de Amplificação de Ácido Nucleico , Elementos Nucleotídeos Curtos e Dispersos , Sistema Nervoso CentralRESUMO
INTRODUCTION: Outcomes for patients with high grade gliomas have changed little over the past thirty years. This realization prompted renewed efforts to increase flexibility in the design and conduct of clinical brain tumor trials. AREAS COVERED: This manuscript reviews the development of clinical trial methods, challenges and considerations of flexible clinical trial designs, approaches to improve identification and testing of active agents for high grade gliomas, and evaluation of their delivery to the central nervous system. EXPERT OPINION: Flexibility can be introduced in clinical trials in several ways. Flexible designs tout smaller sample sizes, adaptive modifications, fewer control arms, and inclusion of multiple arms in one study. Unfortunately, modifications in study designs cannot address two challenges that are largely responsible for the lack of progress in treating high grade gliomas: 1) the identification of active pharmaceutical agents and 2) the delivery of these agents to brain tumor tissue in therapeutic concentrations. To improve the outcomes of patients with high grade gliomas efforts must be focused on the pre-clinical screening of drugs for activity, the ability of these agents to achieve therapeutic concentrations in non-enhancing tumors, and a willingness to introduce novel compounds in minimally pre-treated patient populations.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioma/tratamento farmacológico , HumanosRESUMO
Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O6-methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.
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Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.