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1.
Curr Opin Neurol ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577604

RESUMO

PURPOSE OF REVIEW: Median survival after the diagnosis of brain metastases has historically been on the order of months. With the recent development of immune checkpoint inhibitors, intracranial activity and durable responses have been observed in brain metastases on multiple phase 2 clinical trials, which have primarily been conducted in patients with melanoma. Immune-related adverse events related to checkpoint inhibitor therapy of brain metastasis can present unique challenges for the clinician and underscore the need for a multidisciplinary team in the care of these patients. The goal of this review is to address the current knowledge, limitations of understanding, and future directions in research regarding immune therapy trials and neurologic toxicities based on retrospective, prospective, and case studies. RECENT FINDINGS: Immune therapy has the potential to exacerbate symptomatic edema and increase the risk of radiation necrosis in previously irradiated lesions. Neurologic toxicities will likely increase in prevalence as more patients with brain metastatic disease are eligible for immune therapy. SUMMARY: An improved understanding and heightened awareness of the unique neurologic toxicities that impact this patient group is vital for mitigating treatment-related morbidity and mortality.

3.
J Neurooncol ; 144(3): 553-562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377920

RESUMO

INTRODUCTION: The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT. METHODS: PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals. RESULTS: Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL. CONCLUSIONS: Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

4.
Clin Cancer Res ; 25(18): 5537-5547, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31263031

RESUMO

PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

5.
BMC Med Genomics ; 12(1): 56, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023376

RESUMO

BACKGROUND: Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians. METHODS: A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions. RESULTS: WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time. CONCLUSION: These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.

6.
J Clin Oncol ; 37(9): 741-750, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30715997

RESUMO

PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

7.
Nat Genet ; 51(2): 202-206, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643254

RESUMO

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.


Assuntos
Mutação/genética , Neoplasias/genética , Neoplasias/terapia , Antineoplásicos/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Carga Tumoral/genética , Carga Tumoral/imunologia
8.
Am J Hematol ; 94(4): 455-460, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30663807

RESUMO

Primary vitreoretinal lymphoma (PVRL) is a subset of primary CNS lymphoma that presents as isolated ocular disease without brain involvement. Although ocular radiotherapy (RT) is an effective treatment for PVRL, the optimal treatment is uncertain. PVRL may later involve the brain in 56%-85% of patients. We report on 12 PVRL patients treated with a combination of bilateral RT and a systemic chemotherapy (CT) regimen containing high-dose methotrexate (M). Ten received RT (30-40 Gy) followed by CT, one received RT, and one was treated with intravitreal M; all achieved a complete response (CR). Three patients had tumor recurrence in the brain and received CT and one patient relapsed in the eye with a second recurrence in the brain. Three patients achieved CR-2 remain alive and one died of dementia. One died from recurrent CNS disease. With a median follow of 68 months (range, 17-154 months), median progression-free and overall survival have not been reached. Bilateral RT followed by M-based CT is an effective treatment for reducing CNS progression and prolonging survival.

9.
Clin Cancer Res ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487127

RESUMO

PURPOSE: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume, tumor cell volume fraction and tumor cell kill, as derived from tissue sodium concentration measured by quantitative sodium magnetic resonance imaging at 3 Tesla. These near real-time patterns during treatment are compared with overall survival. EXPERIMENTAL DESIGN: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n=20) using tissue sodium concentration obtained from serial quantitative sodium magnetic resonance imaging at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared to times to disease progression and survival. RESULTS: Residual tumor volume following tumor resection showed decreased cell volume fraction due to disruption of normal cell packing by edema and infiltrating tumor cells. Cell volume fraction showed either increases back towards normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time to progression or overall survival. CONCLUSIONS: These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available.

10.
Blood ; 132(21): 2240-2248, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30262659

RESUMO

The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

11.
J Clin Oncol ; 36(17): 1702-1709, 2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-29683790

RESUMO

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.

12.
CNS Oncol ; 7(1): 7-13, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29388793

RESUMO

Interpretation of MRI abnormalities in patients with malignant gliomas (MG) treated with bevacizumab is challenging. Recent reports describe quantitative analyses of diffusion-weighted imaging abnormalities not available in standard clinical settings, to differentiate tumor recurrence from treatment necrosis. We retrospectively reviewed bevacizumab treated MG patients who underwent surgery or autopsy to correlate radiographic recurrence patterns with pathologic findings. 32 patients with MG (26 glioblastoma, three anaplastic astrocytoma and three anaplastic oligodendroglioma) were identified. Recurrence patterns: local enhancing (n = 23), distant enhancing (n = 1), nonenhancing (n = 7) and leptomeningeal (n = 1). HISTOLOGY: tumor (n = 25), mixed tumor/necrosis (n = 5) and all necrosis (n = 2). On diffusion-weighted imaging, 5/32 had restricted diffusion (three mixed and two necrosis). Irrespective of radiographic recurrence pattern, tumor was found in 94% of cases. Restricted diffusion correlated with necrosis.

13.
Radiology ; 287(2): 667-675, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29388903

RESUMO

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.


Assuntos
Radioisótopos de Flúor/farmacocinética , Glutamina/análogos & derivados , Glutamina/metabolismo , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica , Feminino , Radioisótopos de Flúor/metabolismo , Glutamina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Distribuição Tecidual/efeitos dos fármacos , Estados Unidos , United States Food and Drug Administration
14.
Neuro Oncol ; 20(5): 674-686, 2018 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-29106665

RESUMO

Background: Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported. Methods: Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm. Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients. Conclusions: Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

15.
Curr Med Res Opin ; 34(5): 813-820, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29025274

RESUMO

OBJECTIVE: Glioblastoma (GBM) is an aggressive disease with limited therapeutic options. While bevacizumab was approved in 2009 for the treatment of patients with progressive GBM, its impact on overall survival (OS) remains unclear. Using US population-based cancer registry data (SEER), this study compared OS of patients diagnosed with GBM before and after bevacizumab approval. METHODS: Adult patients from SEER with a GBM diagnosis were divided into two cohorts: patients diagnosed in 2006-2008 (pre-bevacizumab cohort, n = 6,120) and patients diagnosed in 2010-2012 (post-bevacizumab cohort, n = 6,753). Patients were included irrespective of the treatments received. OS post-diagnosis was compared between the study cohorts utilizing Kaplan-Meier analyses and multivariate Cox proportional hazards regression. RESULTS: Among 12,873 patients with GBM, the median age was 62 years, 41% were women, 31% underwent gross total resection, and 75% received radiation therapy. Survival was stable within the 2006-2008 period (median survival = 9 months for each year), but increased after year 2009 (median survival = 10 and 11 months for years 2010/2011 and 2012, respectively). The adjusted hazard of death was significantly lower in the post-bevacizumab approval cohort (hazard ratio = 0.91, p < .01). CONCLUSIONS: The results of this large population-based study suggested an improvement in OS among patients with a GBM diagnosis in 2010-2012 compared to 2006-2008. While the cause of this improvement cannot be proven in a retrospective analysis, the timing of the survival increase coincides with the approval of bevacizumab for the treatment of patients with progressive GBM, indicating a possible benefit of bevacizumab in this population.

16.
JCO Precis Oncol ; 20172017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28890946

RESUMO

PURPOSE: With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS: OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS: To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION: OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

17.
Int J Radiat Oncol Biol Phys ; 99(4): 797-804, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28870792

RESUMO

PURPOSE: To establish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas. METHODS AND MATERIALS: Patients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40 cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy per fraction. RESULTS: A total of 3 patients were enrolled at the 9 Gy × 3 dose level cohort, 5 in the 10 Gy × 3 cohort, and 7 in the 11 Gy × 3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11 Gy × 3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13 months. CONCLUSIONS: Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11 Gy × 3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy × 5 schedule. Promising overall survival warrants further investigation.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Astrocitoma/radioterapia , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Recidiva Local de Neoplasia/radioterapia , Radiocirurgia/métodos , Idoso , Astrocitoma/tratamento farmacológico , Astrocitoma/mortalidade , Astrocitoma/patologia , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Análise de Intenção de Tratamento , Avaliação de Estado de Karnofsky , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Órgãos em Risco/efeitos da radiação , Estudos Prospectivos , Hipofracionamento da Dose de Radiação , Reirradiação , Carga Tumoral
18.
Neuro Oncol ; 19(9): 1248-1254, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28821205

RESUMO

Background: Diagnosis of leptomeningeal metastasis (LM) remains challenging due to low sensitivity of CSF cytology and infrequent unequivocal MRI findings. In a previous pilot study, we showed that rare cell capture technology (RCCT) could be used to detect circulating tumor cells (CTC) in the CSF of patients with LM from epithelial tumors. To establish the diagnostic accuracy of CSF-CTC in the diagnosis of LM, we applied this technique in a distinct, larger cohort of patients. Methods: In this institutional review board-approved prospective study, patients with epithelial tumors and clinical suspicion of LM underwent CSF-CTC evaluation and standard MRI and CSF cytology examination. CSF-CTC enumeration was performed through an FDA-approved epithelial cell adhesion molecule-based RCCT immunomagnetic platform. LM was defined by either positive CSF cytology or imaging positive for LM. ROC analysis was utilized to define an optimal cutoff for CSF-CTC enumeration. Results: Ninety-five patients were enrolled (36 breast, 31 lung, 28 others). LM was diagnosed in 30 patients (32%) based on CSF cytology (n = 12), MRI findings (n = 2), or both (n = 16). CSF-CTC were detected in 43/95 samples (median 19.3 CSF-CTC/mL, range 0.3 to 66.7). Based on ROC analysis, 1 CSF-CTC/mL provided the best threshold to diagnose LM, achieving a sensitivity of 93%, specificity of 95%, positive predictive value 90%, and negative predictive value 97%. Conclusions: We defined ≥1 CSF-CTC/mL as the optimal cutoff for diagnosis of LM. CSF-CTC enumeration through RCCT is a robust tool to diagnose LM and should be considered in the routine LM workup in solid tumor patients.


Assuntos
Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/diagnóstico , Metástase Neoplásica/diagnóstico , Neoplasias Epiteliais e Glandulares/secundário , Células Neoplásicas Circulantes , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Cancer Discov ; 7(9): 1018-1029, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28619981

RESUMO

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Proteínas Adaptadoras de Sinalização CARD/genética , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Guanilato Ciclase/genética , Humanos , Linfoma de Células B/sangue , Linfoma de Células B/líquido cefalorraquidiano , Linfoma de Células B/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
20.
Neuro Oncol ; 19(10): 1380-1390, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472509

RESUMO

Background: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy. Methods: Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3.2 mg/kg/day × 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing. Results: Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors. Conclusions: TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017, accessed 6 January 2017. Clinicaltrials.gov registry: NCT00588523.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamento farmacológico , Adulto , Idoso , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Isocitrato Desidrogenase/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Oligodendroglioma/terapia , Transplante de Células-Tronco , Temozolomida , Transplante Autólogo
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