Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of ...limited access to tumor tissue.
We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
Abstract
BACKGROUND
Thalamic glioblastomas (GBMs) represent a significant neurosurgical challenge. In view of the low incidence of these tumors, outcome data and management strategies are not well ...defined.
OBJECTIVE
To identify the natural history and factors associated with survival in patients with thalamic glioblastoma.
METHODS
A retrospective review of all patients with thalamic glioblastoma over a 10-yr period was performed. Presenting clinical, radiological, and outcome data were collected. Chi-squared and Fisher's exact tests were used to compare clinical characteristics across tumor groups. Cox proportional hazard models were utilized to investigate variables of interest with regard to overall survival.
RESULTS
Fifty-seven patients met inclusion criteria, with a median age of 53 and median Karnofsky Performance Scale (KPS) score of 80. The most common presenting symptoms were weakness, confusion, and headache. Hydrocephalus was present in 47% of patients preoperatively. Stereotactic biopsy was performed in 47 cases, and 10 patients underwent craniotomy. The median overall survival was 12.2 mo. Higher KPS, younger age, and cerebrospinal fluid (CSF) diversion were correlated with better overall survival univariately, respectively, while the presence of language deficits at initial presentation was associated with poorer survival. In multivariate analysis, the only significant predictor of survival was presenting KPS.
CONCLUSION
The overall survival of patients with thalamic glioblastoma is comparable to unresectable lobar supratentorial GBMs. Younger patients and those with good presenting functional status had improved survival. Midbrain involvement by the tumor is not a negative prognostic factor. Improved therapies are needed, and patients should be considered for early trial involvement and aggressive upfront therapy.
Abstract only Introduction: Intracardiac myxomas are associated with cardiovascular mortality most frequently due to embolism and obstruction leading to heart failure. One of the most feared ...complications of intracardiac myxomas are sudden cardiac death, as these tumors are often identified incidentally. Carney Complex (CNC) is a rare disorder characterized by cardiac myxomas, psammomatous melanotic schwannomas, abnormal skin pigmentation, and endocrine disorders. Clinical Case: A 55 year old female with a past medical history of hypertension presented to the hospital with syncopal episodes and intermittent vision loss. Head computed tomography scan noted a large extra-axial mass present within the left cerebellopontine angle. A transthoracic echocardiogram showed a severely dilated left atria containing a large atrial mass (7.9 x 5.0 cm) that was causing obstruction of mitral inflow resulting in peak velocity 246 cm/S with a mean gradient of 12 mmHg. The patient was also noted to have dispersed epithelioid blue nevi present on skin examination. The patient met major criteria for diagnosis of Carney Complex. Conclusion: Carney complex (CNC) is an extremely rare autosomal dominant syndrome with less than 1,000 cases reported worldwide. Patients with familial history of intracardiac myxomas, multiple myxomas, characteristic skin findings, or endocrinopathies should be evaluated for CNC. Patients with cardiac myxoma secondary to CNC typically have a recurrence risk of roughly 30%. Patients with CNC should be screened with biannual transthoracic echocardiograms after resection and patients with suspected CNC should be worked up for additional tumor burden and endocrinopathies.
Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as ...lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy
, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease
. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging
, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost
. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2
, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.
Neoplastic spinal instability is movement-related pain or neurologic compromise under physiologic loads with the Spinal Instability Neoplastic Score (SINS) developed to facilitate diagnosis. There is ...a paucity of evidence that mechanical instability correlates with patient-reported symptoms and that surgical stabilization significantly improves these patient-reported outcomes (PROs).
The objective of this study was to determine if SINS correlates with patient-reported preoperative pain and disability, and if surgical stabilization significantly improves PRO.
A single-institution prospective cohort study was carried out.
A total of 131 patients who underwent stabilization for metastatic spinal tumor treatment between July 2014 and August 2016 were included.
Preoperative baseline and mean difference in perioperative PROs as assessed by the Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory (MDASI) were the outcome measures.
The SINS was analyzed as a continuous, ordinal, and categorical variable (Stable: 0–6, Indeterminate: 7–12, Unstable: 13–18). Statistical analysis was performed using Spearman rank coefficient (rho), the Kruskal-Wallis test, and an extension of the Cochran-Armitage trend test. The SINS and association between the mean differences in post- and preoperative PRO scores was analyzed using the Wilcoxon signed-rank test.
There was a statistically significant positive correlation between increasing SINS and severity of preoperative pain with BPI average pain (rho=0.20; p=.03) and MDASI pain (rho=0.19; p=.03). Increasing SINS correlated with severity of preoperative disability with BPI walking (rho=0.19; p=.04), MDASI activity (rho=0.24; p=.006), and MDASI walking (rho=0.20; p=.03). Similar associations were noted when SINS was analyzed as an ordinal categorical variable. Stabilization significantly improved nearly all PRO measures for patients with indeterminate and unstable SINS. Significant correlations persisted when controlling for neurologic status and were not affected based on the technique of surgical stabilization used.
Patient-related outcome-based validation of SINS confirms this scoring system for diagnosing neoplastic spinal instability and provides surgeons with a tool to determine which patients will benefit from stabilization. Surgical stabilization of cancer patients with SINS consistent with mechanical instability provides significant reduction in pain and improves patient mobility independent of neurologic status and stabilization technique.
Abstract
Background
Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted ...therapies have altered disease management. A barrier to formal study of these therapies in LM is quantification of disease burden. Also, outcomes of patients with targetable mutations in LC-LM are not well defined. This study employs molecular and radiographic measures of LM disease burden and correlates these with outcome.
Methods
We reviewed charts of 171 patients with LC-LM treated at Memorial Sloan Kettering. A subset had MRI and CSF studies available. Radiographic involvement (n = 76) was scored by number of gadolinium-enhancing sites in 8 locations. CSF studies included cytopathology, circulating tumor cell (CTC) quantification (n = 16), and cell-free DNA (cfDNA) analysis (n = 21). Clinical outcomes were compared with Kaplan–Meier log-rank test and Cox proportional hazards methodologies.
Results
Median overall survival was 4.2 months (95% CI: 3.6–4.9); 84 patients (49%) harbored targetable mutations. Among bevacizumab-naïve patients with MRI and CSF cytology at time of LC-LM diagnosis, extent of radiographic involvement correlated with risk of death (hazard ratio HR: 1.16; 95% CI: 1.02–1.33; P = 0.03), as did CSF CTC (HR: 3.39, 95% CI: 1.01–11.37; P = 0.048) and CSF cfDNA concentration (HR: 2.58; 95% CI: 0.94–7.05; P = 0.06). Those without a targetable mutation were almost 50% more likely to die (HR: 1.49; 95% CI: 1.06–2.11; P = 0.02).
Conclusions
Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and staging for clinical management, prognostication, and clinical trial stratification of LC-LM.
Abstract
BACKGROUND
Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted ...therapies have altered disease management. In this new era, outcomes of patients with LC-LM are not well-defined. This study identifies molecular and radiographic characteristics of LC-LM correlating with clinical outcome.
METHODS
We retrospectively reviewed charts of 171 patients with LC-LM between 6/2009 and 6/2017 at Memorial Sloan-Kettering Cancer Center. Presence of targetable mutations (TM) was determined by targeted exome sequencing (MSKCC IMPACT). Radiographic involvement was scored by number of gadolinium-enhancing sites in eight locations. CSF studies included cytopathology, quantification of circulating tumor cells (CTCs), and cell free DNA (cfDNA) analysis. Kaplan-Meier survival curves were compared by log-rank analyses.
RESULTS
Median overall survival after LC-LM diagnosis was 4.2 months; 84 patients (49%) harbored TM. Patients who received targeted therapy (Ttx) after LC-LM diagnosis demonstrated reduced hazard of death (HR:0.63; 95% CI:0.45–0.89; p=0.008). This trend was reversed for those receiving Ttx prior to LC-LM (HR:2.46; 95% CI:1.42–4.26; p-value: 0.001). A subset of 93 patients underwent MRI brain, spine and CSF cytology within 30 days of LC-LM diagnosis. Extent of radiographic involvement (3 or more sites vs. 2 or less sites) correlated with OS: (HR:1.56; 95% CI:0.96–2.54; p=0.075). Enumeration of CSF CTCs at diagnosis from 16 patients revealed that greater than 50 CTCs/3mL increased hazard of death (HR:3.66; 95% CI:1.195–11.22; p=0.02). Similarly, elevated ctDNA concentration in CSF was inversely correlated with survival in 21 patients (HR:2.74; 95% CI:1.01–7; p=0.02). CONCLUSIONS: In this largest study of LC-LM, presence of TM and Ttx for LC-LM was associated with improved survival. Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and CNS staging for clinical management, prognostication and clinical trial stratification of LC-LM.
Abstract
While the genomic landscape of low- and high-grade gliomas has been characterized and incorporated into further disease classification, its relationship to disease progression and treatment ...response remains poorly understood. To address this question, we integrated prospective clinical sequencing of 1,007 primary and recurrent tumors from 924 glioma patients with clinical and treatment phenotypes. Genomic alterations in effectors of cell cycle progression were a biomarker of aggressive disease in 1p19q intact IDH-mutant disease, arising preferentially in enhancing and recurrent tumors. When present at recurrence, the lesions were associated with rapid disease progression. These alterations were also present in all astrocytic tumors that ultimately relapsed with alkylating therapy-associated hypermutation. Analysis of matched pre-treatment and post-progression tumors indicated that cell cycle alterations preceded the emergence of hypermutation. In total, 391 patients (42%) harbored a potentially therapeutically actionable lesion in their tumor of which 73 patients (19%) received a diversity of targeted therapies. Both the type of mutation and its clonality were associated with therapeutic sensitivity in this cohort. For instance, RAF dimer-dependent BRAF hotspot mutations arose predominantly in IDH-wildtype glioblastomas, were subclonal, and affected patients did not respond to MAPK-directed therapy. In contrast, BRAF V600 hotspot mutations arose clonally in histologically distinct gliomas, both low- and high-grade, and responded to MAPK-directed therapy (either RAF, MEK or ERK inhibition). Collectively, these data reveal previously unrecognized genomic determinants of disease progression and treatment response in diverse types of glioma and serve as a rationale for utilizing genomic information in clinical care of patients with glioma.
Citation Format: Philip Jonsson, Andrew L. Lin, Shahiba L. Ogilvie, Shweta S. Chavan, Andrew T. McKeown, Natalie M. DiStefano, Marc Rosenblum, Lisa M. DeAngelis, Ingo K. Mellinghoff, Barry S. Taylor. Genomic determinants of progression and response to therapy in prospectively characterized glioma patients abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2621.
OBJECTIVE The aim of this study was to evaluate the safety and efficacy of kyphoplasty treatment prior to spine stereotactic radiosurgery (SRS) in patients with spine metastases. METHODS A ...retrospective review of charts, radiology reports, and images was performed for all patients who received SRS (single fraction; either standalone or post-kyphoplasty) at a large tertiary cancer center between January 2012 and July 2015. Patient and tumor variables were documented, as well as treatment planning data and dosimetry. To measure the photon scatter due to polymethyl methacrylate, megavolt photon beam attenuation was determined experimentally as it passed through a kyphoplasty cement phantom. Corrected electron density values were recalculated and compared with uncorrected values. RESULTS Of 192 treatment levels in 164 unique patients who underwent single-fraction SRS, 17 (8.8%) were treated with kyphoplasty prior to radiation delivery to the index level. The median time from kyphoplasty to SRS was 22 days. Four of 192 treatments (2%) demonstrated local tumor recurrence or progression at the time of analysis. Of the 4 local failures, 1 patient had kyphoplasty prior to SRS. This recurrence occurred 18 months after SRS in the setting of widespread systemic disease and spinal tumor progression. Dosimetric review demonstrated a lower than average treatment dose for this case compared with the rest of the cohort. There were no significant differences in dosimetry analysis between the group of patients who underwent kyphoplasty prior to SRS and the remaining patients in the cohort. A preliminary analysis of polymethyl methacrylate showed that dosimetric errors due to uncorrected electron density values were insignificant. CONCLUSIONS In cases without epidural spinal cord compression, stabilization with cement augmentation prior to SRS is safe and does not alter the efficacy of the radiation or preclude physicians from adhering to SRS planning and contouring guidelines.
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