Michael Glantz

The assumption that metastases reach the brain by hematogenous spread informs concepts of pathogenesis and therapy in ways that may be incorrect and harmful. We suggest that the initial site of most CNS metastasis may be the CSF and that tumor cells then invade the brain parenchyma. We show that intraventricular (IT) chemotherapy can be expected to reach most brain metastases and thus has the potential to provide effective therapy. Two neuro-radiologists independently assessed whether brain metastases were contiguous to a CSF space in 200 consecutive patients using pre-treatment MRI scans. CSF was examined for malignant cells in 66 consecutive patients with brain metastases. We contoured the normal brain MRIs of 3 individuals to calculate the percentage of brain within 5 mm of a CSF space. Finally, we queried an international neoplastic meningitis registry for patients with both brain metastases and neoplastic meningitis to see whether we could document responses of brain metastases to IT chemotherapy alone. Mean age of the 200 patients was 64.2 (SD 13); 100 were male; 143 had lung cancer, 15 melanoma, 12 gastrointestinal, 11 breast, 9 renal, 7 bladder. The mean number of metastases was 4.63 (SD 6.26), and 85% of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. Neither histology, number or size of brain metastases predicted contiguity with a CSF space. In our consecutive subset of patients, 44% (10/23) with one, 46% (5/11) with two, 63% (5/8) with three, and 71% (17/24) with more than three metastases had malignant cells in the CSF (R2=0.93, p=0.037). In three patients (25, 57, and 67 years old), at least 48%, 75%, and 70% of all brain tissue lay within 5 mm of a CSF space. In 5 of 7 patients with both brain and CSF metastases who received only IT chemotherapy, a substantial reduction in the size of at least some metastases was documented. Our data suggest that brain metastases may access the CNS through the CSF rather than the bloodstream, and that the CSF acts as a protected site for tumor cells during systemic therapy. IT chemotherapy can enter this protected site and may reduce CNS relapses if used in addition to the standard of care. If corroborated by further study, we suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases, and that true cures for patients with brain metastases will require treatment of the CSF space.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults and is known for its invasive and aggressive behavior.^1,2 The optimal combination of medical, surgical, and radiation therapy for patients with GBM has yet to be defined, and the surgical component of therapy can range from a minimally invasive biopsy to a craniotomy with a goal of gross total resection (GTR).² Although the advent of 5-aminolevulinic acid–guided intraoperative techniques has increased the extent of resection (EOR) that is surgically possible, not every patient receives an aggressive resection.³ Moreover, variations in treatment protocols have done very little to extend survival, and fierce debate about this topic continues.^4-6 Although cytoreductive surgery is the cornerstone of therapy in GBM, no consensus exists regarding the optimal EOR necessary to improve survival.^4,7 Even prior meta-analyses on the subject of EOR and overall survival^2,8 have provided contradictory results.

Primary brain tumors constitute a substantial public health problem with 66,290 cases diagnosed in the US in 2012, and 13,700 deaths recorded. With discovery of genetic factors associated with specific brain tumor subtypes, the goal of therapy is changing from treating a class of tumors to developing individualized therapies catering to the molecular composition of the actual tumor. For oligodendrogliomas, the loss of 1p/19q due to an unbalanced translocation improves both survival and the response to therapy, and is thus both a prognostic and a predictive marker. Several additional genetic alterations such as EGFR amplification, MGMT methylation, PDGFR activation, and 9p and 10q loss, have improved our understanding of the characteristics of these tumors and may help guide therapy in the future. For astrocytic tumors, MGMT is associated with a better prognosis and an improved response to temozolomide, and for all glial tumors, mutations in the IDH1 gene are possibly the most potent of good prognostic markers. Three of these markers – 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene – are so potent that a new brain tumor subtype, the “triple negative” glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. Newer markers, such as CD 133, require additional investigation to determine their prognostic and predictive utility. In medulloblastomas, markers of WNT activation, MYCC/MCYN amplification, and TrkC expression levels are reliable prognostic indicators, but do not yet drive specific treatment selection. Many other proposed markers, such as 17q gain, TP53 mutations, and hMOF protein expression show promise, but are not yet ready for prime time. In this chapter, we focus on the markers that have shown convincing prognostic, predictive, and diagnostic value, and discuss potential markers that are being currently being intensively investigated. We also discuss serum profiling of tumors in an effort to discover additional potential markers.

2079 Background: Cerebrospinal fluid (CSF) is a valuable diagnostic tool in patients with cancer. Cytology, culture, glucose, and protein are the most routinely performed analyses of the CSF, however these tests are of questionable usefulness when not guided by clinical judgment. Methods: A retrospective analysis of the utility of CSF cytology was conducted. Assessment of the usefulness of this exam was based on the difference between the pre-test probability of disease and the post-test probability of disease, with a test being considered useful if it changed the probability of disease by a clinically informative degree. Patients without cancer (n=403), patients with known cancer without suspicion of neoplastic meningitis (n=41), and patients with known cancer and suspected neoplastic meningitis (n=81) were analyzed separately, and costs incurred by uninformative testing were estimated. Similar analyses were conducted for CSF culture, glucose, and protein exam. Results: The positive likelihood ratio (LR+) and negative likelihood ratio (LR-) for CSF cytology were >10⁶ and 0.33, respectively, in patients without known cancer. Since the prevalence (pre-test probability) of neoplastic meningitis (NM) in this cohort was already very low (0.7%), a negative test decreased the probability of NM to 0.2% (post-test probabilities). In patients with known cancer, +LR (24.3), LR- (0.29). A positive test increased the likelihood of NM from 15% to 81% and a negative test decreased the likelihood of NM to 5%. In patients with known cancer and suspected NM, +LR (> 10⁶ ) –LR (0.048). A positive test increased the likelihood of NM from 26% to 100% and a negative test decreased the likelihood of NM to 1.6%. The percentage of performed tests which were uninformative (true negative) were 99%, 80%, and 74% for a total cost of $110,432. Similar calculations for utility and cost were applied to CSF culture, glucose, and protein. Conclusions: In patients without known cancer, routine CSF cytology is uninformative, inefficient, and costly. In patients with known cancer but without suspicion of NM, routine CSF cytology is more informative and cost effective, but in patients with known cancer and suspected NM, CSF cytology is most informative, and its routine use can be justified.

2071 Background: Neoplastic meningitis is a devastating and increasingly frequent complication of solid tumor, hematologic, and primary brain cancers. Early diagnosis and intervention may prevent neurologic morbidity and prolong survival, but is hampered by the poor sensitivity (40-60%) of CSF cytology, the current diagnostic gold standard. Methods: A retrospective chart and imaging review was performed on 21 patients with known cancer and suspected neoplastic meningitis who underwent ventricular MRS. For each patient, basic demographic data, tumor histology, conventional MRI, CSF cytology, and CSF laboratory results, type of tumor-directed therapy, clinical and cytologic response, and survival were collected. Ventricular MRS was reviewed by an independent neuro-radiologist blinded to clinical, CSF cytology and conventional MRI imaging results. Results: 71% patients were male. Median age was 65 (range 37-79). Tumor types included glioblastoma (7), DLBCL (3), Melanoma (3), breast, SCLC, NSCLC, renal cancer, rectal cancer (1 each) and other (3). CSF lactate by MRS had a sensitivity of 93% a specificity of 71%, a positive likelihood ration (LR +) of 3.3 a negative LR of 0.1, and substantial agreement (kappa = 0.67) compared with CSF cytology. One patient with a false positive ventricular MRS result developed a positive CSF cytology three weeks after ventricular MRS. If this patient was considered a true positive MRS result, the sensitivity (93%), specificity (83%), LR+ (5.6) LR- (0.08), and kappa statistic (0.77) all improve. If 19% of patients with cancer who develop a new neurologic finding actually have neoplastic meningitis (Glass 1979), a positive MRS result increases this likelihood to 57% while a negative MRS decreases this likelihood to 1.8%. Conclusions: Measurement of the ventricular lactate level in cancer patients using MRS is a sensitive and non-invasive diagnostic technique which may supplement or even supplant CSF cytology, and may be particularly valuable as a screening tool in patients at high risk for developing neoplastic meningitis (for example, patients with ALL, high-risk NHL, and triple negative breast cancer).

The spread of cancer into the central nervous system is a serious problem leading to neurological symptoms and rapid mortality. The current tools available for detecting the spread of cancer into the cerebrospinal fluid (CSF) are cytology, neurologic examination, and neuroimaging. All three of these methods can be applied in concert to reach a diagnosis, but they all suffer from a lack of sensitivity, leading to delays in treatment in many cases. An overview of research tools in the field of CSF cancer detection reveals a variety of promising technologies that can be used to answer questions about the biology of metastatic cancer and to develop more powerful clinical detection methods. Methods currently under investigation include new immunocytochemistry methods and flow cytometry for thein vitrodetection of cells. Additionally, polymerase chain reaction, fluorescencein situhybridization, capillary electrophoresis with laser-induced fluorescence, and mass spectrometry using matrix-assisted laser absorption-deionization time-of-flight and surface-enhanced laser desorption/ionization time-of-flight techniques are being tested forin vitroassessment of the non-cellular biomarkers in CSF. Forin vivodetection of cancer in the CSF, research techniques include certain quantum dot platforms as well as magnetic iron oxide nanoparticles. As systemic therapies for cancer improve, the CNS is becoming a more common site of disease recurrence. This increases the importance of effective detection methods in the CSF, since early intervention can maximize therapeutic benefit. Furthermore, many cell-based detection methods can be combined with therapeutic agents to serve multiple medical functions through a common targeting system.