Andrew E. Sloan

Incidence Proportions of Brain Metastases in Patients Diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System

PURPOSE Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer. PATIENTS AND METHODS Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs. RESULTS Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites. CONCLUSION Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.

Systematic Review of the Diagnosis and Management of Malignant Extradural Spinal Cord Compression: The Cancer Care Ontario Practice Guidelines Initiative‘s Neuro-Oncology Disease Site Group

Purpose This systematic review describes the diagnosis and management of adult patients with a suspected or confirmed diagnosis of extradural malignant spinal cord compression (MSCC). Methods MEDLINE, CANCERLIT, and the Cochrane Library databases were searched to January 2004 using the following terms: spinal cord compression, nerve compression syndromes, spinal cord neoplasms, clinical trial, meta-analysis, and systematic review. Results Symptoms for MSCC include sensory changes, autonomic dysfunction, and back pain; however, back pain was not predictive of MSCC. The sensitivity and specificity for magnetic resonance imaging (MRI) range from 0.44 to 0.93 and 0.90 to 0.98, respectively, in the diagnosis of MSCC. The sensitivity and specificity for myelography range from 0.71 to 0.97 and 0.88 to 1.00, respectively. A randomized study detected higher ambulation rates in patients with MSCC who received high-dose dexamethasone before radiotherapy (RT) compared with patients who did not receive corticosteroids...

Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: An in vitro study

OBJECTIVE:Dependence on glycolysis is a hallmark of malignant tumors. As a consequence, these tumors generate more lactate, which is effluxed from cells by monocarboxylate transporters (MCTs). We hypothesized that 1) MCT expression in malignant tumors may differ from normal tissue in quantity, isoform, or both; and 2) silencing MCT expression would induce intracellular acidification, resulting in decreased proliferation and/or increased cell death. METHODS:We quantified expression of MCT isoforms in human glioblastoma multiforme and glioma-derived cells lines by Western blot analysis. MCTs that were abundant or specific to glioma then were targeted in the model U-87 MG glioma cell line via small interfering ribonucleic acid-mediated gene silencing and tested for inhibition of lactate efflux, intracellular pH changes, reduced proliferation, and/or induction of cell death. RESULTS:MCT 1 and 2 were the primary isoforms expressed in human glioblastoma multiforme and glioma-derived cell lines. In contrast, MCT 3 was the predominantly expressed isoform in normal brain. Small interfering ribonucleic acid specific for MCT 1 and 2 reduced expression of these isoforms in U-87 MG cells to barely detectable levels and reduced lactate efflux by 30% individually and 85% in combination, with a concomitant decrease of intracellular pH by 0.6 units (a fourfold increase in intracellular H+). Prolonged silencing of both MCTs reduced viability by 75% individually and 92% in combination, as measured by both phenotypic and flow cytometric analyses. CONCLUSION:MCT targeting significantly reduced the viability of U-87 MG cells mediated by both apoptosis and necrosis. This indicates that the strategy may be a useful therapeutic avenue for treatment of patients with malignant glioma.

Gliosarcoma with multiple extracranial metastases: case report and review of the literature

Gliosarcoma is a rare malignant neoplasm of the central nervous system with a propensity for metastasis. There are fewer than 20 reported cases of extracranial metastases of gliosarcoma with the majority of cases reflecting a tendency for hematogenous dissemination. Here we describe the case of a 47-year-old man who developed pervasive extracranial metastases from a temporal gliosarcoma following radio- and chemotherapy for a primary glioblastoma. The patient initially presented with progressively worsening headaches, left-sided weakness and numbness associated with right temporo-parietal mass for which he underwent craniotomy with stereotactic gross-total excision. Two months postoperatively, interstitial brachytherapy and external beam radiotherapy were initiated. The patient initially declined chemotherapy. The tumor recurred twice and the patient underwent re-operation and multiple courses of chemotherapy; histopathological diagnosis remained glioblastoma multiforme. Nineteen months following initial resection the patient’s clinical status deteriorated and CT scan demonstrated multiple intrathoracic, hepatic and splenic lesions. Postmortem examination revealed widespread, infiltrating gliosarcoma with intravascular gliomatosis and extensive visceral metastases. This is the first report of pervasive extracranial metastases to numersous sites, several of which have not been previously reported. The histogenesis and the potential role of therapeutic irradiation in the development of gliosarcoma are briefly reviewed.

In vitro drug response and molecular markers associated with drug resistance in malignant gliomas

Purpose: Drug resistance in malignant gliomas contributes to poor clinical outcomes. We determined the in vitro drug response profiles for 478 biopsy specimens from patients with the following malignant glial histologies: astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma multiforme (n = 259), oligodendroglioma (n = 40), and glioma (n = 69). Experimental Design: Samples were tested for drug resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine, paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug resistance were detected by immunohistochemistry, including multidrug resistance gene-1, glutathione S-transferase π (GSTP1), O6-methylguanine-DNA methyltransferase (MGMT), and mutant p53. Results:In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance. Conclusions: Assessment of in vitro drug response and profiles of relevant tumor-associated biomarkers may assist the clinician in stratifying patient treatment regimens.

Metabolic Remodeling of Malignant Gliomas for Enhanced Sensitization during Radiotherapy: An In Vitro Study

OBJECTIVE: To investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. 1H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death. METHODS: We inhibited lactate transport in U87-MG gliomas with α-cyano-4-hydroxycinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays. RESULTS: MRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death. CONCLUSION: Inhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radioand chemotherapeutic regimen.OBJECTIVETo investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. 1H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death. METHODSWe inhibited lactate transport in U87-MG gliomas with α-cyano-4-hydroxycinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays. RESULTSMRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death. CONCLUSIONInhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radio- and chemotherapeutic regimen.

Relationship of gliomas to the ventricular walls

The role of neural stem cells in gliomagenesis remains controversial. The aim of this study was to determine the anatomic relationship of human gliomas to the lining of the ventricular walls, known as the subventricular zone, an area replete with neural stem cells. We performed a retrospective radiographic analysis of 100 consecutive patients with gliomas and sought to determine the relationship of the lesions to the ventricular walls as seen on their MRI scans. Our results indicated that in 93% of cases the lesions contacted at least one region of the lateral ventricular wall. Contact with the ventricular wall was independent of the glioma size or mass effect. These findings were correlated to cytoarchitectural studies of the human subventricular zone. Our findings lend further support that there is an intimate association between gliomas and the subventricular zone.

Clinical trial participation among patients enrolled in the Glioma Outcomes Project

Patient participation in well‐designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi‐institutional registry of patients with malignant glioma.

RNAi based approaches to the treatment of malignant glioma.

RNA interference (RNAi) is a recently discovered, powerful molecular mechanism that can be harnessed to engineer gene-specific silencing in mammalian tissues. A mechanism, where short double-stranded RNA (dsRNA) molecules, when introduced into cells elicit specific “knock-down” of gene expression via degradation of targeted messenger RNA, has lately become the technique of choice for analysis of gene function in oncology research. Thus, RNAi is currently being extensively evaluated as a potential therapeutic strategy against malignant gliomas, since surgical, radiological, and chemotherapeutic interventions during the past few decades have done little to improve the poor prognosis rate for patients with these dreaded tumors. This review summarizes the pre-clinical studies that are currently underway to test the validity of RNAi as a potential therapeutic strategy against malignant gliomas, and discusses the potential technical Hurdles that remain to be overcome before the technique can become a promising clinical therapy to combat this frequently lethal disease.

Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: In vitro induction of cytolytic and natural killer-like T cells

OBJECTIVE: To compare the efficacy of various immunotherapeutic strategies of loading dendritic cells (DCs) with whole-glioma cell antigens and characterize the effector responses induced. METHODS: DCs were either fused with major histocompatibility complex (MHC)-matched glioma cells (Fusion) or pulsed with apoptotic tumor cells (DC/Apo), total tumor ribonucleic acid (RNA) (DC/RNA), or tumor lysate (DC/Lys). These tumor-DC preparations were then assessed for their phenotype, cytokine profile, and capacity to stimulate autologous peripheral blood mononuclear cells (PBMCs) in vitro. Phenotype and tumor-specific cytolytic activities of various effector cell populations were characterized and compared. RESULTS: The various tumor-DC preparations exhibited similar phenotype and cytokine profiles irrespective of the method of loading tumor-cell antigens. However, the fusion, DC/Apo, and DC/RNA induced superior tumor cytolytic activities in PBMCs compared with DC/Lys or DC and tumor controls. DC/Apo induced the greatest expansion of tumor-specific lymphocytes, as detected by trypan blue exclusion and thymidine incorporation assays. Flow cytometric analyses also revealed the highest relative percentages of T helper cells (CD3+CD4+), cytotoxic T lymphocytes (CTLs) (CD3+CD8+), and natural killer (NK)-like T cells (CD3+CD56+) in the DC/Apo group among all the groups studied, indicating that DC/Apo induced expansion of PBMCs bearing multiple T and NK cell markers. Interestingly, isolated NK-like T cells demonstrated significantly higher tumor cytotoxicity compared with CTLs isolated from the same groups and was also non-MHC-restricted. CONCLUSION: Apoptotic tumor cells may be an optimal source of whole-tumor-cell antigen for immunotherapy of gliomas. The study also demonstrates for the first time that both CTLs and NK-like T cells are expanded and stimulated by mature, tumor-pulsed DCs.