Marcus L. Ware

Diffusion tensor imaging with three-dimensional fiber tractography of traumatic axonal shearing injury: an imaging correlate for the posterior callosal "disconnection" syndrome: case report.

OBJECTIVE:To demonstrate that magnetic resonance diffusion tensor imaging (DTI) with three-dimensional (3-D) fiber tractography can visualize traumatic axonal shearing injury that results in posterior callosal disconnection syndrome. METHODS:A 22-year-old man underwent serial magnetic resonance imaging 3 days and 12 weeks after blunt head injury. The magnetic resonance images included whole-brain DTI acquired with a single-shot spin echo echoplanar sequence. 3-D DTI fiber tractography of the splenium of the corpus callosum was performed. Quantitative DTI parameters, including apparent diffusion coefficient and fractional anisotropy, from the site of splenial injury were compared with those of a normal adult male volunteer. RESULTS:Conventional magnetic resonance images revealed findings of diffuse axonal injury, including a lesion at the midline of the splenium of the corpus callosum. DTI performed 3 days posttrauma revealed that the splenial lesion had reduced apparent diffusion coefficient and fractional anisotropy, reflecting a large decrease in the magnitude of diffusion parallel to the white matter fibers, which had partially recovered as revealed by follow-up DTI 12 weeks postinjury. 3-D tractography revealed an interruption of the white matter fibers in the posteroinferior aspect of the splenium that correlated with the patient’s left hemialexia, a functional deficit caused by disconnection of the right visual cortex from the language centers of the dominant left hemisphere. CONCLUSION:DTI with 3-D fiber tractography can visualize acute axonal shearing injury, which may have prognostic value for the cognitive and neurological sequelae of traumatic brain injury.

Surgical Resection and Permanent Brachytherapy for Recurrent Atypical and Malignant Meningioma

OBJECTIVERecurrent atypical and malignant meningiomas are difficult to treat successfully. Chemotherapy to date has been unsuccessful, and radiosurgery is limited to smaller tumors. Reoperation alone provides limited tumor control and limited prolonged survival. The addition of brachytherapy at the time of operation is an option. Here, we report the results of our series of patients with recurrent malignant meningioma treated with resection and brachytherapy with permanent low-dose 125I. METHODSThe charts of patients in our database with recurrent atypical and malignant meningiomas treated by surgical resection and permanent 125I brachytherapy at the University of California, San Francisco, between 1988 and 2002 were selected for this study. Calculations of disease-free survival and overall survival curves were made by the Kaplan-Meier actuarial method. Univariate analysis between Kaplan-Meier curves was based on the log-rank statistic, with a significance level set at a value of P ≤ 0.05. RESULTSSeventeen patients had recurrent malignant meningioma, and four had recurrent atypical meningioma. The median number of sources implanted after surgical resection was 30 (range, 4–112 sources), with a median total activity of 20 mCi (range, 3.3–85.9 mCi). The median time to progression after brachytherapy was 11.6 months for patients with malignant meningioma and 10.4 months for the combined group. There was a trend toward longer disease-free survival time in patients after gross total resection versus subtotal resection and in patients with tumors located at the convexity and parasagittally versus at the cranial base. These differences did not reach statistical significance. The median overall survival after diagnosis was 9.4 years for patients with atypical meningioma, 6.6 years for those with malignant meningioma, and 8.0 years for all patients combined. Survival from the time of resection and implantation of 125I was 1.6 years for patients with atypical meningioma, 2.4 years for patients with malignant meningioma, and 2.4 years for the combined group. Thirty-three percent of patients had complications requiring surgical intervention. Radiation necrosis occurred in 27% of patients; 13% underwent surgery for radiation necrosis. In addition, 27% had a wound breakdown and required surgical intervention. CONCLUSIONThe options for patients with recurrent atypical or malignant meningiomas are limited. Our results suggest that for tumors not suitable for radiosurgery, resection followed by permanent brachytherapy should be considered as a potential salvage treatment. However, this approach results in a relatively high complication rate in these heavily treated patients and requires meticulous surgical technique and medical therapies to assist with wound healing after surgery.

GENETIC ABERRATIONS IN GLIOMATOSIS CEREBRI

OBJECTIVEIdentifying the genetic alterations in gliomatosis cerebri (GC) may yield clinically useful prognostic markers and provide clues as to whether GC represents a distinct pathological entity or is an extreme form of diffusely infiltrative glioma. METHODSClinical histories, treatment histories, magnetic resonance imaging, and pathological analysis of patients with GC treated at either the University of California San Francisco or the Mayo Clinic were reviewed. Degenerate oligonucleotide-primed polymerase chain reaction was performed on biopsy samples of GC. Comparative genomic hybridization was used to determine relative deoxyribonucleic acid copy number. We evaluated relationships of clinical and radiological treatment and comparative genomic hybridization data to survival after diagnosis with Cox regression analysis. RESULTSRadiographic analysis and biopsy specimens were available for study in 29 patients (17 men, 12 women). Comparative genomic hybridization was successfully performed in 22 patients. Contrast enhancement was the most significant predictor of poor survival (P = 0.0026). Loss of chromosomes 13q and 10q and gains of 7q were also independent significant predictors of poor survival (P = 0.0032, 0.0335, and 0.0487, respectively). Patients treated with temozolomide or with radiation therapy had improved survival, but this effect did not reach statistical significance (P = 0.180 and 0.124, respectively). CONCLUSIONChromosomal aberrations associated with aggressive astrocytomas are predictors of poor outcome in patients with GC. This suggests that GC may be an architectural variant of diffuse astrocytomas. The presence of these aberrations and the presence of any contrast enhancement on magnetic resonance imaging scans are possible stratifiers for patients with GC. Stratification of GC into higher- and lower-grade forms may be useful in tailoring treatments to patients with this disease.

A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus - tumor association

Next generation sequencing (NGS) can globally interrogate the genetic composition of biological samples in an unbiased yet sensitive manner. The objective of this study was to utilize the capabilities of NGS to investigate the reported association between glioblastoma multiforme (GBM) and human cytomegalovirus (HCMV). A large-scale comprehensive virome assessment was performed on publicly available sequencing datasets from the Cancer Genome Atlas (TCGA), including RNA-seq datasets from primary GBM (n = 157), recurrent GBM (n = 13), low-grade gliomas (n = 514), recurrent low-grade gliomas (n = 17), and normal brain (n = 5), and whole genome sequencing (WGS) datasets from primary GBM (n = 51), recurrent GBM (n = 10), and normal matched blood samples (n = 20). In addition, RNA-seq datasets from MRI-guided biopsies (n = 92) and glioma stem-like cell cultures (n = 9) were analyzed. Sixty-four DNA-seq datasets from 11 meningiomas and their corresponding blood control samples were also analyzed. Finally, three primary GBM tissue samples were obtained, sequenced using RNA-seq, and analyzed. After in-depth analysis, the most robust virus findings were the detection of papillomavirus (HPV) and hepatitis B reads in the occasional LGG sample (4 samples and 1 sample, respectively). In addition, low numbers of virus reads were detected in several datasets but detailed investigation of these reads suggest that these findings likely represent artifacts or non-pathological infections. For example, all of the sporadic low level HCMV reads were found to map to the immediate early promoter intimating that they likely originated from laboratory expression vector contamination. Despite the detection of low numbers of Epstein-Barr virus reads in some samples, these likely originated from infiltrating B-cells. Finally, human herpesvirus 6 and 7 aligned viral reads were identified in all DNA-seq and a few RNA-seq datasets but detailed analysis demonstrated that these were likely derived from the homologous human telomeric-like repeats. Other low abundance viral reads were detected in some samples but for most viruses, the reads likely represent artifacts or incidental infections. This analysis argues against associations between most known viruses and GBM or mengiomas. Nevertheless, there may be a low percentage association between HPV and/or hepatitis B and LGGs.

Brain Tumors: Epidemiology and Current Trends in Treatment

Background: Brain tumors represent a group of neoplasms arising from brain tissue, each with their own unique biology, prognosis, and treatment. Included in this group are neoplasms not arising from brain parenchyma, which encompass meningiomas, lymphomas, and metastatic disease from other primary sources (often referred to as secondary brain tumors). Despite the diverse group of neoplasms represented, most intracranial tumors follow similar clinical presentations and diagnostic workups. Methods: This review focuses on primary and secondary brain tumor epidemiology, imaging, and treatment modalities. In addition, we will highlight molecular genetic advances in the field that will help shape future treatment approaches. Results: Although tumors affecting the Central Nervous System (CNS) are relatively uncommon, they are often very difficult to treat and cause disproportionate morbidity and mortality. Many of these neoplasms are universally fatal and our ability to treat both benign and malignant tumors is still in its infancy. Our lack of effective treatment leaves many of our patients with few options. Conclusions: The combination of poor prognosis and lack of therapeutic options make further innovation and investigation a priority to improve clinical outcomes for patients suffering from CNS malignancies.

Amplifying small amounts of tumor DNA allows detection of DNA copy number aberrations with array-CGH

Array comparative genomic hybridization (aCGH) is a powerful tool to detect relative DNA copy number at a resolution limited only by the coverage of bacterial artificial chromosomes (BACs) used to print the genomic array. The amount of DNA needed to perform a reliable aCGH analysis has been a limiting factor, especially on minute tissue samples where limited DNA is available. Here we report a simple, highly sensitive and reliable aCGH method to analyze samples of no more than 1 ng genomic DNA. The speed and simplicity of the technique are ideal for studies on small clinical samples such as needle biopsies.

Advances in Neuro-Oncology Imaging Techniques

Background: Central nervous system (CNS) tumors are a rare but devastating malignancy, often robbing patients of the basic quality of life. Despite advances in our understanding of the CNS tumor disease processes, the prognosis for patients with CNS tumors remains poor. Better characterization and diagnostic and monitoring approaches are necessary to assist in diagnosis and treatment of CNS tumors. One important tool in the neuro-oncology armamentarium is the use of advanced imaging techniques. Methods: We searched PubMed using the keywords neuro-oncology imaging, pseudoprogression, molecular imaging, and biomarkers. We limited our search to full-text English articles and identified other relevant articles from the reference lists of previously identified articles. Results: Advances in imaging techniques have allowed investigators to explore various imaging modalities, from tumor characterization to differentiating pseudoprogression from tumor progression. Better imaging can result in better diagnostic approaches, greater and safer resection techniques, and improved monitoring of tumor progression. Conclusion: This review highlights advances in neuro-oncology imaging techniques and their clinical utility in the treatment and management of primary brain tumors.

Abstract A086: Early clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with cancers

Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed phase I and II trials in adult subjects with cancer that had +/- CNS involvement (AACR #1185, 2013; AACR #CT 129, 2017). The aims were to assess clinical responses, monitor toxicities/safety, and confirm MTDs for IV administered DM-CHOC-PEN (IND 68,876). We report here responses and toxicities seen in a phase I DM-CHOC-PEN trial with AYA subjects who have cancer (some of whom had CNS involvement). Subjects and Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer in escalating doses from 39 - 98.7 mg/m2. The dosing schedule accounted for the liver toxicities seen in the adult phase I trial and was 2-tiered: for subjects with liver involvement, the cutoff was 85.8 mg/m2 and for subjects with normal liver function was 98.7 mg/m2. Results: Twelve (12) AYA subjects have been treated to date (with or without CNS involvement). The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast, and lung cancers (NSCL). Most subjects (9) had CNS involvement. The drug was well tolerated; the most common adverse effects were fatigue (17%). No neuro/cognitive, liver dysfunction, hematologic, cardiac, renal, or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-98.7 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively for the AYA subjects, similar to what was seen for older adults. However, the drug and metabolite were still detectable in plasma and rbcs for 21 to 50 days in the AYA (15 - 39 yo) group vs. 3 to 60 yo) subjects (AACR #1185, 2013). Differences in PK profiles between AYA and older adult subjects will be reviewed in depth. Three (3) of the AYA subjects (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier), and OS from 8 to 26+ mos. All subjects will be reviewed. Conclusion: DM-CHOC-PEN is safe in doses of 39 - 98.7 mg/m2 and has produced objective responses with manageable toxicities in AYA subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and R43CA203351A and NIH NIGMS 1 U54 GM104940. Citation Format: Lee Roy Morgan, Andrew H. Rodgers, Roy S. Weiner, Tallat Mahmood, Marcus L. Ware, Manish Bhandari, Philip Friedlander. Early clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A086.

Advances in the Treatment of Primary Brain Tumors: The Realm of Immunotherapy

Central nervous system (CNS) tumors, although rare, represent a group of neoplasms that have a disproportionate morbidity and mortality. Despite advances in our under‐ standing of tumor pathogenesis coupled with improvements in therapeutic options, overall survival for primary brain tumors remains dismal. Although challenging, newer approaches such as brachytherapy, immunotherapy, and electric field generators are currently being evaluated in the clinical setting with promising results. The field of immunotherapy in neurooncology is still in its infancy, but several advances have already been made, including the development of tumor vaccines, utilization of immune checkpoint inhibitors, and activation of tumor dendritic cells to stimulate the host’s immune system. Recent advances in noninvasive electric fields have been applied to the treatment of glioblastoma multiforme (GBM) with encouraging clinical outcome. In this chapter, we will review the latest advances in the treatment of glioblastoma multiforme with a focus on immunotherapy.

The association between human cytomegalovirus and glioblastomas: a review

Human cytomegalovirus (HCMV) was reported in glioblastoma multiforme (GBM) over a decade ago and this finding has the potential to increase our understanding of the disease and it offers an alternative tumor-specific therapeutic target. Due of this promise, there is a fair amount of time, energy and money being directed towards understanding and utilizing this connection for eventual therapeutic purposes. Nevertheless, the association between GBM and HCMV remains controversial. Several studies have reported conflicting results, further undermining the potential clinical value of this association. In this review, the authors will discuss the latest developments on this evolving issue. Specifically, the results of the latest studies, both positive and negative, will be discussed. Furthermore, potential theories to explain discrepancies reported in the literature will be proposed. Clinical implications including potential targets for anti-HCMV therapy and the latest developments in anti-HCMV therapy will be presented. Finally, solutions to remedy this controversial issue in neuro-oncology will be offered.