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Papers by Peter Black

Annals of Neurology, 2008

Objective-Genetic loss of TSC1/TSC2 function in tuberous sclerosis complex (TSC) results in overa... more Objective-Genetic loss of TSC1/TSC2 function in tuberous sclerosis complex (TSC) results in overactivation of the mammalian target of rapamycin complex 1 pathway, leading to cellular dysplasia. We hypothesized that the dysplastic cells in TSC tubers are heterogeneous, including separable classes on a neuronal-glial spectrum, and that these dysplastic cells express glutamate receptor (GluR) patterns consistent with increased cortical network excitability. Methods-Surgically resected human cortical tubers and nondysplastic epileptic cortical samples were analyzed by double-label immunocytochemistry for coexpression of neuronal and glial markers, the TSC1/TSC2 pathway downstream molecule phospho-S6 (pS6) and GluR subunits, and compared with control cortical tissue. Western blotting was used to quantify changes in GluR subunit expression in tubers versus controls. Results-We demonstrate that cortical tubers contain a broad spectrum of cell types including disoriented pyramidal cells, dysplastic neurons, giant neuroglial cells, dysplastic astroglia, and reactive astrocytes. Dysplastic neurons, giant cells, and dysplastic astroglia express high levels of pS6 and demonstrate altered GluR subunit composition, resembling those of normal immature neurons and glia. In contrast, nondysplastic neurons in TSC and non-TSC epileptic lesions express lower pS6 levels and display changes in GluR subunit expression that are distinct from the patterns seen in tuber dysplastic cells. Interpretation-This work significantly expands the spectrum of abnormal cells recognized in tubers beyond the classic tuber giant cell and demonstrates cell-specific abnormalities in GluR expression that may contribute to seizure pathogenesis in TSC. Furthermore, these results suggest that subunit-specific antagonists may be of potential use in the treatment of epilepsy in TSC. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in either the TSC1 or TSC2 gene. 1,2 TSC brain lesions are malformations of cortical development that include cortical tubers, white matter abnormalities, subependymal nodules,

Critical Reviews in Neurosurgery, 2000

Radiotherapy remains one of the cornerstones of treatment of patients with gliomas. Radiationindu... more Radiotherapy remains one of the cornerstones of treatment of patients with gliomas. Radiationinduced damage to DNA can result in the loss of proliferative capacity of neoplastic cells. In addition to mitotic cell death, it has recently been found that other cellular events can lead to reproductive failure. Apoptosis, or programmed cell death, has been described as a response to radiation in many cell types. Gradually, radiation has been found to cause a great variety of other changes in both normal and neoplastic tissue, ranging from necrosis due to changes in the vasculature to alterations in gene expression. As radiosurgery becomes more common and the patients have longer survival, investigators are working to understand the responses of brain tissue to radiation. We present several studies related to the eects of radiation on normal brain and glio-mas. One paper suggests a mechanism of radiation-induced reproductive failure that is separate from mitotic cell death and apoptosis. Others describe changes in cytokine regulation and receptor density. After irradiation, necrosis of normal tissue can be indistinguishable from recurrence of the tumor with conventional studies. However, functional imaging can dierentiate between neoplasm and functional alterations in tissue due to radiation. While much more work must be done in this ®eld, these papers indicate that radiation therapy results in a variety of cellular and molecular alterations. As a result of these changes, they suggest that irradiated brain tissue is functionally and clinically dierent from untreated brain.

Clinical Cancer Research

Purpose: Cerebral metastases represent the most common type of brain tumors. This study investiga... more Purpose: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. Experimental Design: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. Results: In vitro secretion of endostatin by 2.5 × 105 cells within 24 hours was 0.12 ± 0.03 ng, 4.35 ± 0.4, and 1.18 ± 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracer...

Neurosurgery, 2001

OBJECTIVE: We used complementary deoxyribonucleic acid expression microarrays to assess the effec... more OBJECTIVE: We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen. METHODS: Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis. RESULTS: Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor ␤, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor ␣, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients' recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens. CONCLUSION: After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.

Analytical Chemistry, 2010

Often considered benign, meningiomas represent 32% of intracranial tumors with 3 grades of malign... more Often considered benign, meningiomas represent 32% of intracranial tumors with 3 grades of malignancy defined by the WHO histology based classification. Malignant meningiomas are associated with less than 2 years median survival. The inability to predict recurrence and progression of meningiomas induces significant anxiety for patients and limits physicians in implementing prophylactic treatment approaches. This report presents an analytical approach to tissue characterization based on MALDI TOF mass spectrometry imaging (MSI) which is introduced in an attempt to develop a reference database for predictive classification of brain tumors. This pilot study was designed to evaluate the potential of such approach and to begin to address limitations of the current methodology. Five recurrent and progressive meningiomas for which surgical specimens were available from the original and progressed grades were selected and tested against nonprogressive high-grade meningiomas, high-grade gliomas, and non-tumor brain specimens. The common profiling approach of data acquisition was compared to imaging and revealed significant benefits in spatially resolved acquisition for improved spectral definition. A preliminary classifier based on support vector machine showed the ability to distinguish meningioma image spectra from non-tumor brain and from gliomas, a different type of brain tumors, and to enable class imaging of surgical tissue. Although the development of classifiers was shown to be sensitive to data preparation parameters such as recalibration and peak picking criteria, it also suggested the potential for maturing into a predictive algorithm if provided with larger series of well-defined cases.

Journal of Biomedical Optics, 1998

Hardware and software for a customized system to use magnetic resonance imaging (MRI) to noninvas... more Hardware and software for a customized system to use magnetic resonance imaging (MRI) to noninvasively monitor laser-induced interstitial thermal therapy of brain tumors are reported. An open-configuration interventional MRI unit was used to guide optical fiber placement and monitor the deposition of laser energy into the targeted lesion. T1-weighted fast spin echo and gradient echo images were used to monitor the laser tissue interaction. The images were transferred from the MRI scanner to a customized research workstation and were processed intraoperatively. Newly developed software enabled rapid (27-221 ms) availability of calculated images. A case report is given showing images which reveal the laser-tissue interaction. The system design is feasible for on-line monitoring of interstitial laser therapy.

Journal of Neurosurgery, 1982

✓ Cerebral blood vessels are devoid of vasa vasorum. Therefore, the authors have studied the micr... more ✓ Cerebral blood vessels are devoid of vasa vasorum. Therefore, the authors have studied the microarchitecture of the adventitia of large feline cerebral vessels and systemic vessels of the same size, in an effort to determine how the vessels are nourished. The cerebral vessels contain a rete vasorum in the adventitia that is permeable to large proteins and is in continuity with the subarachnoid space. This substructure may be analogous to the systemic vasa vasorum and may contribute to the nutrition of the cerebral arteries.

Journal of Computer Assisted Tomography, 1982

ABSTRACT

International Journal of Radiation Oncology*Biology*Physics, 1998

Cell and Tissue Research, 1986

The experiments described herein use an in vitro preparation of choroid plexus to demonstrate tha... more The experiments described herein use an in vitro preparation of choroid plexus to demonstrate that it is a vasopressin-responsive organ by morphologic criteria. Choroid plexus from rats was incubated for one hour in graded concentrations of arginine vasopressin (AVP). Within physiologic range of molar concentration, incubation in vasopressin induced a decrease in basal and lateral spaces in choroid plexus epithelial cells as well as an increase in number of dark cells. The number of cells with basal spaces decreased significantly from 82.7 +/- 9.2 in control tissue to 19 +/- 18 in tissue incubated in 10(-12) M AVP; similarly, the number with lateral cellular spaces decreased from 20 +/- 8.8 to 7.6 +/- 2.2 cells in 10(-10) M AVP. Dark cells increased in number from 3.8 +/- 2.6 in control conditions to 49 +/- 4 with 10(-9) M vasopressin. These data suggest important effects of arginine vasopressin in cerebrospinal fluid (CSF) on choroid plexus, compatible with enhanced fluid transport across choroid epithelial cells.

Acta Neurochirurgica, 2001

Background. Recent study series have reported that post-operative external beam radiation therapy... more Background. Recent study series have reported that post-operative external beam radiation therapy and stereotactic radiosurgery with the linear accelerator or gamma knife improves long-term local control of subtotally resected or recurrent meningiomas. Methods. Analysis of treatment results in 100 consecutive patients with skull base meningiomas managed by one surgeon with a median follow-up of ®ve years. Treatment principles included observation for asymptomatic tumors; surgery for progressive or symptomatic tumors unless surgery was medically contraindicated or refused by the patient; to make surgery as aggressive as possible but with the goal of preserving full function of the patient; and to use radiosurgery or conformal fractionated radiation therapy if residual tumor was demonstrated. Preoperative, postoperative, and observational data were prospectively accumulated and stored in a large database system. Median follow up was 5 years with a range from 2 to 10 years. Findings. The most frequent presenting symptoms were headache (45%) and changes in vision (29%). Cranial nerve de®cits (49%) and cerebellar signs (24%) were the most common physical ®ndings. Seventy-two patients had surgical resection. Of these, 93% had greater than 50% resection and 47% had radiographically complete resection. There were no perioperative deaths and there were ®ve surgical complications for a rate of 7%. Complications included hemiparesis (2.8%), new cranial nerve palsy (2.8%), and indolent osteomyelitis (1.4%). Fifteen patients had observation only; none of who progressed. Thirteen patients had radiation only, primarily because of patient preference or medical contraindications to surgery in the setting of substantial symptoms. There were no complications of this therapy. With a median ®ve-year follow-up, only one patient (1%) demonstrated tumor progression using the treatment paradigm outlined here. Interpretation. These results demonstrate that skull base meningiomas which require treatment can be managed with a combination of aggressive surgery and conformal radiation with an acceptable functional status in 99% of cases.

Journal of the National Comprehensive Cancer Network, 2011

All recommendations are Category 2A unless otherwise specified. The believes that the best manage... more All recommendations are Category 2A unless otherwise specified. The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN To find clinical trials online at NCCN member institutions, click here: nccn.org/clinical_trials/physician.html See NCCN Categories of Evidence and Consensus The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment.

Clinical Cancer Research, 2005

A unique characteristic of neural stem cells is their capacity to track glioma cells that have mi... more A unique characteristic of neural stem cells is their capacity to track glioma cells that have migrated away from the main tumor mass into the normal brain parenchyma. PEX, a naturally occurring fragment of human metalloproteinase-2, acts as an inhibitor of glioma and endothelial cell proliferation, migration, and angiogenesis. In the present study, we evaluated the antitumor activity of PEX-producing human neural stem cells against malignant glioma. The HB1.F3 cell line (immortalized human neural stem cell) was transfected by a pTracer vector with PEX. The retention of the antiproliferative activity and migratory ability of PEX-producing HB1.F3 cells (HB1.F3-PEX) was confirmed in vitro. For the in vivo studies, DiI-labeled HB1.F3-PEX cells were stereotactically injected into established glioma tumor in nude mice. Tumor size was subsequently measured by magnetic resonance imaging and at the termination of the studies by histologic analysis including tumor volume, microvessel density...

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2003

Relatively few studies have examined glioma risk in relation to history of cancer in first-degree... more Relatively few studies have examined glioma risk in relation to history of cancer in first-degree relatives. We sought to describe such risks in a large hospital-based case-control study. Histologically confirmed incident adult glioma cases (n = 489) were identified at three regional referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were frequency-matched on age, sex, race/ethnicity, hospital, and proximity of residence to hospital. Participants received a personal interview, including questions regarding cancer in family members. Odds ratios (ORs) were calculated to estimate the risk of glioma associated with a history of cancer in a first-degree relative using conditional logistic regression and compared with standardized incidence ratios among relatives of cases versus relatives of controls. Among participants reporting a family history of a brain cancer or a brain tumor, risk of glioma was 1.6 [95%...

2008 5th IEEE International Symposium on Biomedical Imaging: From Nano to Macro, 2008

Change detection is a critical task in the diagnosis of many slowly evolving pathologies. This pa... more Change detection is a critical task in the diagnosis of many slowly evolving pathologies. This paper describes an approach that semi-automatically performs this task using longitudinal medical images. We are specifically interested in meningiomas, which experts often find difficult to monitor as the tumor evolution can be obscured by image artifacts. We test the method on synthetic data with known tumor growth as well as ten clinical data sets. We show that the results of our approach highly correlate with expert findings but seem to be less impacted by inter-and intra-rater variability.

Neurosurgery, 2010

OBJECTIVE This work evaluated the clinical feasibility of transcranial magnetic resonance imaging... more OBJECTIVE This work evaluated the clinical feasibility of transcranial magnetic resonance imaging–guided focused ultrasound surgery. METHODS Transcranial magnetic resonance imaging–guided focused ultrasound surgery offers a potential noninvasive alternative to surgical resection. The method combines a hemispherical phased-array transducer and patient-specific treatment planning based on acoustic models with feedback control based on magnetic resonance temperature imaging to overcome the effects of the cranium and allow for controlled and precise thermal ablation in the brain. In initial trials in 3 glioblastoma patients, multiple focused ultrasound exposures were applied up to the maximum acoustic power available. Offline analysis of the magnetic resonance temperature images evaluated the temperature changes at the focus and brain surface. RESULTS We found that it was possible to focus an ultrasound beam transcranially into the brain and to visualize the heating with magnetic resona...

international Journal of Oncology, 1992

Brain tumors are one of the leading causes of death in adults with cancer; however, molecular cla... more Brain tumors are one of the leading causes of death in adults with cancer; however, molecular classification of these tumors with in vivo magnetic resonance spectroscopy (MRS) is limited because of the small number of metabolites detected. In vitro MRS provides highly informative biomarker profiles at higher fields, but also consumes the sample so that it is unavailable for subsequent analysis. In contrast, ex vivo high-resolution magic angle spinning (HRMAS) MRS conserves the sample but requires large samples and can pose technical challenges for producing accurate data, depending on the sample testing temperature. We developed a novel approach that combines a two-dimensional (2D), solid-state, HRMAS proton (1 H) NMR method, TOBSY (total through-bond spectroscopy), which maximizes the advantages of HRMAS and a robust classification strategy. We used 2 mg of tissue at-8°C from each of 55 brain biopsies, and reliably detected 16 different molecules. We compared two classification strategies, the support vector machine (SVM) classifier and a feedforward neural network using the Levenberg-Marquardt back-propagation algorithm. We used the minimum redundancy/maximum relevance (MRMR) method as a powerful feature-selection scheme along with the SVM classifier. We also used the minimum redundancy/maximum relevance (MRMR) method as a powerful feature-selection scheme along with the SVM classifier.