F H Hochberg

Johns Hopkins University, Baltimore, MD, United States

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Publications (146)795.11 Total impact

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    ABSTRACT: Glioma is the most common brain tumor. For the more aggressive form, glioblastoma, standard treatment includes surgical resection, irradiation with adjuvant temozolomide and, on recurrence, experimental chemotherapy. However, the survival of patients remains poor. There is a critical need for minimally invasive biomarkers for diagnosis and as measures of response to therapeutic interventions. Glioma shed extracellular vesicles (EVs), which invade the surrounding tissue and circulate within both the cerebrospinal fluid and the systemic circulation. These tumor-derived EVs and their content serve as an attractive source of biomarkers. In this review, we discuss the current state of the art of biomarkers for glioma with emphasis on their EV derivation.
    Expert Review of Molecular Diagnostics 05/2014; 14(4):439-52. · 4.09 Impact Factor
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    ABSTRACT: Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma (GBM) that identifies miR-1 as an orchestrator of EV function and GBM growth and invasion. Ectopic expression of miR-1 in GBM cells blocked in vivo growth, neovascularization and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by EVs released by cancer stem-like GBM cells. An EV-dependent phenotype defined by GBM invasion, neurosphere growth and endothelial tube formation was mitigated by loading miR-1 into GBM-derived EVs. Protein cargo in EVs was characterized to learn how miR-1 directed EV function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in GBM-derived EVs, was found to be a direct target of miR-1 control. In addition, EV-derived miR-1 along with other ANXA2 EV networking partners targeted multiple pro-oncogenic signals in cells within the GBM microenvironment. Together, our results showed how EV signalling promotes the malignant character of GBM and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for GBM management.
    Cancer Research 12/2013; · 8.65 Impact Factor
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    ABSTRACT: Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.
    Proceedings of the National Academy of Sciences 11/2013; · 9.74 Impact Factor
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    ABSTRACT: The treatment of metastatic brain lesions remains a central challenge in oncology. Because most chemotherapeutic agents do not effectively cross the blood-brain barrier, it is widely accepted that radiation remains the primary modality of treatment. The mode by which radiation should be delivered has, however, become a source of intense controversy in recent years. The controversy involves whether patients with a limited number of brain metastases should undergo whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) delivered only to the radiographically visible tumours. Survival is comparable for patients treated with either modality. Instead, the controversy involves the neurocognitive function (NCF) of radiating cerebrum that appeared radiographically normal relative to effects of the growth from micro-metastatic foci. A fundamental question in this debate involves quantifying the effect of WBRT in patients with cerebral metastasis. To disentangle the effects of WBRT on neurocognition from the effects inherent to the underlying disease, we analysed the results from randomised controlled studies of prophylactic cranial irradiation in oncology patients as well as studies where patients with limited cerebral metastasis were randomised to SRS versus SRS+WBRT. In aggregate, these results suggest deleterious effects of WBRT in select neurocognitive domains. However, there are insufficient data to resolve the controversy of upfront WBRT versus SRS in the management of patients with limited cerebral metastases.
    Journal of neurology, neurosurgery, and psychiatry 05/2013; · 4.87 Impact Factor
  • Ophthalmology 03/2013; 120(3):646-646.e2. · 5.56 Impact Factor
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    ABSTRACT: Object The authors' goal was to review the current understanding of the underlying molecular and genetic mechanisms involved in low-grade glioma development and how these mechanisms can be targets for detection and treatment of the disease and its recurrence. Methods On October 4, 2012, the authors convened a meeting of researchers and clinicians across a variety of pertinent medical specialties to review the state of current knowledge on molecular genetic mechanisms of low-grade gliomas and to identify areas for further research and drug development. Results The meeting consisted of 3 scientific sessions ranging from neuropathology of IDH1 mutations; CIC, ATRX, and FUBP1 mutations in oligodendrogliomas and astrocytomas; and IDH1 mutations as therapeutic targets. Sessions consisted of a total of 10 talks by international leaders in low-grade glioma research, mutant IDH1 biology and its application in glioma research, and treatment. Conclusions The recent discovery of recurrent gene mutations in low-grade glioma has increased the understanding of the molecular mechanisms involved in a host of biological activities related to low-grade gliomas. Understanding the role these genetic alterations play in brain cancer initiation and progression will help lead to the development of novel treatment modalities than can be personalized to each patient, thereby helping transform this now often-fatal malignancy into a chronic or even curable disease.
    Neurosurgical FOCUS 02/2013; 34(2):E9. · 2.49 Impact Factor
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    ABSTRACT: Glioblastoma cells secrete extra-cellular vesicles (EVs) containing microRNAs (miRNAs). Analysis of these EV miRNAs in the bio-fluids of afflicted patients represents a potential platform for biomarker development. However, the analytic algorithm for quantitative assessment of EV miRNA remains under-developed. Here, we demonstrate that the reference transcripts commonly used for quantitative PCR (including GAPDH, 18S rRNA, and hsa-miR-103) were unreliable for assessing EV miRNA. In this context, we quantitated EV miRNA in absolute terms and normalized this value to the input EV number. Using this method, we examined the abundance of miR-21, a highly over-expressed miRNA in glioblastomas, in EVs. In a panel of glioblastoma cell lines, the cellular levels of miR-21 correlated with EV miR-21 levels (p<0.05), suggesting that glioblastoma cells actively secrete EVs containing miR-21. Consistent with this hypothesis, the CSF EV miR-21 levels of glioblastoma patients (n=13) were, on average, ten-fold higher than levels in EVs isolated from the CSF of non-oncologic patients (n=13, p<0.001). Notably, none of the glioblastoma CSF harbored EV miR-21 level below 0.25 copies per EV in this cohort. Using this cut-off value, we were able to prospectively distinguish CSF derived from glioblastoma and non-oncologic patients in an independent cohort of twenty-nine patients (Sensitivity=87%; Specificity=93%; AUC=0.91, p<0.01). Our results suggest that CSF EV miRNA analysis of miR-21 may serve as a platform for glioblastoma biomarker development.
    PLoS ONE 01/2013; 8(10):e78115. · 3.73 Impact Factor
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    ABSTRACT: The emergence of publications on extracellular RNA (exRNA) and extracellular vesicles (EV) has highlighted the potential of these molecules and vehicles as biomarkers of disease and therapeutic targets. These findings have created a paradigm shift, most prominently in the field of oncology, prompting expanded interest in the field and dedication of funds for EV research. At the same time, understanding of EV subtypes, biogenesis, cargo and mechanisms of shuttling remains incomplete. The techniques that can be harnessed to address the many gaps in our current knowledge were the subject of a special workshop of the International Society for Extracellular Vesicles (ISEV) in New York City in October 2012. As part of the "ISEV Research Seminar: Analysis and Function of RNA in Extracellular Vesicles (evRNA)", 6 round-table discussions were held to provide an evidence-based framework for isolation and analysis of EV, purification and analysis of associated RNA molecules, and molecular engineering of EV for therapeutic intervention. This article arises from the discussion of EV isolation and analysis at that meeting. The conclusions of the round table are supplemented with a review of published materials and our experience. Controversies and outstanding questions are identified that may inform future research and funding priorities. While we emphasize the need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results, we also recognize that continual development and evaluation of techniques will be necessary as new knowledge is amassed. On many points, consensus has not yet been achieved and must be built through the reporting of well-controlled experiments.
    Journal of extracellular vesicles. 01/2013; 2.
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    ABSTRACT: Development of biofluid-based molecular diagnostic tests for cancer is an important step towards tumor characterization and real-time monitoring in a minimally invasive fashion. Extracellular vesicles (EVs) are released from tumor cells into body fluids and can provide a powerful platform for tumor biomarkers because they carry tumor proteins and nucleic acids. Detecting rare point mutations in the background of wild-type sequences in biofluids such as blood and cerebrospinal fluid (CSF) remains a major challenge. Techniques such as BEAMing (beads, emulsion, amplification, magnetics) PCR and droplet digital PCR (ddPCR) are substantially more sensitive than many other assays for mutant sequence detection. Here, we describe a novel approach that combines biofluid EV RNA and BEAMing RT-PCR (EV-BEAMing), as well droplet digital PCR to interrogate mutations from glioma tumors. EVs from CSF of patients with glioma were shown to contain mutant IDH1 transcripts, and we were able to reliably detect and quantify mutant and wild-type IDH1 RNA transcripts in CSF of patients with gliomas. EV-BEAMing and EV-ddPCR represent a valuable new strategy for cancer diagnostics, which can be applied to a variety of biofluids and neoplasms.Molecular Therapy-Nucleic Acids (2013) 2, e109; doi:10.1038/mtna.2013.28; published online 23 July 2013.
    Molecular therapy. Nucleic acids. 01/2013; 2:e109.
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    ABSTRACT: The discovery that tumor-derived proteins and nucleic acids can be detected in nano-sized vesicles in the plasma and cerebrospinal fluid of patients afflicted with brain tumors has expanded opportunities for biomarker and therapeutic discovery. Through delivery of their contents to surrounding cells, exosomes, microvesicles and other nano-sized extra-cellular vesicles secreted by tumors modulate their environment as to promote tumor growth and survival. In this review, we discuss the biologic processes mediated by these extra-cellular vesicles as well as their applications in terms of brain tumor diagnosis, monitoring, and therapy. We review the normal physiology of these extra-cellular vesicles, their pertinence to tumor biology, and directions for research in this field.
    Neurosurgery 12/2012; · 2.53 Impact Factor
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    ABSTRACT: Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status 0-1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m(2) was given orally once daily for 5 consecutive days during each 28-day cycle. The primary endpoint was progression-free survival at 6 months. A Simon 2-stage optimal design was used in which 19 patients were evaluated in the 1st stage, with an additional 36 patients accrued if >4 patients in stage 1 achieved PFS at 6 months. 29 patients were enrolled in the study, with median age of 58 years (range, 25-77 years); 58.6 % female. All patients received prior surgery, radiation therapy, and at least one chemotherapy regimen. The daily dose was reduced to 1.0 mg/m(2) after four of the first 10 patients experienced grade 4 hematologic toxicity. Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2 %), leukopenia (17.2 %) and neutropenia (10.3 %). None of the 19 patients treated at 1.0 mg/m(2)/day experienced grade 4 hematologic toxicity. One patient had a partial radiographic response by modified Macdonald criteria. Only 3 patients (12 %) were progression-free at 6 months. Median time to progression was 12.0 weeks (7.0, 17.0).Treatment with gimatecan 1.0 mg/m(2)/day for 5 days, repeated every 28-days showed minimal efficacy.
    Journal of Neuro-Oncology 12/2012; · 3.12 Impact Factor
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    ABSTRACT: Glioblastomas shed large quantities of small, membrane-bound microvesicles into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating microvesicles directly from blood samples of patients with glioblastoma. Microvesicles, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate glioblastoma multiforme (GBM) microvesicles from nontumor host cell-derived microvesicles. We also show that circulating GBM microvesicles can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.
    Nature medicine 11/2012; · 27.14 Impact Factor
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    ABSTRACT: RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9) and normal controls (N = 7) were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups). Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down) in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size < 500 nt. Gene ontology of the down-regulated genes indicated these are coding for ribosomal proteins and genes related to ribosome production. Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size < 500 nt.
    BMC Cancer 01/2012; 12:22. · 3.33 Impact Factor
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    ABSTRACT: Microvesicles are nano-sized lipid vesicles released by all cells in vivo and in vitro. They are released physiologically under normal conditions but their rate of release is higher under pathological conditions such as tumors. Once released they end up in the systemic circulation and have been found and characterized in all biofluids such as plasma, serum, cerebrospinal fluid, breast milk, ascites, and urine. Microvesicles represent the status of the donor cell they are released from and they are currently under intense investigation as a potential source for disease biomarkers. Currently, the "gold standard" for isolating microvesicles is ultracentrifugation, although alternative techniques such as affinity purification have been explored. Viscosity is the resistance of a fluid to a deforming force by either shear or tensile stress. The different chemical and molecular compositions of biofluids have an effect on its viscosity and this could affect movements of the particles inside the fluid. In this manuscript we addressed the issue of whether viscosity has an effect on sedimentation efficiency of microvesicles using ultracentrifugation. We used different biofluids and spiked them with polystyrene beads and assessed their recovery using the Nanoparticle Tracking Analysis. We demonstrate that MVs recovery inversely correlates with viscosity and as a result, sample dilutions should be considered prior to ultracentrifugation when processing any biofluids.
    Frontiers in Physiology 01/2012; 3:162.
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    ABSTRACT: Primary central nervous system non-Hodgkin lymphoma (PCNSL) carries a poor prognosis and, although it responds to chemotherapy, fewer than 20% of patients are long-term disease-free survivors. Secondary CNS non-Hodgkin lymphoma (SCNSL) has an even worse prognosis with a median survival of only months and very few reported long-term survivors. For both of these groups of patients, there has been interest in using high-dose chemotherapy with autologous stem cell transplantation (ASCT) following conditioning with thiotepa, busulfan, and cyclophosphamide (TBC). We performed a retrospective review (from 2006-2010) of 32 patients from the Dana-Farber Cancer Institute and Massachusetts General Hospital with PCNSL or SCNSL who underwent ASCT with TBC conditioning. Of the 32 patients, 56% received TBC/ASCT after achieving brain magnetic resonance imaging (MRI) and/or cerebrospinal fluid complete response in brain, and 44% of patients were treated with TBC/ASCT in the setting of measurable CNS disease. The 100-day transplant-related mortality rate was only 3%. The most common nonhematologic grade 3 or 4 toxicity was mucositis, which occurred in 73% of patients. Notably, there was only 1 patient with prolonged significant neurologic toxicity that manifested as ataxia and dysphagia. The 1-year OS estimate is 93% (95% confidence interval [CI]: 75%-98%), and the 1-year progression-free survival (PFS) estimate is 90% (95% CI: 72%-96%) from the date of transplantation. Although these outcomes are encouraging, longer follow-up is required and comparison with other traditional ASCT regimens used for patients with non-Hodgkin lymphoma (NHL) is warranted.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(1):76-83. · 3.15 Impact Factor
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    ABSTRACT: The central nervous system (CNS) manifestations of Waldenström's macroglobulinemia (WM) are known as the Bing-Neel syndrome (BNS). Patients with BNS can be classified into Group A and Group B based on the presence of lymphoplasmacytoid (LMP) cells within the brain parenchyma, leptomeninges, dura, and/or cerebrospinal fluid (CSF). To identify characteristic imaging findings for both Group A and Group B patients, we reviewed all 36 cases (26 referenced, 10 unreported) of proven WM with CNS symptoms, CSF analysis and/or biopsy, and magnetic resonance imaging (MRI) of the brain and/or spinal cord. Enhancement on MRI suggests invasion of the central neuraxis by LMP cells, and can help distinguish between Group A and Group B patients. In addition to differentiating true WM lesions in the CNS from ischemia, hyperviscosity events, and demyelinating lesions, evaluation of brain and spinal cord with gadolinium-enhanced MRI has the potential to guide management.
    Clinical lymphoma, myeloma & leukemia 02/2011; 11(1):180-3.
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    ABSTRACT: Bing-Neel syndrome (BNS) is defined as intracranial involvement of Waldenström macroglobulinemia (WM). Few cases of orbital involvement have been reported. A 51-year-old man with a history of WM developed bilateral orbitopathy and optic neuropathy. Orbital biopsy, cerebrospinal fluid studies, and neuroimaging confirmed the diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina. The neuro-ophthalmic manifestations resolved after parenteral and intrathecal chemotherapy in addition to autologous stem cell transplantation. The rare neuro-ophthalmic manifestations of BNS may require a multifaceted approach to therapy.
    Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society 09/2010; 30(3):255-9. · 1.09 Impact Factor
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    ABSTRACT: Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
    Journal of Clinical Oncology 06/2010; 28(17):2817-23. · 18.04 Impact Factor
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    ABSTRACT: Distinguishing recurrent glial tumor from radiation necrosis can be challenging. The purpose of this pilot study was to preliminarily compare unenhanced arterial spin-labeled (ASL) imaging, dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) magnetic resonance imaging, and positron emission tomographic (PET) imaging in distinguishing predominant glioma recurrence or progression from predominant radiation necrosis in postoperative patients treated with proton-beam therapy. Patients with grade II to IV glioma previously treated with surgery and proton-beam therapy were enrolled on the basis of new enhancing nodules or masses with primary differential diagnoses of predominant tumor recurrence or progression versus radiation necrosis. ASL, DSCE-CBV, and PET examinations were assessed by visual qualitative and quantitative analysis for the detection of predominant tumor recurrence. Imaging results were correlated with a clinical-pathologic reference standard. Thirty patients were studied, resulting in 33 ASL, 32 DSCE-CBV, and 26 PET examinations. On the basis of visual inspection, the sensitivities of PET, ASL, and DSCE-CBV examinations for detecting high-grade tumor foci were 81%, 88%, and 86%, respectively. The highest sensitivity values for quantitative ASL imaging were obtained using a normalized cutoff ratio of 1.3, resulting in sensitivity of 94% for ASL imaging and 71% for DSCE-CBV imaging. When predominant high-grade tumors with superimposed regions of predominant mixed radiation necrosis were excluded, DSCE-CBV sensitivity improved to 90%, but ASL sensitivity remained unchanged. Compared with DSCE-CBV imaging, ASL imaging may more accurately distinguish predominant recurrent high-grade glioma from radiation necrosis, especially in regions with mixed radiation necrosis, for which DSCE-CBV imaging may underestimate true blood volume because of leakage artifacts.
    Academic radiology 03/2010; 17(3):282-90. · 2.09 Impact Factor
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    ABSTRACT: We have retrospectively reviewed toxicities and response of a cohort of primary central nervous system lymphoma (PCNSL) patients treated with high dose parenteral methotrexate (MTX) monotherapy without whole brain radiation. From The Massachusetts General Hospital (MGH) Cancer Registry, active since 1946, we selected all immunocompetent patients with histologic and/or radiographic PCNSL diagnosed between 1980 and 2007. We identified the recipients of MTX with leucovorin rescue as sole therapy. No patient received radiation therapy (XRT). We analyzed this cohort for toxicity, response and patterns of recurrence. The cohort of 121 patients received on average 11 cycles of intravenous MTX at a median dose of 8 g/m(2). Median interval between cycles was 10 days. After 3 months of therapy, the overall response rate was 85% (58% CR, 27% PR). The overall survival (OS) for the cohort was 7 years and progression-free survival (PFS) was 3.14 years. A trend toward a higher PFS was seen in patients who continued to receive MTX (3.48 years) every three months as compared to patients who ceased MTX after one year (2.86 years). Of 68 patients who achieved initial CR, there were 40 recurrences. Twenty-six of the 40 were re-induced with MTX as above; Sixty-nine percent again achieved CR. Eighty-one treatment-related toxicities occurred in 1316 MTX cycles. These toxicities included MRI white matter changes (N = 8) and lead to MTX cessation in 16 patients. High-dose MTX monotherapy of PCNSL is well-tolerated and provides PFS of >3 years and OS >7 years.
    Journal of Neuro-Oncology 12/2009; 98(3):385-93. · 3.12 Impact Factor

Publication Stats

6k Citations
795.11 Total Impact Points


  • 2013
    • Johns Hopkins University
      • Department of Molecular and Comparative Pathobiology
      Baltimore, MD, United States
  • 2011
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1986–2011
    • Massachusetts General Hospital
      • • Department of Radiology
      • • Department of Neurology
      Boston, Massachusetts, United States
  • 2009
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 2008
    • Yale University
      New Haven, Connecticut, United States
    • Tufts Medical Center
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1998–2008
    • Harvard Medical School
      • • Department of Radiation Oncology
      • • Department of Neurology
      Boston, Massachusetts, United States
  • 2001
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
  • 2000
    • Stanford University
      • Department of Neurobiology
      Stanford, CA, United States
  • 1999
    • Boston College, USA
      Boston, Massachusetts, United States
  • 1992–1996
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, NE, United States
  • 1994
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 1989
    • University of Nebraska Medical Center
      • Division of Nephrology
      Omaha, NE, United States