Jorge Gutierrez

Correlation between Magnetic Resonance Spectroscopy Imaging and Image-guided Biopsies: Semiquantitative and Qualitative Histopathological Analyses of Patients with Untreated Glioma

OBJECTIVESince intratumoral heterogeneity of gliomas is not adequately reflected in conventional magnetic resonance imaging (MRI), we sought to determine a correlation between different proton magnetic resonance spectroscopic imaging (1H MRSI) metabolic ratios and the degree of tumor infiltration in diffusely infiltrating gliomas. In this report, we describe the microscopic anatomy of gliomas on imaging. METHODSImage-guided biopsies with semiquantitative and qualitative histopathological analyses from a series of 31 untreated patients with low- and high-grade gliomas were correlated with multivoxel 1H MRSI referenced to the same spatial coordinates. RESULTSThis series yielded 247 tissue samples and 307 observations. Choline-containing compounds using contralateral creatine and choline for normalization or ipsilateral N-acetylaspartate appear to correlate best with the degree of tumor infiltration. Similar correlations were present within each grade after stratification. Despite the interpatient overlap of metabolic ratios between normal tissue and mild tumor infiltration, preliminary analyses revealed that 1H MRSI appears more accurate than conventional MRI in defining the tumor boundary and quantifying the degree of tumor infiltration. CONCLUSIONThis is the first study showing histopathological validation of tumor boundaries using 1H MRSI. These results support the conclusion that 1H MRSI accurately reflects the extent of the disease in patients with gliomas. This has important diagnostic and therapeutic implications for more accurately assessing the burden of disease as well as for planning and assessing response to therapy.

Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31.

Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.

Meningeal Melanocytoma: An Aggressive Course for a Benign Tumor

A 79-year-old female presented with difficulty ambulating and was found to have weakness and hyperreflexia in the lower extremities. Magnetic resonance imaging (MRI) revealed a large T8–T9 intraspinal tumor. She underwent a thoracic laminectomy, and excision of an intradural extramedullary lesion.The surgical specimen was soft, black tissue that consisted of a moderately cellular, deeply pigmented tumor. The neoplastic cells proved to be melanocytic, and were devoid of overt features of anaplasia, i.e., prominent nuclear pleomorphism, necrosis, significant mitotic activity, and high proliferation indices.Four months postoperatively, MRI demonstrated focal areas of enhancement in the conus medullaris and in the fourth ventricle, indicating leptomeningeal spread. Subsequently, the patient underwent whole brain radiation. On repeat imaging, there was nodular enhancement of the fourth ventricle and throughout the spinal cord. Despite chemotherapy and radiation therapy, the disease advanced and the patient expired.Meningeal melanocytoma is a rare, histologically benign tumor with good prognosis. However, local aggressive behavior has been recorded, especially in cases of subtotal gross resection. On a literature review, there was one case of cranial posterior fossa meningeal melanocytoma with associated lesions in both suprarenal glands and the left kidney, but there were no cases with distant metastasis.In this report, we present an unusual case of spinal meningeal melanocytoma with diffuse spread throughout the craniospinal axis that proved to be fatal.

Meningeal neurosarcoidosis mimicking convexity en-plaque meningioma

A 34-year old man presented with headaches. Computed tomography scanning revealed an enhancing subdural mass extending from the skull base to the convexity, thought to represent an en-plaque meningioma. Pathologic study revealed extraaxial subdural granulomatous inflammation consistent with neurosarcoidosis.

PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling

SPARC (secreted protein acidic and rich in cysteine) is expressed in all grades of astrocytoma, including glioblastoma (GBM). SPARC suppresses glioma growth but promotes migration and invasion by mediating integrin and growth factor receptor-regulated kinases and their downstream effectors. PTEN (phosphatase and tensin homolog deleted on chromosome 10), which is commonly lost in primary GBMs, negatively regulates proliferation and migration by inhibiting some of the same SPARC-mediated signaling pathways. This study determined whether PTEN reconstitution in PTEN-mutant, SPARC-expressing U87MG cells could further suppress proliferation and tumor growth but inhibit migration and invasion in SPARC-expressing cells in vitro and in vivo, and thereby prolong survival in animals with xenograft tumors. In vitro, PTEN reduced proliferation and migration in both SPARC-expressing and control cells, with a greater suppression in SPARC-expressing cells. PTEN reconstitution suppressed AKT activation in SPARC-expressing and control cells but suppressed the SHC-RAF-ERK signaling pathway only in SPARC-expressing cells. Importantly, coexpression of SPARC and PTEN resulted in the smallest, least proliferative tumors with reduced invasive capacity and longer animal survival. Furthermore, direct inhibition of the AKT and SHC-RAF-ERK signaling pathways suppressed the proliferation and migration of SPARC-expressing cells in vitro. These findings demonstrate that PTEN reconstitution or inhibition of signaling pathways that are activated by the loss of PTEN provide potential therapeutic strategies to inhibit SPARC-induced invasion while enhancing the negative effect of SPARC on tumor growth.

Fractionated radiosurgery for 9L gliosarcoma in the rat brain.

PURPOSE Fractionated radiosurgery is being carried out in the clinic to improve the therapeutic ratio of single-dose radiosurgery using various fractionation schemes. Because there is a paucity of experimental radiobiological data in the literature on the tumor response and late-responding normal tissue of critical intracranial structures to radiosurgery, the present animal study was designed to compare the response following a single high dose of radiation with that obtained from calculated fractionated doses of radiosurgery. METHODS AND MATERIALS Male Fischer rats with 9L gliosarcoma growing in their brains were stereotactically irradiated and assayed for the tumor control rate and brain tissue damage. The radiation dose needed for 50% tumor control (TCD50) was used as the endpoint of the efficacy of radiosurgery. Normal brain damage was measured histologically following a period of time over 270 days. Histological evaluation included hematoxylin-eosin (H & E), Luxol fast blue and periodic acid Schiff (LFB/PAS) for the presence of myelin and glial fibrillary acidic protein (GFAP) for the assessment of astrocytic re-activity. The optical density of optic nerves and chiasms staining with LFB/PAS was quantitatively measured using a computer image analysis to assess the magnitude of demyelination. RESULTS Radiosurgery (RS) was found to be more effective in curing small tumors than large tumors. The dose required to control 50% of the tumored animals for 120 days was 24, 31, and 40 Gy for 2-, 6-, and 12-day-old tumors, respectively. Using 12-day-old brain tumors, two fractions of 23.5 Gy and three fractions of 18.5 Gy were found to be equivalent to the single dose of 35 Gy for tumor control. For normal brain damages, the visual pathways including optic nerves and chiasm were found to be highly radiosensitive structures. A single dose of 35 Gy produced 100% severe optic neuropathy. The fractionated RS regimens spared substantial optic nerve damage. CONCLUSION The present data provide a strong radiobiological rationale for the use of fractionated RS in the treatment of tumors located near critical normal structures, including visual pathways. The sparing effect of fractionated RS is greater for late-responding tissues, relative to the rapidly proliferating tumor tissues. This report also characterizes the dose/time tolerance relationship of optic neuropathy after single and fractionated RS.

Treatment induced necrosis versus recurrent/progressing brain tumor: going beyond the boundaries of conventional morphologic imaging

Brain tumor patients undergo various combinations therapies, leading to very complex and confusing imaging appearances on follow up MR imaging and hence, differentiating recurrent or progressing tumors from treatment induced necrosis or effects has always been a challenge in neuro-oncologic imaging. This particular topic has become more relevant these days because of the advent of newer anti-angiogenic and anti-neoplastic chemotherapeutic agents as well as use of salvage radiation therapy. Various clinically available functional imaging modalities can provide additional physiologic and metabolic information about the tumors which could be useful in identifying viable tumor from treatment induced necrosis and hence, can guide treatment planning. In this review we will discuss various functional neuro-imaging modalities, their advantages and limitations and also their utility in treatment planning.

Primary leptomeningeal gliomatosis and "numb, clumsy hands": a case report.

A 48-year-old man presented with the numb, clumsy hand syndrome. Evaluation revealed a high cervical cord lesion. Surgical exploration discovered leptomeningeal gliomatosis with no discernible intraparenchymal component. The clinical features of the case, the neuroimaging studies including magnetic resonance scanning, and the most unusual pathological nature of the lesion are discussed.

Tumorigenicity of cortical astrocyte cell line induced by the protease ADAM17.

The metalloprotease ADAM17 (a.k.a. TACE) plays a pivotal role in the cleavage and activation of membrane‐anchored receptor ligands. More recently, it has been revealed that ADAM17 is a potent sheddase of the epidermal growth factor (EGF) family of ligands and regulates epidermal growth factor receptor (EGFR) activity in a variety of tumors. EGFR is a key component of autonomous growth signaling in several tumors, and correlates with the malignancy grade of astrocytoma. In this study, we tested the hypothesis that over‐expression of ADAM17 in cortical astrocytes derived from normal brain would induce a progression towards a malignant phenotype. Over‐expression of human ADAM17 (hADAM17) in the CTX‐TNA2 cortical astrocyte cell line resulted in non‐adherent growth, increased proliferation, invasiveness, production of angiogenic factors, and expression of genes associated with immature and/or neoplastic cells. hADAM17 up‐regulated EGFR and AKT phosphorylation, and increased proliferation and cell invasion were significantly dependent upon EGFR activity. When implanted in the nude mouse brain, CTX‐TNA2 cells induced low histological grade, benign intraventricular gliomas. In contrast, the same astrocytes with hADAM17 formed large malignant gliomas. Taken together, these findings suggest that unregulated ADAM17 activity induces functional changes in astrocytes that significantly advance the malignant phenotype. (Cancer Sci 2009; 100: 1597–1604)

Morphologic magnetic resonance imaging features of therapy-induced cerebral necrosis

To describe the morphologic magnetic resonance imaging (MRI) findings in histologically proven therapy-induced cerebral necrosis. We retrospectively reviewed the morphologic MRI findings in patients with therapy-induced cerebral necrosis. Images were reviewed for size, location, and characteristics of signal intensity abnormalities and T1-contrast enhancement. Images were also assessed for mass effect, necrosis, cyst, atrophy, cortical thinning, and leukoencephalopathy. The individual imaging characteristics were correlated with clinical and treatment variables. There were 44 patients. Seventy percent had a glioma, all patients had received radiation, and 57% had received chemotherapy in close proximity to radiation. All images demonstrated contrast enhancement, predominantly in the white matter. Enhancement was present in the periventricular/subependymal region in 50% of cases and the corpus callosum in 27%. The most common pattern of lesion peripheral enhancement was “spreading wavefront” and of interior enhancement was “Swiss cheese/soap bubble.” The enhancing lesion was single in 60% of cases. Mass effect was present in 93% of patients. Location and patterns of enhancement were significantly associated with the interval from brain radiation to the diagnosis of therapy-induced cerebral necrosis, tumor histology, patient age, type of radiation, and administration of systemic chemotherapy. This is the largest study of the morphologic conventional MRI findings in pathologically confirmed therapy-induced cerebral necrosis. We characterized the imaging findings in a variety of tumor types following a variety of radiation treatments and other antineoplastic therapy. These findings may be of value in identifying therapy-induced cerebral necrosis in patients treated for a brain tumor.