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ABSTRACT: We report a 66-year-old man with a spinal, extradural solitary fibrous tumor showing unique retiform and papillary architecture. The patient presented in May 2008 with worsening right-sided lower back pain and urinary frequency. Magnetic resonance imaging of the spine documented a heterogeneously enhancing dumbbell-shaped extradural lesion causing cord compression at T11/12 level. The tumor extended to the paravertebral soft tissue and invaded the right adjacent vertebral pedicles and laminae. An angiogram showed prominent vascular supply mainly from the right T11 radicular artery. The patient underwent surgery to relieve cord compression in May 2008 and a second operation following embolization with coils in October 2009. No recurrence was observed at the last neuroimaging follow-up in June 2012. The tumor was composed of vimentin, CD34, Bcl-2, and CD99-positive rounded or slightly elongated cells with scant cytoplasm and oval to spindle nuclei. Several pseudovascular spaces reminiscent of the rete testis were present, and several of them contained papillary projections. Cytologic atypia was minimal, and mitotic activity was low. Focal infiltration of the paraspinal adipose tissue was seen at microscopic level. To our knowledge, retiform and papillary features have never been reported in a solitary fibrous tumor.
Annals of diagnostic pathology 02/2013;
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ABSTRACT: The primary progressive form of multiple sclerosis is characterized by accrual of neurological dysfunction from disease onset without remission and it is still a matter of debate whether this disease course results from different pathogenetic mechanisms compared with secondary progressive multiple sclerosis. Inflammation in the leptomeninges has been identified as a key feature of secondary progressive multiple sclerosis and may contribute to the extensive cortical pathology that accompanies progressive disease. Our aim was to investigate the extent of perivascular and meningeal inflammation in primary progressive multiple sclerosis in order to understand their contribution to the pathogenetic mechanisms associated with cortical pathology. A comprehensive immunohistochemical analysis was performed on post-mortem brain tissue from 26 cases with primary progressive multiple sclerosis. A variable extent of meningeal immune cell infiltration was detected and more extensive demyelination and neurite loss in the cortical grey matter was found in cases exhibiting an increased level of meningeal inflammation. However, no tertiary lymphoid-like structures were found. Profound microglial activation and reduction in neuronal density was observed in both the lesions and normal appearing grey matter compared with control cortex. Furthermore, cases with primary progressive multiple sclerosis with extensive meningeal immune cell infiltration exhibited a more severe clinical course, including a shorter disease duration and younger age at death. Our data suggest that generalized diffuse meningeal inflammation and the associated inflammatory milieu in the subarachnoid compartment plays a role in the pathogenesis of cortical grey matter lesions and an increased rate of clinical progression in primary progressive multiple sclerosis.
Brain 08/2012; 135(Pt 10):2925-37. · 9.46 Impact Factor
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ABSTRACT: We report a rare occurrence of intracranial Rosai-Dorfman disease (RDD), in a young patient with multiple bilateral intracerebral lesions, and discuss her management. RDD is an histiocytic proliferative disorder, which seldom presents with intracranial pathology. Intraparenchymal RDD without concurrent systemic features is rare. This 31-year old woman presented with two focal seizures, but no peripheral lymphadenopathy, and no significant systemic abnormalities. Preoperative imaging showed intrinsic space-occupying lesions in the left frontal lobe, and right parietal and right inferior frontal white matter. She underwent excision of the peripherally located left frontal lesion, and aside from a five-day course of postoperative dexamethasone, received no further active treatment. Histopathological analysis revealed the characteristic features of RDD. Postoperative imaging, taken at 10 weeks and 12 months, demonstrated resolution of all three lesions. This patient had a rare multifocal, bilateral, intracerebral RDD, illustrating that although a histological diagnosis is necessary, further treatment may not be required.
Journal of Clinical Neuroscience 06/2012; 19(9):1308-10. · 1.25 Impact Factor
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ABSTRACT: Background: Neurodegenerative diseases are characterized by key features such as loss of neurons, astrocytosis, and microglial activation/proliferation. These changes cause differences in the density of cell types between control and disease subjects, confounding results from gene expression studies. Chromosome X (ChrX) is known to be specifically important in the brain. We hypothesized the existence of a chromosomal signature of gene expression associated with the X-chromosome for neurological conditions not normally associated with that chromosome. The hypothesis was investigated using publicly available microarray datasets from studies on Parkinson's disease, Alzheimer's disease, and Huntington's disease. Data were analyzed using Chromowave, an analytical tool for detecting spatially extended expression changes along chromosomes. To examine associations with neuronal density and astrocytosis, the expression of cell specific reporter genes was extracted. The association between these genes and the expression patterns extracted by Chromowave was then analyzed. Further analyses of the X:Autosome ratios for laser dissected neurons, microglia cultures and whole tissue were performed to detect cell specific differences. Results: We observed an extended pattern of low expression of ChrX consistent in all the neurodegenerative disease brain datasets. There was a strong correlation between mean ChrX expression and the pattern extracted from the autosomal genes representing neurons, but not with mean autosomal expression. No chromosomal patterns associated with the neuron specific genes were found on other chromosomes. The chromosomal expression pattern was not present in datasets from blood cells. The X:Autosome expression ratio was also higher in neuronal cells than in tissues with a mix of cell types. Conclusions: The results suggest that neurological disorders show as a reduction in mean expression of many genes along ChrX. The most likely explanation for this finding relates to the documented general up-regulation of ChrX in brain tissue which, this work suggests, occurs primarily in neurons. If validated, this cell specific ChrX expression warrants further research as understanding the biological reasons and mechanisms for this expression, may help to elucidate a connection with the development of neurodegenerative disorders.
Frontiers in Neuroscience 01/2012; 6:161.
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Owain W Howell,
Cheryl A Reeves,
Richard Nicholas,
Daniele Carassiti,
Bishan Radotra,
Steve M Gentleman,
Barbara Serafini,
Francesca Aloisi, Federico Roncaroli,
Roberta Magliozzi,
Richard Reynolds
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ABSTRACT: Meningeal inflammation in the form of ectopic lymphoid-like structures has been suggested to play a prominent role in the development of cerebral cortical grey matter pathology in multiple sclerosis. The aim of this study was to analyse the incidence and distribution of B cell follicle-like structures in an extensive collection of cases with secondary progressive multiple sclerosis with a wide age range and to determine their relationship to diffuse meningeal inflammation, white matter perivascular infiltrates and microglial activation. One hundred and twenty three cases with secondary progressive multiple sclerosis were examined for the presence of meningeal and perivascular immune cell infiltrates in tissue blocks and/or whole coronal macrosections encompassing a wide array of brain areas. Large, dense, B cell-rich lymphocytic aggregates were screened for the presence of follicular dendritic cells, proliferating B cells and plasma cells. Ectopic B cell follicle-like structures were found, with variable frequency, in 49 cases (40%) and were distributed throughout the forebrain, where they were most frequently located in the deep sulci of the temporal, cingulate, insula and frontal cortex. Subpial grey matter demyelinated lesions were located both adjacent to, and some distance from such structures. The presence of B cell follicle-like structures was associated with an accompanying quantitative increase in diffuse meningeal inflammation that correlated with the degree of microglial activation and grey matter cortical demyelination. The median age of disease onset, time to disease progression, time to wheelchair dependence and age at death all differed significantly in these cases when compared with those without B cell follicle-like structures. Our findings suggest that meningeal infiltrates may play a contributory role in the underlying subpial grey matter pathology and accelerated clinical course, which is exacerbated in a significant proportion of cases by the presence of B cell follicle-like structures.
Brain 08/2011; 134(Pt 9):2755-71. · 9.46 Impact Factor
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ABSTRACT: Multiple sclerosis is the major inflammatory condition affecting the central nervous system (CNS) and is characterised by disseminated focal immune-mediated demyelination. Demyelination is accompanied by variable axonal damage and loss and reactive gliosis. It is this pathology that is thought to be responsible for the clinical relapses that often respond well to immunomodulatory therapy. However, the later secondary progressive stage of MS remains largely refractory to treatment and it is widely suggested that accumulating axon loss is responsible for clinical progression. Although initially thought to be a white matter (WM) disease, it is increasingly apparent that extensive pathology is also seen in the grey matter (GM) throughout the CNS. GM pathology is characterised by demyelination in the relative absence of an immune cell infiltrate. Neuronal loss is also seen both in the GM lesions and in unaffected areas of the GM. The slow progressive nature of this later stage combined with the presence of extensive grey matter pathology has led to the suggestion that neurodegeneration might play an increasing role with increasing disease duration. However, there is a paucity of studies that have correlated the pathological features with clinical milestones during secondary progressive MS. Here, we review the contributions that the various types of pathology are likely to make to the increasing neurological deficit in MS.
Acta Neuropathologica 05/2011; 122(2):155-70. · 9.32 Impact Factor
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ABSTRACT: A 29-year-old Ethiopian man presented with marked bilateral visual loss, headache, hypopituitarism and significant hyponatraemia (115 mmol/L). A brain MRI scan demonstrated a large, lobulated, sellar and suprasellar mass, elevating the floor of the 3rd ventricle and compressing the optic chiasm. The patient underwent a transphenoidal resection of the mass followed by a craniotomy 10 days later. Histological examination demonstrated a Hyams' grade III neuroblastoma with ectopic expression of vasopressin. He underwent fractionated radiotherapy at a dose of 60 Gy in 30 fractions. Fourteen months after the onset, he is well with no neuroimaging evidence of tumour recurrence. His serum and urine sodium are completely normalised.
Endocrine Pathology 11/2010; 21(4):266-73. · 1.36 Impact Factor
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ABSTRACT: Prominent inflammation with formation of ectopic B-cell follicle-like structures in the meninges in secondary progressive multiple sclerosis (MS) (SPMS) is associated with extensive cortical pathology and an exacerbated disease course. Our objective was to evaluate the cellular substrates of the cortical damage to understand the role of meningeal inflammation in MS pathology.
Using >600 tissue blocks from 37 cases of SPMS and 14 non-neurological controls, we carried out a detailed quantitative analysis of cortical atrophy and layer-specific changes in cell populations in SPMS cases with (F(+) SPMS) and without (F⁻ SPMS) B-cell follicle-like structures.
B-cell follicle-like structures were detected in the inflamed meninges of 20 of 37 SPMS cases (54%) and were associated with increased subpial cortical demyelination and cortical atrophy. A clear gradient of neuronal loss was observed in grey matter lesions and normal-appearing grey matter in the motor cortex of F(+) SPMS cases. The density of pyramidal neurons was significantly reduced in layers III and V of the motor cortex. Neuronal loss was accompanied by glia limitans damage with astrocyte loss and an opposite gradient of increased density of activated microglia. No gradient of neuronal loss was seen in F⁻ SPMS cases.
We demonstrate substantial cortical neurodegeneration and generalized cell loss in progressive MS in association with meningeal inflammation and lymphoid tissue formation, supporting the hypothesis that cytotoxic factors diffusing from the meningeal compartment contribute to grey matter pathology and the consequent increase in clinical disability.
Annals of Neurology 10/2010; 68(4):477-93. · 11.09 Impact Factor
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ABSTRACT: Microdialysis allows sampling of the extra cellular fluid of normal and pathological tissues. Accurate positioning of catheters in viable, representative tumour tissue is crucial for the accuracy and effectiveness of the technique. We have performed microdialysis with the aid of intra-operative three-dimensional ultrasonography (3D-US) to guide the placement of catheters in seven patients undergoing resection for supratentorial high-grade astrocytoma. The final position of the catheter tip membrane was confirmed by intra-operative ultrasound scanning. The accuracy of the spatial targeting was validated by pathological examination and the quality of the microdialysate was checked with ultra performance liquid chromatography-mass spectrometry. Our results indicate that intra-operative 3D-US can be used to correctly position catheters for microdialysis and allows adjustment to the catheters, when necessary, prior to the dialysis of viable target tumour tissue.
Journal of Clinical Neuroscience 04/2010; 17(4):506-10. · 1.25 Impact Factor
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ABSTRACT: We report a case of primary leptomeningeal gliomatosis limited to the spinal cord occurring in a 52 years-old patient, who presented with back pain and leg weakness. MRI-scan of the craniospinal axis revealed an enhancing cervicothoracic lesion confined to the leptomeninges. A diagnostic biopsy was taken followed by a six level cervicothoracic laminoplasty with the aim of debulking of the dorsal portion of the tumour and relieving cord compression. Two weeks following surgery, the patient developed bilateral arm weakness. Repeat imaging revealed extension of the lesion to the level of the lower medulla. This patient underwent spinal radiotherapy and concomitant chemotherapy with Temozolomide, but she died of pneumonia 8.5 months after the time of diagnosis. No post-mortem was performed. Primary leptomeningeal gliomatosis exclusively involving the spinal cord is an extremely rare condition bearing a dismal prognosis. It can be suspected on neuroimaging, but histopathological examination is required for the final diagnosis. No current treatment protocols are available. Decompressive surgery may have a role in relieving symptoms, but no substantial benefit has been proven in administering radio-chemotherapy.
Journal of Neuro-Oncology 11/2009; 98(1):125-9. · 3.21 Impact Factor
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Neuropathology and Applied Neurobiology 10/2009; 36(1):90-4. · 3.80 Impact Factor
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ABSTRACT: We describe an intraosseous angiolipoma of the cranium and discuss the outcome. Angiolipomas are benign tumors that consist of mature adipose tissue and abnormal vessels. They occur predominantly in the subcutaneous tissue of the trunk and upper limbs. Only 4 examples of intraosseous angiolipomas have been reported in the literature, all of which involved the mandible and ribs.
A 39-year-old man presented with a right parietal swelling. The patient initially refused surgery; thus it was possible to follow this case for 11 years, allowing us to evaluate the natural history of this rare condition.
Complete surgical excision of the intraosseous lesion was achieved with a titanium cranioplasty performed at intervals. Fifteen months after surgery, no recurrence was seen.
This is the first known report of intraosseous angiolipoma of the cranium. Angiolipomas are rare, benign, slow-growing tumors with an excellent prognosis. On preoperative neuroimaging, they may mimic intraosseous angiomas, lipomas, or intraosseous meningiomas. Total resection is curative.
Neurosurgery 02/2009; 64(1):E189-90; discussion E190. · 2.79 Impact Factor
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ABSTRACT: Galectin-3 expression has been reported in spindle cell oncocytoma, certain pituitary adenoma subtypes, astrocytomas, oligodendrogliomas, and meningiomas. We evaluated galectin-3 protein expression by immunohistochemistry in 201 cases of a variety of nervous system and sellar tumors, as well as mRNA expression by reverse transcription-polymerase chain reaction in formalin-fixed paraffin-embedded tissue in a subset (20 cases). Immunohistochemical results were evaluated in a semiquantitative fashion on a 4-tiered scale (0 to 3). Strong (3+) immunoreactivity was seen in most of the cases (61%), followed by 2+(22%), and 1+(13%) staining. Only 4% of the lesions studied were immunonegative. Galectin-3 mRNA was present in 15 of the 18 cases (83%) in which reverse transcription-polymerase chain reaction was successful. Significant differences in protein expression were noted in the following 2 settings: specific meningioma subtypes (P=0.004, Fisher exact test) wherein clear cell meningioma demonstrated weak protein expression when compared with other meningioma variants. No significant difference was noted with respect to World Health Organization grade. Galectin-3 was also strongly expressed in benign nerve sheath tumors but only moderately expressed in malignant peripheral nerve sheath tumors (P=0.0009, Fisher exact test). Although galectin-3 positivity is a key feature of the immunophenotype of spindle cell oncocytoma, its consistent expression in other morphologically similar tumors (meningioma, pituicytoma, nerve sheath tumors, granular cell tumor, metastases) makes it of little use in the differential diagnosis of sellar region tumors, a setting in which it should be discouraged. Diagnostic uses of this marker may be limited to specific settings, including some meningioma subtypes and nerve sheath tumors.
The American journal of surgical pathology 10/2008; 32(9):1344-52. · 4.06 Impact Factor
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ABSTRACT: 11C-(R)-PK11195 is a PET radiotracer for the quantification of peripheral benzodiazepine binding sites (PBBSs). The PBBS is a consistent marker of activated microglia, and 11C-(R)-PK11195 has been used to image microglial activity in the diseased brain and in neoplasia. However, the PBBS is also expressed in the brain vasculature (endothelium and smooth muscles), and no evidence, to our knowledge, exists of a change in the vascular PBBS in pathologic brains or of such a change having an effect on the quantification of 11C-(R)-PK11195 binding. To investigate this issue, we have used a modified reference-tissue model (SRTMV) that accounts for tracer vascular activity both in reference and target tissues and applied it for the estimation of binding potential (BP) in a cohort of patients with Alzheimer's disease (AD).
A total of 10 patients with AD and 10 age-matched healthy subjects who underwent a 11C-(R)-PK11195 scan were considered in the analysis. The time-activity curves of 11 regions of interest were extracted using the Hammersmith maximum probability atlas. BPs were first estimated using the standard simplified reference-tissue model (SRTM) with the reference tissue computed with a supervised selection algorithm. Subsequently, we applied an SRTMV that models PBBS vascular activity using an additional linear term for both target (VbT) and reference (VbR) regions accounting for vascular tracer activity (C(B)), whereas C(B) was extracted directly from the images. VbR was fixed to 5%, and R1, k2, BP, and VbT were estimated. PBBS density in the vasculature was also assessed by immunocytochemistry on a separate cohort of young and elderly controls and 3 AD postmortem brains.
The inclusion of a vascular component in the SRTM increased BPs in all subjects, but the amount of the increase was different (about 11.9% in controls and 16.8% in patients with AD). In addition, average VbT values derived using the SRTMV were 4.22% for controls but only 2.87% in patients with AD. Immunochemistry showed reduced PBBS expression in AD due to vascular fibrosis.
The reduction of VbT in AD can be interpreted as a consequence of 2 independent but concurring phenomena. The vascular fibrosis in the AD brain causes the well-documented decrease of the size of lumens and the reduction of blood volume. At the same time, the fibrotic process determines the loss of vascular PBBS, particularly in smooth muscles, as here documented by immunochemistry. The inclusion of the additional vascular component in the SRTM effectively models these 2 concurrent processes and amplifies the BP in AD more than in controls because of the decrease in tracer binding to the vasculature in the disease cohort.
Journal of Nuclear Medicine 08/2008; 49(8):1249-56. · 6.38 Impact Factor
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ABSTRACT: Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread transcriptional dysregulation. Mutant huntingtin also interacts with histone acetyltransferases, consequently interfering with the acetylation and deacetylation states of histones. Because histone modifications and chromatin structure coordinate the expression of gene clusters, we have applied a novel mathematical approach, Chromowave, to analyse microarray datasets of brain tissue and whole blood to understand how genomic regions are altered by the effects of mutated huntingtin on chromatin structure. Results show that, in samples of caudate and whole blood from Huntington's disease patients, transcription is indeed deregulated in large genomic regions in coordinated fashion, that transcription in these regions is associated with disease progression and that altered chromosomal clusters in the two tissues are remarkably similar. These findings support the notion of a common genome-wide mechanism of disruption of RNA transcription in the brain and periphery of Huntington's disease patients.
Brain 03/2008; 131(Pt 2):381-8. · 9.46 Impact Factor
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Shigetoshi Takaya,
Kazuo Hashikawa,
Federico E Turkheimer,
Nicholas Mottram,
Manuel Deprez,
Koichi Ishizu,
Hidekazu Kawashima,
Haruhiko Akiyama,
Hidenao Fukuyama,
Richard B Banati, Federico Roncaroli
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ABSTRACT: The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [(11)C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson's disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [(11)C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.
Journal of Neuro-Oncology 11/2007; 85(1):95-103. · 3.21 Impact Factor
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ABSTRACT: We have reviewed the features of two recently described intracranial tumors, which have been formally recognized as distinct entities by the 2007 WHO Classification of Brain Tumours: Papillary tumor of the pineal region and spindle cell oncocytoma of the pituitary gland. Their salient clinicopathological features, differential diagnosis, histogenetic hypothesis and outcome are discussed.
Brain Pathology 08/2007; 17(3):314-8. · 3.99 Impact Factor
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Brain Pathology 05/2007; 17(2):251-2. · 3.99 Impact Factor
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ABSTRACT: Although p53 overexpression detected by immunohistochemistry has been reported in pituitary adenomas and carcinomas, genetic mutations in the p53 gene have not been previously detected in these tumors. We analyzed a series of eight pituitary adenomas and six pituitary carcinomas by immunohistochemistry, polymerase chain reaction amplification, and sequencing of p53 exon 5 through exon 8 for genetic mutations. Three carcinomas showed more than 20% expression of p53 protein in the tumor cells. One of these tumors with 60% overexpression of p53 protein had a mutation in codon 248, a common "hot spot" for p53 mutation, while the other carcinoma with 90% overexpression of p53 protein had a mutation in codon 135. All adenomas were negative for p53 mutations and had 15% of the cells expressing the p53 protein. Analysis of control tumors including four lung carcinomas with proven p53 mutations also had greater than 85% of the tumor cells overexpressing p53 protein. Two breast carcinoma cell lines with known p53 mutations, MBA-MD 231 and MBA-MD-486, also showed greater than 85% of the tumor cells overexpressing p53. These results show that p53 mutations are present in a subset of pituitary carcinomas and are usually associated with a high percentage of tumor cells overexpressing the p53 protein.
Endocrine Pathology 02/2007; 18(4):217-22. · 1.36 Impact Factor
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ABSTRACT: PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level.
The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease.
The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596).
Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain.
Journal of Nuclear Medicine 02/2007; 48(1):158-67. · 6.38 Impact Factor
