Glioblastoma radiomics: can genomic and molecular characteristics correlate with imaging response patterns?

PURPOSE: For glioblastoma (GBM), imaging response (IR) or pseudoprogression (PSP) is frequently observed after chemoradiation and may connote a favorable prognosis. With tumors categorized by the Cancer Genome Atlas Project (mesenchymal, classical, neural, and proneural) and by methylguanine-methyltransferase (MGMT) methylation status, we attempted to determine if certain genomic or molecular subtypes of GBM were specifically associated with IR or PSP. METHODS: Patients with GBM treated at two institutions were reviewed. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Mantel-cox test determined effect of IR and PSP on OS and PFS. Fisher's exact test was utilized to correlate IR and PSP with genomic subtypes and MGMT status. RESULTS: Eighty-two patients with GBM were reviewed. The median OS and PFS were 17.9 months and 8.9 months. IR was observed in 28 (40%) and was associated with improved OS (median 29.4 vs 14.5 months p < 0.01) and PFS (median 17.7 vs 5.5 months, p < 0.01). PSP was observed in 14 (19.2%) and trended towards improved PFS (15.0 vs 7.7 months p = 0.08). Tumors with a proneural component had a higher rate of IR compared to those without a proneural component (IR 60% vs 28%; p = 0.03). MGMT methylation was associated with IR (58% vs 24%, p = 0.032), but not PSP (34%, p = 0.10). CONCLUSION: IR is associated with improved OS and PFS. The proneural subtype and MGMT methylated tumors had higher rates of IR.

Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). RESULTS: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases). CONCLUSION: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. IMPLICATIONS FOR PRACTICE: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.

Evisceration With Injectable Hydrogel Implant in a Rabbit Model.

PURPOSE: To determine the safety, durability, and biocompatibility of 2.5% polyacrylamide hydrogel (Aquamid, Specialty European Pharma, Ltd., London, UK) as an injectable viscoelastic implant following evisceration in a rabbit model. METHODS: The protocol was reviewed and approved by the Wake Forest Institutional Animal Care and Use Committee. Adult New Zealand rabbits underwent cornea-sparing evisceration of the right eye with injection of 2.5% polyacrylamide hydrogel implant. The rabbits were sacrificed after 2 weeks (n = 1), 5 weeks (n = 2), 12 weeks (n = 3), 25 weeks (n = 3), and 1 year (n = 3) to evaluate the implant volume and host reaction to the implant. Both eyes were enucleated and their diameters were measured. The eviscerated eyes were fixed in formalin and processed using routine histopathologic methods to assess inflammatory reaction and vascularization. RESULTS: The implant material was well tolerated with a moderate giant cell reaction seen at 6 weeks that improved over time. Extensive vascularization of the implant was noted starting at 6 weeks. There was excellent maintenance of globe volume that did not diminish over time. The relative diameters of the eviscerated eyes compared with control were 89 ± 6% (mean% ± SD) at 12 weeks (n = 3), 94 ± 2% at 25 weeks (n = 3), and 93 ± 4% at 1 year (n = 3). CONCLUSION: With further study, injectable 2.5% polyacrylamide hydrogel may provide an excellent alternative to solid orbital implants. The implant material was universally well tolerated and maintained appropriate volume in the orbit for the study period of 1 year. Extensive vascularization of the implant was noted indicating biointegration.

Anaplastic ganglioglioma: a report of three cases and review of the literature.

Gangliogliomas are rare tumors of the central nervous system that are thought to arise from a glioneuronal precursor and consist of both neuronal and glial elements. Grade III, or anaplastic ganglioglioma (AGG), most commonly affects children and young adults, generally arises in a supratentorial location, is highly epileptogenic, and often results in diffuse local and distant failure within the craniospinal axis. Pathologically, these tumors are graded by the degree of malignancy in their glial portion and radiologic diagnosis is difficult due to the wide variation in its degree of solid and cystic components, contrast uptake, and calcification patterns. This report presents three cases of AGG, with initial treatment including subtotal resection followed by conformal radiotherapy. In the case where the AGG developed in the setting of an existent low-grade astrocytoma, the patient received no chemotherapy. Both of the other de novo cases were managed with adjuvant chemoradiotherapy with temozolomide. Recurrence occurred at 6, 16, and 20 months following therapy. Two of the three patients experienced symptomatic decline at recurrence, but experienced Karnofsky performance status (KPS) improvement after salvage therapy, including the reduction of cranial neuropathy and balance. All patients had a significant reduction in presenting symptoms following salvage therapy. Patients died at 23, 20, and 22 months following initial surgical management, respectively. A review of anaplastic and malignant gangliogliomas is presented in the context of these three cases.

Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer.

Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1-cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1-induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1-deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre-malignant mammary glands from Dmp1(+/+);MMTV-cyclin D1 and Dmp1(+/+);MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer.

Patterns of failure after treatment of atypical meningioma with gamma knife radiosurgery.

Atypical meningiomas have poor local control with emerging literature indicating the use of radiosurgery in treatment. The purpose of this study was to evaluate clinical outcomes including local control and failure pattern after Gamma Knife radiosurgery (GKRS) and factors that may affect these outcomes. Between 1999 and 2008, 24 patients were treated with GKRS as either primary or salvage treatment for pathologically proven atypical meningiomas. Treatment failures were determined by serial magnetic resonance imaging. A median marginal dose of 14 Gy was used (range 10.5-18 Gy). Overall local control rates at 1, 2, and 5 years were 75, 51, and 44%, respectively. With median follow-up time of 42.5 months, 14 of 24 patients experienced a treatment failure at time of last follow-up. Eight recurrences were in-field, four were marginal failures, and two were distant failures. Wilcoxon analysis revealed that the conformality index (CI) was a significant predictor of local recurrence (P = 0.04). CI did not predict for distant recurrences (P = 0.16). On multivariate analysis evaluating factors predicting progression free survival, dose >14 Gy was found to be statistically significant (P = 0.01). There appears to be a dose response using GKRS beyond 14 Gy but given the suboptimal local control rates in this study, higher doses may still be needed to obtain better local control.

PTCH1 mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Radiation-induced adult medulloblastoma: a two-case report and review of the literature.

Radiation-induced medulloblastoma is an exceedingly rare phenomenon for which treatment standards have not been established. The literature suggests that these tumors are high grade with aggressive behavior. We report two cases of radiation-induced medulloblastoma which have been treated with full dose re-irradiation with curative intent. In both cases, treatment toxicity and tumor progression proved to be insurmountable obstacles. Further reports are necessary in order to fully characterize this clinical entity so that more effective therapies may be sought.

Metastatic Alveolar Rhabdomyosarcoma with Extensive Bone Marrow Replacement in an Older Adult.

Rhabdomyosarcoma is extremely rare in adults. Metastatic rhabdomyosarcoma can resemble other malignancies, which can delay diagnosis and prompt treatment. This case illustrates an example of metastatic alveolar rhabdomyosarcoma with concurrent bone marrow infiltration. A 67-year-old woman presented with epistaxis and diffuse bone pain. She developed progressive thrombocytopenia requiring platelet transfusions. The patient was initially thought to have leukemia. She was found to have a large sinonasal mass with extensive metastatic disease and bone marrow infiltration. The patient was ultimately diagnosed with metastatic alveolar rhabdomyosarcoma. She was started on chemotherapy with vincristine, actinomycin, and cyclophosphamide. Unfortunately, she died prior to discharge home. Alveolar rhabdomyosarcoma can resemble a primary bone marrow malignancy when it infiltrates the bone marrow. Further investigation is needed to clarify its clinical behavior and expedite diagnosis and treatment.

Ovarian malignant mixed mesodermal tumor with neuroectodermal differentiation: a multifaceted evaluation.

Malignant mixed mesodermal tumors (MMMTs) of the ovary are rare, highly aggressive neoplasms that arise most commonly in postmenopausal women. Histologically, they consist of a mixed population of malignant epithelial and mesenchymal elements. Neuroectodermal differentiation in ovarian MMMTs is exceedingly uncommon, with only a few case reports in the literature. We present a case of an ovarian MMMT with neuroectodermal differentiation in a 78-year-old female patient. Histologically, the tumor was composed of epithelial, mesenchymal, and neuroectodermal elements. The neuroectodermal component was predominantly that of a medulloepithelioma, with scattered areas displaying features of an anaplastic astrocytoma, including rare ganglion cell differentiation. The neuroectodermal component showed immunoreactivity for glial fibrillary acidic protein, synaptophysin, and S100 protein. Ultrastructurally, the neuroectodermal component was populated by cells with irregular nuclei, finely dispersed chromatin, rudimentary cell junctions, and a delicate basement membrane, all of which have been described in medulloepitheliomas. DNA ploidy analysis was also performed on the various components of the tumor and compared with 3 additional cases of MMMT without neuroectodermal differentiation and 2 ovarian immature teratomas. Our findings suggest that the neuroectodermal component may arise from a separate clone or at least evolves at an earlier stage of tumor development.

Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.

Ultrasonographic Tinel sign.

High-resolution ultrasound has become increasingly useful in the evaluation of peripheral nerves. As we have gained experience, clinically helpful ultrasonographic signs have been detected. One of these is the ultrasonographic Tinel sign, in which paresthesias are produced when the transducer compresses a nerve lesion. This sign has not been previously described. We present a case in which the ultrasonographic Tinel sign helped accurately guide a nerve biopsy in a woman with mononeuritis multiplex.

Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation.

OBJECT: Diffusely infiltrating astrocytomas are the most common primary brain tumors. As a group, they demonstrate an inherent tendency toward malignant progression. Histological grading using the guidelines of the World Health Organization (WHO) remains the gold standard for predicting the biological behavior of these tumors. Although useful, this grading system is often limited due to small sample sizes and the subjectivity in interpretation. Given the important roles for EGFR and PTEN in the malignant progression of astrocytomas, the authors hypothesized that the fraction of tumor cells with aberrations in these genetic loci would correlate with the histological grade. METHODS: The authors evaluated 217 consecutive diffusely infiltrating astrocytomas that were graded using the WHO guidelines, including 16 diffuse astrocytomas (WHO Grade II), 72 anaplastic astrocytomas ([AAs] WHO Grade III), and 129 glioblastomas multiforme ([GBMs] WHO Grade IV). Cases were evaluated quantitatively using dual-color fluorescence in situ hybridization with probes for the EGFR and PTEN loci and the centromeres of chromosomes 7 and 10. RESULTS: The population of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus correlated significantly with histological grade. In particular, high-grade astrocytomas (that is, AAs and GBMs) had elevated fractions of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus. Using these findings, the authors generated a mathematical model capable of subcategorizing high-grade astrocytomas. The successful model incorporated only the percentage of tumor cells with polysomy of EGFR and monosomy of PTEN, as well as patient age. The predictions of this model correlated with survival in a manner similar to histopathological grading. CONCLUSIONS: The findings presented in this study emphasize the utility of combining histological interpretation and molecular testing in the evaluation of infiltrating astrocytomas. These results underscore the utility of building a grading framework that combines histopathological and molecular analysis.

Hypoxia-inducible factor 2α: a novel target in gliomas.

Hypoxia is an important contributor to aggressive behavior and resistance mechanisms in glioblastoma. Upregulation of hypoxia inducible transcription factors (HIFs) is the primary adaptive cellular response to a hypoxic environment. While HIF1α has been widely studied in cancer, HIF2α offers a potentially more specific and appealing target in glioblastoma given expression in glioma stem cells and not normal neural progenitors, activation in states of chronic hypoxia and expression that correlates with glioma patient survival. A first-in-class HIF2α inhibitor, PT2385, is in clinical trials for renal cell carcinoma, and provides the first opportunity to therapeutically target this important pathway in glioma biology.

Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control.

We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (≤4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p-value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT.

Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.

BACKGROUND: Microglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain. Neuritic plaques are fibrous deposits composed of the amyloid beta-peptide fragments (Abeta) of the amyloid precursor protein (APP). Numerous studies have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical (Th-1) immune activation in AD. Nonetheless, the complex role of microglial activation has yet to be fully explored since recent studies show that peripheral macrophages enter an "alternative" activation state. METHODS: To study alternative activation of microglia, we used quantitative RT-PCR to identify genes associated with alternative activation in microglia, including arginase I (AGI), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and chitinase 3-like 3 (YM1). RESULTS: Our findings confirmed that treatment of microglia with anti-inflammatory cytokines such as IL-4 and IL-13 induces a gene profile typical of alternative activation similar to that previously observed in peripheral macrophages. We then used this gene expression profile to examine two mouse models of AD, the APPsw (Tg-2576) and Tg-SwDI, models for amyloid deposition and for cerebral amyloid angiopathy (CAA) respectively. AGI, MRC1 and YM1 mRNA levels were significantly increased in the Tg-2576 mouse brains compared to age-matched controls while TNFalpha and NOS2 mRNA levels, genes commonly associated with classical activation, increased or did not change, respectively. Only TNFalpha mRNA increased in the Tg-SwDI mouse brain. Alternative activation genes were also identified in brain samples from individuals with AD and were compared to age-matched control individuals. In AD brain, mRNAs for TNFalpha, AGI, MRC1 and the chitinase-3 like 1 and 2 genes (CHI3L1; CHI3L2) were significantly increased while NOS2 and IL-1beta mRNAs were unchanged. CONCLUSION: Immune cells within the brain display gene profiles that suggest heterogeneous, functional phenotypes that range from a pro-inflammatory, classical activation state to an alternative activation state involved in repair and extracellular matrix remodeling. Our data suggest that innate immune cells in AD may exhibit a hybrid activation state that includes characteristics of classical and alternative activation.

Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias.

The frontotemporal dementias (FTDs) are a heterogeneous group of neurodegenerative disorders that are characterized clinically by dementia, personality changes, language impairment, and occasionally extrapyramidal movement disorders. Historically, the diagnosis and classification of FTDs has been fraught with difficulties, especially with regard to establishing a consensus on the neuropathologic diagnosis. Recently, an international group of scientists participated in a consensus conference to develop such neuropathologic criteria. They recommended a diagnostic classification scheme that incorporated a biochemical analysis of the insoluble tau isoform composition, as well as ubiquitin immunohistochemistry. The use and reliability of this classification system has yet to be examined. In this study, we evaluated 21 cases of FTD. Using traditional histochemical stains and tau protein and ubiquitin immunohistochemistry, we separated each case into one of the following categories: classic Pick disease (PiD; n = 7), corticobasal degeneration (CBD; n = 5), dementia lacking distinctive histopathologic features (DLDH; n = 4), progressive supranuclear palsy (PSP; n = 2), frontotemporal lobar degeneration with motor neuron disease or motor neuron disease-type inclusions (FTLD-MND/MNI; n = 2), and neurofibrillary tangle dementia (NFTD; n = 1). Additionally, we independently categorized each case by the insoluble tau isoform pattern, including 3R (n = 5), 4R (n = 7), 3R/4R (n = 3), and no insoluble tau (n = 6). As suggested by the proposed diagnostic scheme, we found that the insoluble tau isoform patterns correlated strongly with the independently derived histopathologic diagnoses (p < 0.001). The data show that cases containing predominantly 3R tau were classic PiD (100%). Cases with predominantly 4R tau were either CBD (71%) or PSP (29%). Cases with both 3R and 4R tau were either a combination of PiD and Alzheimer disease (67%) or NFTD (33%). Finally, cases with no insoluble tau were either DLDH (67%) or FTLD-MND/MNI (33%). To further characterize these cases, we also performed quantitative Western blots for soluble tau, APOE genotyping, and, in selected cases, tau gene sequencing. We show that soluble tau is reduced in DLDH and FTLD-MND/MNI and that APOE4 is overrepresented in PiD and DLDH. We also identified a new family with the R406W mutation and pathology consistent with NFTD. This study validates the recently proposed diagnostic criteria and forms a framework for further refinement of this classification scheme.

Neuropathology of Alzheimer's disease.

In 1907, Alois Alzheimer described the presence of plaques and neurofibrillary tangles in a demented patient. Currently, Alzheimer's disease is known to be the most common cause of dementia in elderly patients. In this article, we summarize the most important neuropathologic features of Alzheimer's disease, including amyloid plaques, neurofibrillary tangles, neuronal loss, synaptic depletion, cerebral amyloid angiopathy, Hirano bodies, and granulovacuolar degeneration. We also review the history and application of Alzheimer's disease diagnostic criteria.

Relapsing intracranial plasma cell granuloma: A case report.

Plasma cell granuloma is a pathological entity reported in nearly every organ system; however, intracranial cases remain rare. In the current case report, we present a case of intracranial plasma cell granuloma with the longest known follow-up period in the literature. Medical follow-up over 14 years, detailing four recurrences following the patient's initial presentation and management, is presented. The patient's treatment course consisted of three craniotomies, 3,600-cGy fractionated radiation and two courses of glucocorticoid therapy. In addition to disease surveillance using clinical examination and imaging, this case represents the first description of the clinical utility of analyzing changes in an inflammatory blood marker, the erythrocyte sedimentation rate, which coincided with recurrence and response to therapy.

Malignant transformation of an intramedullary epidermoid cyst in the thoracic region of the spinal cord: case report.

Malignant transformation of epidermoid cysts (ECs) to squamous cell carcinomas (SCCs) in the CNS is exceedingly rare and has only been described in intracranial ECs. In this article, the authors describe a 53-year-old man with a history of a previously resected T3-4 EC, who presented with a 2-month history of progressively worsening weakness in the left side of his body. Magnetic resonance imaging revealed an enhancing mass in the T3-4 region, the exact location of the previous cyst. The mass was resected in gross-total fashion, and pathological analysis revealed an SCC. Postoperatively, the patient regained full strength in his lower extremities. After the resection, he received radiotherapy administered at an isodose of 50 Gy. To the authors' knowledge, this is the first reported case of malignant transformation of an intramedullary spinal EC in the literature.