Genomic Profiling in Patients With Malignant Peripheral Nerve Sheath Tumors Reveals Multiple Pathways With Targetable Mutations.

Background: The aim of this study was to determine the frequency of alterations in BRAF and other RAS/RAF genes, as well as other targetable pathways in malignant peripheral nerve sheath tumors (MPNSTs). Patients and Methods: Pathology specimens were available for 2 cohorts: (1) patients with MPNST at Swedish Cancer Institute (n=17) from 2004 through 2016, and (2) patients with MPNST evaluated for >300 genomic alterations at Foundation Medicine from 2014 through 2016 (n=186; including 2 Swedish patients with BRAF-mutated MPNST). Results: Of 201 MPNSTs, 13 (6.5%) demonstrated BRAF alterations. In the Foundation Medicine cohort, 10 of 84 tumors (11.9%) with no NF1 alterations had BRAF mutations (5 were V600E, 5 other), as did 3 of 102 (2.9%) tumors with NF1 alterations (1 V600E, 2 other). In the Foundation Medicine cohort, 47% of patients had an alteration in at least one other gene in the RAS/RAF pathway (not including NF1 or BRAF); 46% had alterations in the PI3 pathway, with 70% having alterations in at least 1 of the 2 pathways; 57% had a CDKN2A alteration (80% in BRAF-mutated and 71% in NF1-altered patients); and 70% had an alteration in DNA repair genes. MPNST, both NF1 wild-type and NF1-mutated, often harbor alterations in the RAS/RAF pathway as well as changes related to DNA repair and CDKN2A/B V600E and other mutations occur in BRAF, suggesting the need for second-generation activating BRAF inhibitors. The concurrence of BRAF and/or NF1 alterations with CDKN2A/B mutations, in particular, may be significant in the transformation of neurologic tumors from benign to malignant. Conclusions: All MPNSTs would benefit from a comprehensive genomic analysis. Treatments targeted to RAS/RAF, DNA repair, and CDKN2A/B pathways should be used and/or developed to treat this uncommon tumor.

Preoperative relative cerebral blood volume analysis in gliomas predicts survival and mitigates risk of biopsy sampling error.

Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II-IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan-Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.

A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels.

BACKGROUND: IgG4-related hypophysitis is a rare clinical entity that forms part of an emerging group of multi-organ IgG4-related fibrosclerotic systemic diseases. The rare prevalence of the disease, presenting features that overlap with other sellar pathologies, and variable imaging features can make preoperative identification challenging. PURPOSE AND METHODS: We report three cases of isolated IgG4-related hypophysitis with atypical clinical and imaging features that mimicked those of pituitary apoplexy and other sellar lesions. Additionally, we review the literature of IgG4-related hypophysitis to provide context for individual patient data described herein. RESULTS: All patients presented with symptoms that mimicked those of pituitary apoplexy and visual disturbance, and MRI findings suggestive of pituitary macroadenoma, Rathke's cleft cyst and craniopharyngioma. The clinical presentation warranted surgical decompression, resulting in rapid symptomatic improvement. Preoperative high-dose followed by postoperative low-dose glucocorticoid replacement therapy was administered in all cases. Histopathology showed dense infiltrate of IgG4 cells. Post-operative follow-up monitoring for 12-26 months revealed normal serum IgG4 levels with no other organ involvement, while endocrinological testing revealed persistent pituitary hormone deficiencies. CONCLUSIONS: Our cases highlight the importance of considering IgG4-related hypophysitis in the differential diagnosis of solid and cystic sellar lesions presenting acutely with pituitary apoplexy symptoms. Existing diagnostic criteria may not be sufficiently precise to permit rapid and reliable identification, or avoidance of surgery in the acute setting. In contrast to other reports of the natural history of this condition, despite the severity of presenting features, the disease in our cases was pituitary-restricted with normal serum IgG4 levels.

TGFß-Responsive HMOX1 Expression Is Associated with Stemness and Invasion in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common and lethal adult brain tumor. Resistance to standard radiation and chemotherapy is thought to involve survival of GBM cancer stem cells (CSCs). To date, no single marker for identifying GBM CSCs has been able to capture the diversity of CSC populations, justifying the needs for additional CSC markers for better characterization. Employing targeted mass spectrometry, here we present five cell-surface markers HMOX1, SLC16A1, CADM1, SCAMP3, and CLCC1 which were found to be elevated in CSCs relative to healthy neural stem cells (NSCs). Transcriptomic analyses of REMBRANDT and TCGA compendiums also indicated elevated expression of these markers in GBM relative to controls and non-GBM diseases. Two markers SLC16A1 and HMOX1 were found to be expressed among pseudopalisading cells that reside in the hypoxic region of GBM, substantiating the histopathological hallmarks of GBM. In a prospective study (N = 8) we confirmed the surface expression of HMOX1 on freshly isolated primary GBM cells (P0). Employing functional assays that are known to evaluate stemness, we demonstrate that elevated HMOX1 expression is associated with stemness in GBM and can be modulated through TGFß. siRNA-mediated silencing of HMOX1 impaired GBM invasion-a phenomenon related to poor prognosis. In addition, surgical resection of GBM tumors caused declines (18% ± 5.1SEM) in the level of plasma HMOX1 as measured by ELISA, in 8/10 GBM patients. These findings indicate that HMOX1 is a robust predictor of GBM CSC stemness and pathogenesis. Further understanding of the role of HMOX1 in GBM may uncover novel therapeutic approaches. Stem Cells 2016;34:2276-2289.

Autologous Bone Harvest in Anterior Cervical Spine Surgery: A Quantitative and Qualitative In Vitro Analysis of Cadaveric Tissue.

BACKGROUND: The cervical spine may be used as a harvesting site of local autograft material during anterior cervical discectomy and fusion procedures. We analyzed the quality and composition of bone grafts obtained from different parts of the cervical vertebrae in a cadaveric model. METHODS: Five fresh adult human cadavers with intact cervical spines were used. Using a Smith-Robinson anterior approach to expose C4-5 and C5-6 vertebrae, samples from 4 vertebral sites were harvested under a microscope. Anterior osteophytes were removed piecemeal by a Leksell rongeur (sample A). A high-speed burr was used to drill the endplates of C4-5 and C5-6 (sample C) and uncovertebral joints of C4-5 (sample B) and C5-6 (sample D). Then 20 slides (4 per cadaver) were prepared and analyzed. RESULTS: Tissue fragmentation was associated with use of the high-speed burr. Sample A had minimal tissue fragmentation. Samples B-D showed moderate to high fragmentation. Cartilage was found in all samples. Of the 20 slides, 6 contained soft tissues (sample A in 4, sample D in 2). Disc material was identified in 6 slides (sample A in 1, sample B in 4, sample D in 1). Sample A had the greatest number of intact osteocytes and chondrocytes, and sample B had the least. CONCLUSIONS: Anterior osteophytes provide the highest number of osteocytes, with the highest osteocyte/chondrocyte ratio. Osteocyte viability is a function of vertebral body site and collection technique, with fragmentation caused by use of a high-speed burr decreasing the number of viable osteocytes.

The First Histological Analysis of the Tissues Lining the Fossa Navicularis: Insights to its Etiology.

The fossa navicularis (FN) is an anatomical variant on the ventral surface of the basilar part of the occipital bone that, to date, has only been investigated in bone specimens. We aim to clarify the structure of the fossa navicularis by gross anatomical, radiological, and histological methods. The FN was found in the occipital bone of the Caucasian male cadaver. There was no bony or histological continuity between the FN and posterior cranial fossa. The histological analysis found that the overlying tissue was composed of loose connective tissue with a mixture of collagen and elastic fibers and a vascular matrix including arteries, veins, and capillaries. There was no evidence of lymphoid, glandular, or notochordal tissues. As no previous studies have performed histological analysis of the FN, this report adds to our knowledge of tissues that are involved in its formation.

Adult Apical Ligament of the Dens Lacks Notochordal Tissue: Application to Better Understanding the Origins of Skull Base Chordomas.

INTRODUCTION: The apical ligament has long been reported to contain notochord remnants and thus might serve as a site of origin of chordoma formation at the skull base. However, to our knowledge, the histologic study of the apical ligament using histologic staining specific for notochordal tissue has not been previously performed. Therefore the current study was undertaken. METHODS: Fifteen apical ligament samples underwent histologic examination with specific markers for notochordal differentiation. RESULTS: Across all samples, there was no indication of any notochordal remnants. CONCLUSIONS: On the basis of our cadaveric study, the apical ligament does not contain notochord tissue and in adults should not be considered a remnant of this structure. Moreover, it is unlikely that the apical ligament gives rise to chordomas at the craniocervical junction under normal circumstances.

Dynamic susceptibility contrast and dynamic contrast-enhanced MRI characteristics to distinguish microcystic meningiomas from traditional Grade I meningiomas and high-grade gliomas.

OBJECTIVE Microcystic meningioma (MM) is a meningioma variant with a multicystic appearance that may mimic intrinsic primary brain tumors and other nonmeningiomatous tumor types. Dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI techniques provide imaging parameters that can differentiate these tumors according to hemodynamic and permeability characteristics with the potential to aid in preoperative identification of tumor type. METHODS The medical data of 18 patients with a histopathological diagnosis of MM were identified through a retrospective review of procedures performed between 2008 and 2012; DSC imaging data were available for 12 patients and DCE imaging data for 6. A subcohort of 12 patients with Grade I meningiomas (i.e., of meningoepithelial subtype) and 54 patients with Grade IV primary gliomas (i.e., astrocytomas) was also included, and all preoperative imaging sequences were analyzed. Clinical variables including patient sex, age, and surgical blood loss were also included in the analysis. Images were acquired at both 1.5 and 3.0 T. The DSC images were acquired at a temporal resolution of either 1500 msec (3.0 T) or 2000 msec (1.5 T). In all cases, parameters including normalized cerebral blood volume (CBV) and transfer coefficient (kTrans) were calculated with region-of-interest analysis of enhancing tumor volume. The normalized CBV and kTrans data from the patient groups were analyzed with 1-way ANOVA, and post hoc statistical comparisons among groups were conducted with the Bonferroni adjustment. RESULTS Preoperative DSC imaging indicated mean (± SD) normalized CBVs of 5.7 ± 2.2 ml for WHO Grade I meningiomas of the meningoepithelial subtype (n = 12), 4.8 ± 1.8 ml for Grade IV astrocytomas (n = 54), and 12.3 ± 3.8 ml for Grade I meningiomas of the MM subtype (n = 12). The normalized CBV measured within the enhancing portion of the tumor was significantly higher in the MM subtype than in typical meningiomas and Grade IV astrocytomas (p < 0.001 for both). Preoperative DCE imaging indicated mean kTrans values of 0.49 ± 0.20 min-1 in Grade I meningiomas of the meningoepithelial subtype (n = 12), 0.27 ± 0.12 min-1 for Grade IV astrocytomas (n = 54), and 1.35 ± 0.74 min-1 for Grade I meningiomas of the MM subtype (n = 6). The kTrans was significantly higher in the MM variants than in the corresponding nonmicrocystic Grade 1 meningiomas and Grade IV astrocytomas (p < 0.001 for both). Intraoperative blood loss tended to increase with increased normalized CBV (R = 0.45, p = 0.085). CONCLUSIONS An enhancing cystic lesion with a normalized CBV greater than 10.3 ml or a kTrans greater than 0.88 min-1 should prompt radiologists and surgeons to consider the diagnosis of MM rather than traditional Grade I meningioma or high-grade glioma in planning surgical care. Higher normalized CBVs tend to be associated with increased intraoperative blood loss.

Recurrent Craniocervical Pseudogout: Indications for Surgical Resection, Surveillance Imaging, and Craniocervical Fixation.

BACKGROUND: Calcium pyrophosphate dihydrate (CPPD) crystallization is known to occur in the spine, leading to the development of visible calcification as seen by imaging. Occasionally, the deposition of this material can lead to larger accumulations that are seen as masses in the articular processes, intervertebral discs, and posterior longitudinal ligaments. A particularly significant manifestation of this process is at the craniocervical junction, where symptomatic presentations can arise. CLINICAL PRESENTATION:  A 74-year-old woman presented after several falls from standing, complaining of leg and arm weakness. Imaging revealed a mass arising from the C1-C2 articulation dorsal to the dens, extending to the clivus. The mass compressed the medulla and cervicomedullary junction. INTERVENTION: The patient underwent a left, far lateral craniotomy with C1 laminectomy to approach the cervicomedullary junction. The mass was cyst-like and contained scattered crystals and amorphous material consistent with pseudogout. There were no cells with an elevated Ki-67 index. The patient's symptoms and exam improved at follow-up two months later. However, seven months after surgery, she declined once again and was found to have a recurrence. CONCLUSION: A subtotal resection of pseudogout may lead to recurrence. The recurrence can occur in a rapid fashion. Serial MRIs are indicated following resection. Occipitocervical fusion could reduce the likelihood of recurrence in such cases.

Atypical Presentation of a Sequestered Posterolateral Disc Fragment.

Sequestered disc fragments typically occur ventrally but can also migrate dorsally or intradurally. At times, atypical disc herniations can be misinterpreted on imaging as other lesions, such as neoplasms, hematomas, or abscesses. We present an uncommon case of a patient presenting with cauda equina syndrome secondary to an enhancing sequestered disc fragment mimicking a tumor.

Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review.

Most prolactin-secreting pituitary adenomas demonstrate slow growth and are effectively managed with medical/surgical therapy. Rarely, these tumors can behave aggressively with rapid growth and invasion of local tissues, and are refractory to medical, surgical, or radio-surgical therapies. We report a case of a prolactin-secreting adenoma in a young woman, which became progressively aggressive and refractory to usual treatment modalities, but responded to treatment with the chemotherapeutic agent temozolomide. In addition, we review the literature for treatment of refractory adenomas with temozolomide. The clinical and pathologic characteristics of aggressive prolactin-secreting adenomas are reviewed, as well as their response to dopamine agonists, surgery, radiotherapy, and chemotherapy.

Dural-Based Cavernoma of the Posterior Cranial Fossa Mimicking a Meningioma: A Case Report.

Cavernous angiomas usually occur in the parenchyma of both the supra and infratentorial compartments. At times, they can both clinically and radiologically mimic other dural-based lesions. We present a case of a patient with chronic occipital headaches, initially thought to have a meningioma, but proven to be a cavernoma with histological analysis.

Herpes Simplex Encephalitis of the Parietal Lobe: A Rare Presentation.

A 69-year-old female with a history of breast cancer and hypertension presented with a rare case of herpes simplex encephalitis (HSE) isolated to her left parietal lobe. The patient's first biopsy was negative for herpes simplex virus (HSV) I/II antigens, but less than two weeks later, the patient tested positive on repeat biopsy. This initial failure to detect the virus and the similarities between HSE and symptoms of intracranial hemorrhage (ICH) suggests repeat testing for HSV in the presence of ICH. Due to the frequency of patients with extra temporal HSE, a diagnosis of HSE should be more readily considered, particularly when a patient may not be improving and a concrete diagnosis has not been solidified.

Cellular pleomorphism in papillary tumors of the pineal region.

Papillary tumor of the pineal region (PTPR) is a recently recognized entity. We present the pathologic findings of two cases of PTPR as examples, and discuss the presence of cellular pleomorphism in these tumors. Patient 1 is a 48-year-old man with a pineal region mass. The tumor had unique biphasic patterns, papillary/pseudopapillary areas, and increased mitotic activity. Juxtaposed areas had marked pleomorphism, including nuclear enlargement, smudgy chromatin, nuclear pseudoinclusions, and cytoplasmic vacuolation. Mitoses were absent in these areas. Immunohistochemical staining revealed strong S100 expression. CAM 5.2 and CK18 were strongly positive in a patchy fashion. MIB1 labeling indices were high in classic PTPR regions but very low in pleomorphic areas. Patient 2 was a 35-year-old male with a pineal region tumor characterized by papillary architecture and overall cellular monotony, rare mitoses, and pleomorphism as a more isolated finding, with associated nuclear enlargement and crowding. S100 and CAM 5.2 labeling were present, and MIB1 labeling index was very low throughout the tumor. We discuss the pathologic and phenotypic features of PTPR. Variable pleomorphism may be present, reflected in size variation and nuclear hyperchromasia, but was not accompanied by increased proliferative activity in these cases, suggesting a degenerative phenomenon.

Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer's disease brains.

Lipoprotein lipase (LPL) is involved in regulation of fatty acid metabolism, and facilitates cellular uptake of lipoproteins, lipids and lipid-soluble vitamins. We evaluated LPL distribution in healthy and Alzheimer's disease (AD) brain tissue and its relative levels in cerebrospinal fluid. LPL immunostaining is widely present in different neuronal subgroups, microglia, astrocytes and oligodendroglia throughout cerebrum, cerebellum and spinal cord. LPL immunoreactivity is also present in leptomeninges, small blood vessels, choroid plexus and ependymal cells, Schwann cells associated with cranial nerves, and in anterior and posterior pituitary. In vitro studies have shown presence of secreted LPL in conditioned media of human cortical neuronal cell line (HCN2) and neuroblastoma cells (SK-N-SH), but not in media of cultured primary human astrocytes. LPL was present in cytoplasmic and nuclear fractions of neuronal cells and astrocytes in vitro. LPL immunoreactivity strongly associates with AD-related pathology, staining diffuse plaques, dystrophic and swollen neurites, possible Hirano bodies and activated glial cells. We observed no staining associated with neurofibrillary tangles or granulovacuolar degeneration. Granule cells of the dentate gyrus and the associated synaptic network showed significantly reduced staining in AD compared to control tissue. LPL was also reduced in AD CSF samples relative to those in controls.

Intracranial sebaceous neoplasm: a case report.

BACKGROUND AND IMPORTANCE: Sebaceous neoplasms range from hyperplastic hamartomas to malignant tumors and are most commonly cutaneous lesions. We describe the first reported case of an intracranial sebaceous neoplasm, discussing the differential diagnosis and possible pathogenesis in relation to the current literature. CLINICAL PRESENTATION: A 58-year-old man presented with evolving neck stiffness, facial pain, and progressively worsening diplopia. Magnetic resonance imaging identified a moderate-sized lesion intimately related to the left cavernous sinus, which had extended into the posterior fossa. The patient underwent endoscopic, transnasal subtotal resection of the neoplasm with significant improvement. Histologically, the tumor was identified as a sebaceous neoplasm previously unreported intracranially. Follow-up imaging at 6 months revealed no further recurrence. CONCLUSION: This is the first reported case of an intracranial sebaceous neoplasm. Careful follow-up is required to help elucidate the biology of this tumor in an effort to determine the role of adjuvant therapy.

Increased ictal discharge frequency and neocortex gliosis in lateral temporal lobe epilepsy.

PURPOSE: Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis has both a scalp EEG initial ictal discharge frequency, which is faster, and also an intracranial EEG onset site that is more restricted to the hippocampus, than lateral TLE without hippocampal sclerosis. This study was performed to determine if lateral TLE patients have either intracranial EEG neocortical initial ictal frequencies or measures of lateral neocortex (LNC) histopathology that differ from patients whose seizures start in medial or multiple temporal lobe areas. METHODS: Thirty-six TLE patients undergoing ictal depth and subdural strip electrode recordings were studied to determine the initial ictal discharge site (epileptogenic zone) within the temporal lobe and neocortical ictal frequency. In 25 patients, the number of reactive astrocytes in the neocortex and other measures of pathologic assessment of LNC were assessed. RESULTS: The initial neocortical ictal frequency was significantly faster when the initial ictal discharge was in the LNC ± medial paleocortex than either when it was in the hippocampus ± medial paleocortex or when it occurred simultaneously over the entire temporal lobe. Intracortical and Chaslin gliosis were both significantly greater when the initial ictal discharge was limited to the LNC than when it was in the hippocampus and/or medial paleocortex. CONCLUSIONS: Temporal lobe seizures originating in neocortex had a faster initial neocortical ictal frequency than seizures arising either medially in the hippocampus or widely over the whole temporal lobe. Epileptogenic zones limited to temporal neocortex were associated with greater intraneocortical and Chaslin gliosis compared with zones confined to medial structures.

Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM.

O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR  = 5.23, 95% CI [2.089-13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR  = 3.076, 95% CI [1.301-7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting.

Neocortical gliosis in temporal lobe epilepsy: gender-based differences.

OBJECTIVE: Sex hormones can influence the timing and frequency of seizure activity. In addition, gender may influence the age of epilepsy onset and hemispheric location of focal epilepsy. Whether gender alters temporal lobe pathologies differentially is not clear. In this study, we assess if neocortical or hippocampal pathologies from patients who underwent en bloc anteriomedial temporal lobectomy (AMTR) for medically refractory epilepsy differ by gender. METHOD: Consecutive en bloc AMTR resections (n = 128), including hippocampal tissues, were systematically studied. Cortical and intracortical gliosis from a standardized location, 1.5 cm from the temporal lobe tip, was assessed for quantifiable gliotic change. Corresponding hippocampal sections were characterized according to Watson grade. These outcomes were then compared by gender. Other correlates such as age of epilepsy onset, age of risk exposure, and duration of epilepsy were similarly compared. RESULTS: Subpial and intracortical gliosis was more pronounced in women (p = 0.02, p < 0.01). Cortical thickness was reduced in women compared to men (p < 0.05). No similar gender effects were seen in Watson grade of hippocampal sclerosis or CA1-4 neuronal dropout. CONCLUSIONS: Gender may differentially influence neocortical pathologies in patients with refractory temporal lobe epilepsy. No gender effect was seen when studying hippocampal pathologies.

Oxidative changes in the DNA of stroma and epithelium from the female breast: potential implications for breast cancer.

Reciprocal interactions between the stroma and epithelium are considered to be intimately associated with the development of breast cancer. In studies of whole breast tissues, a keen interest exists in the occurrence of the mutagenic DNA lesions 8-hydroxy-2'-deoxyguanosine and 8-hydroxy-2'-deoxyadenosine. However, there is an apparent lack of information on the presence of these lesions in the DNA of the stroma, epithelium, and myoepithelium, despite the fact that these oxidation products may significantly influence reciprocal interactions between these cell types implicated in carcinogenesis. We report age-related increases in concentrations of both lesions in the stromal DNA, which occur roughly commensurate with the known rise in breast cancer incidence between 30 and 40 years of age. However, no further increases in these concentrations occurred in the older women. Plots of lesion concentrations revealed an uneven distribution, with some younger women having relatively high concentrations and some older women having relatively low concentrations. This finding implies that while increased age is a probable factor in lesion accumulations, other factors may also be influential [e.g., cellular concentrations of reactive oxygen species (ROS)]. Distinct differences were found between the base and backbone structures of the stromal DNA from younger women (ages 17 - 30), compared to older women (ages 50 - 62). In addition, comparisons of matched stromal, epithelial, and myoepithelial DNA (from the same individual) showed no differences in DNA damage, suggesting a random attack by the hydroxyl radical on all three groups. Collectively, the findings imply that the structural changes in DNA described may potentially disrupt normal reciprocal interactions between the cell types, thus increasing breast cancer risk.