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David R. Hinton

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Lawrence S. Chin and David R. Hinton

✓ Tissue markers of cellular proliferation have been recently utilized as prognostic indicators in tumors of the central nervous system. Nucleolar organizer regions represent transcriptionally active sites of ribosomal deoxyribonucleic acid (DNA) and can be identified by a simple argyrophilic technique. The authors describe a standardized approach to the assessment of these argyrophilic nucleolar organizer regions in meningeal tumors. Twenty-five meningiomas were classified histologically into benign, atypical, or malignant groups. In addition, two hemangiopericytomas and one leptomeningeal melanoma were examined. Appropriate sections were silver stained and argyrophilic nucleolar organizer regions were counted in 200 nuclei. The mean argyrophilic nucleolar organizer region count was statistically different (p < 0.001) between benign tumors (245 ± 156, 1.23/cell), atypical tumors (497 ± 135, 2.49/cell), and malignant tumors (921 ± 59, 4.61/cell). The count for recurrent meningiomas (544 ± 76) was also statistically different (p < 0.02) from non-recurrent tumors (329 ± 183). The standardized assessment of argyrophilic nucleolar organizer regions can be easily performed by any surgical pathology laboratory without specialized equipment and, in meningeal tumors, may be useful as an independent indicator of biological behavior.

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Felipe C. Albuquerque, David R. Hinton and Martin H. Weiss

✓ The authors report the case of a 48-year-old woman who presented with a nonprolactin-secreting adenoma and a preoperative prolactin level of 662 ng/ml. The patient's neoplasm subsequently enlarged despite normalization of her prolactin level with dopamine agonist therapy. Hyperprolactinemia, with levels of prolactin as high as 150 ng/ml, is commonly associated with sellar tumors and is attributed to disruption of the normal delivery of dopamine to the adenohypophysis. The prolactin level found in this patient represents the highest level attributed to the stalk-section effect reported in the literature and underscores the need for repeated radiographic assessment of patients who are undergoing treatment with bromocriptine and have prolactin levels in the 25 to 1000 ng/ml range.

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John Schneider, Florence M. Hofman, Michael L. J. Apuzzo and David R. Hinton

✓ Cytokines are important regulatory proteins controlling growth and differentiation of normal and malignant glial cells. Astrocytes and microglial cells produce and respond to many of the same cytokines employed by cells of the immune system. The authors have analyzed 15 histologically confirmed malignant glial neoplasms for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules using a panel of specific monoclonal and polyclonal antibodies on frozen-tissue sections. All neoplasms showed focal T-cell infiltration with CD8 cells predominating. Infiltration of activated macrophages (positive for CD11c, class II, and interleukin-2 receptor) was marked in all tumors. Within the neoplasm, tumor necrosis factor-α (TNF-α)- and interleukin (IL)-6-positive macrophages were prominent in five cases, while the tumor cells themselves were only weakly positive. In the other 10 cases, the numerous infiltrating macrophages were only rarely immunoreactive for TNF-α or IL-6. Transforming growth factor-β (TGF-β) immunoreactivity was most prominent in those tumors with little TNF-α-positive macrophage infiltration, although intratumoral variability was present. This study suggests that, in malignant gliomas, the cytokines TNF-α and IL-6, although weakly present in neoplastic cells, are most prominent in infiltrating macrophages and in those regions of the tumors that show little immunoreactivity for TGF-β. The important interactions among neoplastic, reactive glial, and inflammatory cells, which regulate tumor growth, are likely to be in part mediated through these molecules.

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William T. Couldwell, Martin H. Weiss, Ronald E. Law and David R. Hinton

✓ The monoclonal antibody Ki-67 recognizes a nuclear antigen expressed in the G1, S, G2, and M phase of the cell cycle and has been used extensively as an indicator of cellular proliferation in malignant gliomas, both in the laboratory and clinically. Recently, protein kinase C (PKC) inhibitors have been demonstrated to inhibit malignant glioma growth both in in vitro and in vivo. This study was undertaken to determine whether Ki-67 could function as an indicator of cellular proliferation rate after PKC inhibition in gliomas and to explore cell cycle specificity of such inhibition. Both established and low-passage malignant glioma cell lines have previously been shown to be sensitive to growth inhibition by the PKC inhibitors staurosporine and tamoxifen in vitro (IC50 in the nanomolar and micromolar ranges, respectively), as measured by cell numbers, [3H]thymidine uptake, and flow-cytometric DNA analysis. However, in the same cells that are inhibited by staurosporine and tamoxifen on these assays, and on the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in the present study, the Ki-67 labeling index paradoxically increased in a dose-related manner with the same treatments, as measured by immunohistochemistry and confirmed by flow cytometry. For example, in established line U-87, a 20.5% decrease in thymidine uptake and a 28.5% decrease in absorbance on the MTT assay produced by tamoxifen at 1 µM was associated with an increase in Ki-67 labeling from 42% to 62%; staurosporine, which produces a 78.8% decrease in thymidine uptake in cell line A-172 at 10 nM, produced an increase in Ki-67 labeling from 19% to 32%. In this regard, Ki-67 labeling of glioblastoma tissue from a patient treated with high-dose tamoxifen yielded results within the range of 10% to 15% (consistent with values seen in untreated glioblastoma), despite tumor regression with treatment. The authors' interpretation of these results is that these PKC inhibitors are halting the cell cycle in the G1 phase or the G1—S transition (beyond G0 but before S-phase), resulting in a paradoxical increase in labeling while arresting growth. Two important implications from these observations are that Ki-67 is not a reliable indicator of cellular proliferation after treatment with PKC inhibitors and that these inhibitors used at the doses given above halt cell growth in a phase-specific manner.

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Michael A. Lefkowitz, David R. Hinton, Martin H. Weiss, Steven L. Giannotta and William T. Couldwell

The authors have retrospectively analyzed selected surgical and pathological observations made among a group of 20 patients harboring recurrent cranial base meningiomas in an attempt to reveal which factors may be important in predicting tumor recurrence. This cohort was compared with a group of 34 patients with cranial base meningiomas that underwent primary resection and in whom tumor recurrence has not been demonstrated over a median follow-up period of 33 months. Features analyzed included brain, cranial nerve, carotid artery, or muscle invasion as well as tumor cellularity, nucleolar prominence, cellular pleomorphism, and percentage of cells staining positive for the Ki-67 antigen. As expected, increased cellularity and tumor necrosis were relatively more prevalent in recurrent tumors. With regard to tumor type, atypical and anaplastic tumors were more common in the group of patients with recurrent tumor compared with the primary group (p < 0.02). As expected, increased cellularity was relatively more prominent in recurrent tumors. Invasion of muscle and bone (72%) was more frequently associated with recurrent tumors, suggesting that these characteristics may be important features of recurrent skull base meningiomas.

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Lambdoid synostosis

Part 1: The lambdoid suture: normal development and pathology of “synostosis”

David R. Hinton, Laurence E. Becker, Kamel F. Muakkassa and Harold J. Hoffman

✓ The microscopic development of the normal lambdoid suture was studied in autopsy specimens from 19 normal subjects ranging in age from 20 weeks' gestation to 60 years. The cellular activity at the suture varied considerably with age; however, maximal activity was seen in specimens approximately 3 months of age. There were several unusual features, including a high incidence of cartilaginous differentiation and the presence of intrasutural Wormian bones. Forty-one specimens from 37 patients with isolated lambdoid synostosis were also studied pathologically. Only three cases showed bone union across the suture, which appears to be a result of closure rather than fusion as in other synostoses. The remainder of the cases showed varying degrees of increased cellular proliferation at the suture line, resulting in exaggerated and prolonged sutural activity. Morphologically, this produced increased interdigitation and fibrous adhesion between the suture margins.

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Lambdoid synostosis

Part 2: Review of cases managed at The Hospital for Sick Children, 1972–1982

Kamel F. Muakkassa, Harold J. Hoffman, David R. Hinton, E. Bruce Hendrick, Robin P. Humphreys and Judith Ash

✓ Seventy-four patients with premature union of the lambdoid suture were treated at The Hospital for Sick Children during the years 1972 through 1982. Lambdoid synostosis is considered to be a rare form of craniosynostosis, but this is more likely due to lack of recognition rather than to infrequent occurrence. The skull deformity resulting from lambdoid synostosis is often mistakenly attributed to positional molding rather than to actual synostosis. When the lambdoid suture closes, the occiput on the involved side is flat, the forehead on the same side tends to bulge forward, and the ear on this side adopts a low and forward position. Skull x-ray films may demonstrate obliteration of the lambdoid suture, but more frequently one sees sclerosis along one edge of the closing suture. Radionuclide bone scanning will show increased activity during the active phase of union and decreased or absent activity once union has occurred. Craniectomy performed during the neonatal period will correct the deformity and provide for normal cranial growth. Delay in surgery beyond 6 months will frequently necessitate a more extensive cranial repair.

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Nam D. Tran, Stefan Kim, Heather K. Vincent, Anthony Rodriguez, David R. Hinton, M. Ross Bullock and Harold F. Young

Object

Dysregulation of water homeostasis induces cerebral edema. Edema is a major cause of morbidity and mortality following traumatic brain injury (TBI). Aquaporin-1 (AQP-1), a water channel found in the brain, can function as a transporter for CO2 across the cellular membrane. Additionally, AQP-1's promoter contains a glucocorticoid response element. Thus, AQP-1 may be involved with edema-related brain injury and might be modulated by external conditions such as the pH and the presence of steroids. In this study, the authors investigated the hypotheses that: 1) AQP-1 participates in brain water homeostasis following TBI; 2) secondary injury (for example, acidosis) alters the expression of AQP-1 and exacerbates cerebral edema; and 3) corticosteroids augment brain AQP-1 expression and differentially affect cerebral edema under nonacidotic and acidotic conditions.

Methods

Anesthetized Sprague-Dawley rats were subjected to moderate to severe TBI (2.5–3.5 atm) or surgery without injury, and they were randomized to receive a 3-mg/kg bolus of intravenous dexamethasone within 10 minutes after injury or surgery, a 3-mg/kg bolus of dexamethasone followed by 1-mg/kg maintenance doses every 8 hours for 24 hours, or saline boluses at similar time intervals. A second group of animals was subjected to respiratory acidosis with target arterial blood pH 6.8–7.2 for 1 hour following the surgery or injury. To evaluate selective blockage of AQP-1, some animals received a single intraperitoneal dose of HgCl2 (0.3–30.0 mmol/L) within 30 minutes of injury or surgery. At 4 or 24 hours postinjury, animals were killed and their brains were harvested for mRNA, protein, or water content analyses.

Results

The authors demonstrated elevated cerebral edema levels at 4 and 24 hours following TBI. Dexamethasone administration within 1 hour of TBI attenuated the cerebral edema under nonacidotic conditions but worsened it under acidotic conditions. Selective blockage of AQP-1 channels with HgCl2 attenuated the edematous effects of corticosteroids and acidosis. Reverse transcriptase polymerase chain reaction and immunohistochemical analyses demonstrated a paucity of AQP-1 in the cerebral cortices of the uninjured animals. In contrast, AQP-1 mRNA and protein levels were higher in the cerebral cortices of animals that sustained a TBI.

Conclusions

These findings implicate an important, modifiable role for AQP-1 in water homeostasis within the CNS following TBI.

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H. Bruce Hamilton, David R. Hinton, Ronald E. Law, Rayudu Gopalakrishna, Yu Zhuang Su, Zhen-Hai Chen, Martin H. Weiss and William T. Couldwell

✓ Protein kinase C (PKC) is an enzyme involved in the regulation of cellular growth, proliferation, and differentiation in a number of tissues including the anterior pituitary, in which it is also believed to play a role in hormone secretion. Protein kinase C activity and expression have been found to be greater in adenomatous pituitary cells than in normal human and rat pituitary cells and higher in invasive pituitary tumor cells than in noninvasive ones. Inhibition of PKC activity has been shown in a variety of tumor cells to inhibit growth in a dose-related fashion. The purpose of the current study was to determine whether hypericin, a potent inhibitor of PKC activity that may be administered clinically, alters the growth and proliferation in established pituitary adenoma lines and to determine if inhibition of PKC activity induces apoptosis, as reported in some other tumor cell types. Two established pituitary adenoma cell lines, AtT-20 and GH4C1, were treated with hypericin in tissue culture for defined periods following passage. Inhibition of growth was found to be dose dependent in all three cell lines in low micromolar concentrations of hypericin, as determined by viable cell counts, methylthiotetrazole assay, and [3H]thymidine uptake studies. Concentrations of hypericin as low as 100 nM also induced apoptosis in these established lines, whereas treatment of normal human fibroblasts with a concentration of 10 µM failed to induce apoptosis. The potential use of hypericin in the therapy of pituitary adenomas warrants additional in vitro investigations with the aim of later moving toward therapeutic trials in selected patients in whom surgical or medical therapy has failed.