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Biomedical subjects

W F Chandler

Publications and source records attributed to W F Chandler.

At least 37 records · Page 2Linked to original sources
PubMed1994

Persistence of rapid growth hormone (GH) pulsatility after successful removal of GH-producing pituitary tumors.

GH concentration profiles in patients with acromegaly are characterized by rapid GH pulsatility and high interpulse GH concentrations. Animal and human studies have shown that GH pulses are consequent upon periodic discharges of hypothalamic GHRH, whereas interpulse GH levels might reflect tonic secretion of hypothalamic SRIH. Thus, the pattern of GH secretion in acromegaly may conceivably be attributed to high GHRH pulse frequency and/or SRIH deficiency. If this assumption is correct, removal of a GH-producing tumor should be followed by a persistently high GH pulse frequency and a high recurrence rate. We have studied pulsatile GH secretion in 12 patients with acromegaly before and after apparently complete removal of their pituitary tumors. Despite normalization of GH secretion after surgery, the disease recurred in 3 patients within 3 yr. The other 9 patients had normal insulin-like growth factor-I and basal and dynamic GH concentrations for 24 +/- 4 months postsurgery. Parameters of GH secretion in this group (pre- and postsurgery) were compared to sex-, age-, and body mass index-matched controls. Plasma GH concentrations in the postoperative and control series were analyzed by a chemiluminescent assay with a sensitivity of 0.01 micrograms/L. Removal of the somatotroph tumor led to normalization of mean and interpulse (but not the nadir) GH levels, pulse amplitude, and responses to GHRH. However, GH pulse frequency (14.2 +/- 1.2 vs. 11.8 +/- 0.9 pulses/24 h) did not change and was significantly (P < 0.001) higher than the control value (8.7 +/- 0.9 pulses/24 h). Thus, SRIH secretion in acromegaly is not inherently deficient, and high interpulse GH levels reflect the mass of tumorous somatotrophs. The persistence of rapid GH pulsatility in apparently "cured" patients with acromegaly suggests that abnormally rapid GHRH pulsatility may be an inherent component of the disease process.

Acromegaly↗
PubMed1994

Radiosensitization with carotid intra-arterial bromodeoxyuridine +/- 5-fluorouracil biomodulation for malignant gliomas.

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR +/- 5-FU over 8 1/2 weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 8 1/2 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Craniopharyngiomas--the utility of contrast medium enhancement for MR imaging at 1.5 T.

To evaluate the efficacy of i.v. contrast medium administration in MR imaging at 1.5 T in patients with craniopharyngiomas, MR studies of 10 men and 6 women with pathologically proven craniopharyngiomas were made. The MR images were obtained as 3- to 5-mm-thick coronal (n = 13) or axial (n = 3) Tl-weighted images (T1WI) prior to and following i.v. Gd-DTPA administration. Proton density- (PD) and T2-weighted images (T2WI) were also obtained. Conspicuity of tumor margins, cystic versus solid components, size, location and effect upon adjacent structures were separately characterized in all imaging sequences. In 6 patients contrast medium-enhanced T1WI. PD and T2WI demonstrated cystic tumor components not seen on unenhanced T1WI. There were significant differences (p < 0.004) on 2-tailed Student's t-test comparing tumor conspicuity on contrast medium-enhanced T1WI with unenhanced T1WI, PD and T2WI. Optimal tumor delineation on MR imaging of patients with craniopharyngiomas justifies the use of i.v. contrast medium.

Adolescent↗
PubMed1993

Differentiation of human pituitary adenomas determines the pattern of chromogranin/secretogranin messenger ribonucleic acid expression.

The distribution of chromogranin/secretogranin (Cg/Sg) mRNAs, determined by Northern and in situ hybridization, was analyzed in 14 cultured pituitary adenomas characterized by immunohistochemistry and hormone secretion in a defined medium in vitro. There were 5 functional GH adenomas, 1 silent GH adenoma, 7 null cell adenomas, and 1 oncocytoma. The null cell adenomas, oncocytoma, and silent GH adenomas were also analyzed by electron microscopy. Most null cell adenomas and the oncocytoma secreted FSH and LH into the culture medium. GH adenomas, which are examples of well differentiated tumors based on morphological examination, expressed significantly more SgIII mRNA compared to the null cell adenomas and oncocytoma (70 +/- 6% vs. 22 +/- 5%; P < 0.001). GH adenomas also expressed significantly less CgA mRNA compared to the less well differentiated null cell adenomas and oncocytoma (27 +/- 6% vs. 67 +/- 4%; P < 0.001), which could be considered less well differentiated based on ultrastructural morphological features. After treatment with phorbol 12-myristate 13-acetate (10(-7) M) for 7 days, there was an increase in the mRNA for CgB and SgII mRNAs in GH and null cell tumors, while dexamethasone treatment for 7 days increased CgA mRNA in GH and null cell adenomas. GnRH treatment for 7 days increased CgB mRNA in null cell adenomas. Phorbol 12-myristate 13-acetate also decreased the percentage of immunoreactive GH cells and GHm RNA, determined by in situ and Northern hybridization analyses. These results indicate that pituitary adenomas have a distinct pattern of Cg/Sg mRNA expression, which appears to be related to the degree of morphological differentiation of these neoplasms, and suggest that the effects of secretagogues on various Cg/Sg mRNA levels may be related to the stimulation of hormone secretion.

Adenoma↗
PubMed1993

Pituitary specific transcription factor messenger ribonucleic expression in adenomatous and nontumorous human pituitary tissues.

BACKGROUND: The pituitary-specific transcription factor, Pit-1/GHF-1 (Pit-1) is a member of the POU family of homeobox genes. This transacting factor has a role in the development and expression of selected anterior pituitary cells including prolactin, growth hormone (GH), and thyrotropin, cell types in rodent pituitary. The expression of Pit-1 mRNA in human pituitaries has not been previously analyzed and the role of specific secretagogues in the regulation of Pit-1 transcripts in human pituitary adenomas has not been examined. Analysis of Pit-1 expression in normal and neoplastic human pituitaries may provide insight into the specificity of this transcription factor for pituitary cell types and the role of Pit-1 in human pituitary function. EXPERIMENTAL DESIGN: In situ and Northern hybridization analyses were used to study the expression of Pit-1 mRNA in surgically removed human pituitary adenomas and nontumorous pituitaries obtained within 6 hours postmortem. A cultured GH surgically removed adenoma was used to analyze the regulation of GH and Pit-1 in vitro. RESULTS: In situ hybridization localized Pit-1 mRNA in all pituitary adenomas, although the mRNA levels in GH and prolactin adenomas were significantly higher than those in ACTH, null cell and gonadotroph tumors. Northern hybridization analysis revealed a 2.4 and a 1.2 kb mRNA transcript for Pit-1. Although GH mRNA transcript was markedly changed by dexamethasone and phorbol 12-myristate 13-acetate in vitro, Pit-1 mRNA transcripts were not changed significantly by these secretagogues. CONCLUSIONS: Pit-1 mRNA transcripts are expressed mainly in prolactin and GH pituitary adenomas, but are also found in other adenomas and in the nontumorous adult human pituitary. Pit-1 mRNA transcript levels are not readily modulated in cultured GH adenoma cells by various secretagogues in vitro compared with the marked modulation of GH mRNA transcripts by these same secretagogues.

Adenoma↗
PubMed1993

Protein kinase C (PKC) activity and PKC messenger RNAs in human pituitary adenomas.

Protein kinase C (PKC) is involved in the differentiation and growth regulation of a variety of tissues including anterior pituitary gland cells. To determine the distribution of PKC in different types of adenomas, PKC activity was analyzed in human pituitary tumors and the effects of hypothalamic hormone stimulation on PKC activity were examined in cultured adenoma cells. Gonadotroph (LH/FSH) and null cell adenomas had significantly higher levels of particulate, soluble, and total PKC activity compared with growth hormone (GH) adenomas (P < 0.05). Chronic stimulation of null cell adenomas with gonadotropin hormone-releasing hormone or of one GH adenoma with GH-releasing hormone for 7 days did not significantly alter total PKC activity in pituitary cells cultured in serum-free medium. Localization of the calcium-dependent PKC isozymes (alpha, beta and gamma) by immunohistochemistry and in situ hybridization revealed predominantly PKC alpha in all adenomas and variable expression of PKC beta and gamma in some tumors. When the calcium-independent PKC isozymes (delta, epsilon, and zeta) were localized by in situ hybridization, normal and neoplastic pituitaries expressed abundant mRNA for PKC epsilon, whereas some tumors and one normal pituitary had a few cells positive for PKC zeta mRNA as evaluated by grain density and the number of cells labeled. These results indicate that there is a variable distribution of PKC mRNA isozymes in human pituitary adenomas and that normal pituitaries and pituitary adenoma cells express the mRNA for both the calcium-dependent and some of the calcium-independent PKC isozymes. Chronic treatment with the hypothalamic gonadotropin hormone-releasing hormone and GH-releasing hormone, which increased LH/FSH and GH secretion, respectively, did not increase PKC activity in cultured adenoma cells. The presence of calcium-dependent and calcium-independent PKC isozymes in normal and neoplastic pituitary cells indicates that PKC probably plays a major role in signal transduction in the human pituitary adenomas examined in this study.

Adenoma↗
PubMed1992

Development of neurosurgery at the University of Michigan.

The University of Michigan Medical School was founded in 1847, 30 years after the university itself. The first hospital in Ann Arbor was a 20-bed unit converted from a private house, that admitted only charity patients. The second University Hospital was built in 1925. The Section of Neurosurgery was founded by Dr. Max Peet, who was followed by Drs. Kahn and Schneider as section heads.

History, 19th Century↗
PubMed1991

In situ hybridization in the study of pituitary tissues.

This presentation summarizes the use of in situ hybridization in the study of pituitary abnormalities. The basic techniques, technical problems and pitfalls in in interpretation and the application of in situ hybridization are discussed.

Adenoma↗
PubMed1991

Analysis of pituitary hormones and chromogranin A mRNAs in null cell adenomas, oncocytomas, and gonadotroph adenomas by in situ hybridization.

To study the relationship between null cell adenomas, oncocytomas and gonadotroph adenomas, we analyzed 32 surgically removed formalin-fixed paraffin-embedded pituitary tumors for the expression of pituitary hormone messenger RNAs (mRNAs) by in situ hybridization (ISH). Most tumors were also analyzed for chromogranin A mRNA. To identify the cell type constituting the tumors and to assess hormone content, all tumors were investigated by histology, transmission electron microscopy and immunohistochemistry. Most null cell adenomas (6/11) and gonadotroph adenomas (9/10) expressed the mRNAs for alpha-subunit of glycoprotein hormones whereas only 2/11 oncocytomas expressed alpha-subunit mRNA. FSH beta and/or LH beta mRNA were present in most null cell and gonadotroph adenomas but only in a few oncocytomas. Prolactin (PRL) mRNA was detected in two null cell tumors and in one gonadotroph adenoma, whereas GH and POMC mRNA were present in one null cell adenoma. Chromogranin A mRNA, which codes for the major secretory granule protein, was present in 25/26 tumors including all tumors that were negative for pituitary hormone mRNAs, indicating adequate preservation of specific mRNA transcripts in the paraffin-embedded sections of tumor cells. These results indicate that null cell adenomas and gonadotroph adenomas are closely related neoplasms and that oncocytomas may represent a functionally defective form of null cell adenoma characterized by mitochondrial abundance, which has retained the capacity to synthesize the major secretory granule protein chromogranin A. Although the cytogenesis of null cell adenomas and oncocytomas is not clear, it can be suggested that these two tumor types are derived from a pluripotential precursor cell that is capable of undergoing multidirectional differentiation and synthesizing various hormones, mainly glycoproteins.

Adenoma↗
PubMed1990

Random sampling by glitter drop method.

In the course of a study on glioblastoma tissue and cultured cell lines, a glitter drop technique for random sampling was introduced (1). Here, we report the initial description of the details of this procedure and its application to cell counts from explant slides and to determining bromodeoxyuridine (BUdR) labeling indices (LI) in tissues. The method is without bias, easy to perform and takes only a short time. It compares well with three other generally used random sampling procedures.

Bromodeoxyuridine↗
PubMed1990

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas.

In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Adult↗
PubMed1990

Nuclear parameters as prognostic indicators in glioblastoma patients.

The objective of this study was to determine whether nuclear parameters were associated with prognosis in glioblastoma multiforme. DNA indices, cell cycle parameters, and nuclear population densities were compared with patient survival. Selection criteria included the pathologic diagnosis of a cerebral glioblastoma multiforme, absence of therapy before surgery, and adequate tissue to measure each nuclear parameter studied. Nine cases accrued over a two year period. The amount of DNA per nucleus was quantified in fresh tissue specimens by nuclear-isolation flow cytometry in Vindelov's solution. One particular association was significant when tested by Cox models: The percentage of nuclei with S-phase amounts of nuclear DNA was a significant predictor of decreased survival (regression coefficient = 0.20, p = 0.04). The percentage of nuclei in the G0/G1 peak was marginally associated with longer survival. These data are evidence of an association between nuclei in certain phases of the DNA cell cycle and postoperative survival.

Adolescent↗
PubMed1990

Gonadotropin-releasing hormone regulates gonadotropin beta-subunit and chromogranin-B messenger ribonucleic acids in cultured chromogranin-A-positive pituitary adenomas.

Chromogranin-A-positive pituitary adenomas include glycoprotein hormone-producing adenomas, null cell adenomas, and a few other pituitary adenomas. We studied the effects of GnRH, CRF, dexamethasone, and phorbol 12-myristate 13-acetate on FSH and LH secretion and on FSH beta and chromogranin-A and -B mRNA expression in 10 chromogranin-A-positive adenomas in vitro to analyze the regulation of FSH and chromogranin-A and -B expression in these neoplasms. Most adenomas responded to GnRH stimulation during 7 days in culture with a 2- to 10-fold increase in FSH and LH secretion and a 2- to 7-fold increase in FSH beta mRNA compared to control values. CRF and phorbol 12-myristate 13-acetate also stimulated FSH and LH secretion 2- to 5-fold in five of seven and three of three cases, respectively, during 7 days in culture. Dexamethasone stimulated both FSH and LH secretion in two of three cases as well as FSH beta mRNA in vitro in the one case examined. GnRH treatment consistently produced a 2-fold increase in chromogranin-B mRNA, but not in chromogranin-A mRNA, after 7 days of culture. These results indicate that many chromogranin-A-positive adenomas respond to GnRH and CRF in vitro by increased hormone secretion and that GnRH stimulation leads to increased amounts of FSH beta and chromogranin-B mRNAs. The differential response of chromogranin-A and -B mRNAs after GnRH stimulation indicates that the chromogranin genes are highly regulated in these tumors.

Adenoma↗
PubMed1989

Intracerebral arteriovenous malformations: intraoperative color Doppler flow imaging.

Color Doppler flow ultrasound (US) was used to locate and image intracerebral arteriovenous malformations (AVMs). US was deemed useful in eight of 12 patients who underwent AVM resection. Blood flow in the eight lesions was clearly evident, and major feeding arteries and draining veins, such as the superior sagittal sinus, were identified. Color Doppler flow imaging was used to differentiate adjacent hematoma from AVM in three patients, locate a small (6-mm) AVM deep in the brain in two patients, detect a deep major feeding artery in one patient, detect a residual unresected AVM in one patient, and confirm complete resection in all eight patients.

Cerebral Angiography↗
PubMed1989

Human growth hormone and prolactin secreting pituitary adenomas analyzed by in situ hybridization.

Acidophilic pituitary adenomas commonly produce growth hormone (GH) or prolactin (PRL), according to studies employing immunohistochemical and ultrastructural methods. To examine this question, in situ hybridization with oligonucleotide probes was done on routinely processed tissues received in the pathology laboratory to analyze for the presence of GH and PRL messenger RNA (mRNA) in 4 normal pituitaries, 10 prolactinomas, and 16 GH-secreting adenomas. Most acidophilic cells in normal pituitaries expressed either GH or PRL hormone and the respective mRNAs, but GH mRNA and PRL hormone were also detected in some of the same cells. Patients with a clinical diagnosis of prolactinoma had cells with only PRL mRNA in their tumors, while most (14 of 16) patients with a clinical diagnosis of acromegaly or gigantism had both GH and PRL mRNAs in their tumors. The GH adenomas varied in these studies. In situ hybridization was helpful in characterizing the adenoma from a patient with acromegaly who had immunoreactive PRL, but no immunoreactive GH in the resected tumor; in situ hybridization analysis revealed mRNAs for both GH and PRL in the same tumor cells. Our findings indicate that pituitary adenomas from patients with acromegaly commonly express PRL mRNA. It is concluded that in situ hybridization provides new information about the clinical biology and the histopathologic classification of pituitary adenomas.

Adenoma↗