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K Thapar

Publications and source records attributed to K Thapar.

At least 19 recordsLinked to original sources
PubMed2002

Cushing's disease resulting from pituitary corticotrophic microadenoma. Treatment results from transsphenoidal microsurgery and gamma knife radiosurgery.

Cushing's disease and its associated clinical syndrome reflect the effects of excess cortisol on the individual. The cause of Cushing's disease is ordinarily an ACTH-secreting benign pituitary adenoma. The diagnosis of Cushing's disease is established by sophisticated endocrine testing and comprehensive imaging studies. Because of the devastating effects of excess cortisol, therapy that provides prompt and effective normalization of serum cortisol is essential. Currently this goal is best achieved by transsphenoidal microsurgery. This paper reviews the clinical presentation, laboratory analysis, surgical management and outcome in patients with Cushing's disease.

Adenoma↗
PubMed2001

Goal oriented general anesthesia for Cesarean section in a parturient with a large intracranial epidermoid cyst.

PURPOSE: To illustrate the anesthetic management of a term parturient with a large brain tumour scheduled for Cesarean section. CLINICAL FEATURES: A 26-yr-old woman presented at 33 weeks gestation with a generalized grand mal seizure. Magnetic resonance imaging demonstrated a 5-cm multi-lobulated extra axial mass compatible with an epidermoid cyst, arising from the left temporal lobe associated with shift of the midline structures and compression of the brainstem. She remained stable neurologically until elective Cesarean section at 38 weeks. Immediately prior to induction of general anesthesia, the proposed incision site was infiltrated with lidocaine and the supraglottic structures anesthetized with bilateral superior laryngeal nerve blocks. Remifentanil, thiopentone sodium and succinylcholine were administered in a rapid sequence fashion following voluntary hyperventilation to an endtidal CO2 of 28 mmHg. Anesthesia was maintained with desflurane in oxygen/air and an infusion of remifentanil. Postoperative pain control was achieved using a multi-modal approach which included intraperitoneal deposition of local anesthetic, im ketorolac and rectal acetaminophen prior to emergence followed by regular administration of naproxen and acetaminophen for 72 hr. CONCLUSION: In a parturient with a large intracranial tumour, general anesthesia combined with multi-modal balanced analgesia met the predefined anesthetic management goals and was associated with a favourable outcome.

Adult↗
PubMed2001

Acromegaly: historical perspectives and current therapy.

Soon after the initial description of acromegaly in the late 19th century, neurosurgeons performed the first operative procedures for the disease. Transcranial procedures eventually yielded to the transsphenoidal approach. Reasonably effective medical therapy was introduced in the 1970s and pharmacological progress continues to be realized. It is now recognized that excess growth hormone is associated with significant morbidity and mortality and that biochemical remission improves outcome. Although medical and radiation treatments offer useful adjuncts, surgery provides optimal results.

Acromegaly↗
PubMed2001

Fluoroscopic frameless stereotaxy for transsphenoidal surgery.

OBJECTIVE: To assess the value of frameless fluoroscopy-guided stereotactic transsphenoidal surgery using the FluoroNav Virtual Fluoroscopy System (Medtronic Sofamor Danek, Inc., Memphis, TN). METHODS: Twenty consecutive patients undergoing transsphenoidal surgery for sellar lesions were assigned to transsphenoidal surgery with or without computer-assisted fluoroscopic image guidance using the FluoroNav system. Prospective data regarding patient age, sex, lesion characteristics, operative time, and treatment cost were obtained. RESULTS: Although patients in the FluoroNav group were, on average, 17 years younger than the patients in the control group, more patients with recurrent adenomas were treated in the image guidance group. No other significant differences between the groups were found. FluoroNav provided accurate, continuous information regarding the anatomic midline trajectory to the sella turcica as well as anatomic structures (e.g., sella, sphenoid sinus) in the lateral view. No patient required reversion to intraoperative videofluoroscopy. No statistically significant differences were found with regard to preincision setup time, operative time, or cost. FluoroNav allowed procedures to be performed with significantly fewer x-rays being taken. CONCLUSION: Fluoroscopic computer-assisted frameless stereotaxy furnishes accurate real-time information with regard to midline structures and operative trajectory. Although it is useful in first-time transseptal transsphenoidal surgery, its primary benefit is realized in recurrent surgery.

Adenoma↗
PubMed2000

Pituitary surgery for the management of acromegaly.

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.

Acromegaly↗
PubMed1999

Pituitary surgery.

Surgical management of pituitary adenomas continues to be a safe and effective method for treating many patients with these lesions. The goal of overall management should be to provide the patient with the most effective means of long-term control of this benign but potentially disabling disease. Currently, surgery has a significant role. It is hoped that with advances in the understanding of pituitary pathophysiology and with advances in pharmacotherapy, surgical management may become even more focused, more precise, and more effective over time.

Adenoma↗
PubMed1999

Lactotroph hyperplasia in the pituitaries of female mice expressing high levels of bovine growth hormone.

PEPCK/bGH transgenic mice have very high blood levels of foreign GH, and prominent reproductive disturbances, especially in females. To obtain a deeper insight into the causes of these abnormalities, pituitaries of PEPCK/bGH transgenics were studied by immunocytochemistry, electron microscopy and in situ hybridization (ISH) techniques. Pituitary weights were significantly reduced (P < 0.05) in transgenic males, while in transgenic females they were increased without reaching significance compared to nontransgenic controls. In both sexes, GH cells were inhibited, as previously described in other lines of GH transgenic mice. In females, PRL cells were increased by 37% compared to controls. Ultrastructurally, the lactotrophs had characteristics of stimulation and PRL mRNA was increased by 35%. In males the increase in the number of PRL immunoreactive cells was not significant, the PRL mRNA signal did not differ from controls, and there were no changes in their ultrastructure. Only in females ACTH cells were significantly reduced (P < 0.05) in number and unchanged in males; however, POMC mRNA signal was increased in both genders and reached significance (P < 0.05) in males. In females, but not in males, the percentage of LH cells was lower than in control mice. In conclusion, the high blood bGH levels induced sex related changes in transgenic mice from the present line. The infertility of PEPCK/bGH transgenic females may be attributed to lactotroph hyperplasia and marked reduction in number of gonadotrophs.

Adrenocorticotropic Hormone↗
PubMed1999

New developments in pituitary surgical techniques.

Despite ongoing advances in the pharmacological, radiotherapeutic and endocrine management of pituitary tumours, surgery remains the therapy of choice for the large majority of these lesions. As surgical efficacy is now being judged by more rigorous technical standards and by more stringent endocrine criteria than ever before, such scrutiny has only served to reinforce the fundamental role of surgery in pituitary tumour management. With the revival of the trans-sphenoidal approach, together with its ongoing technical evolution during the past three decades, pituitary tumours have emerged as eminently treatable lesions, with trans-sphenoidal microsurgery affording long-term, high-quality survival in many patients. Pituitary surgery is, however, not without limitation or liability. Even in experienced hands, endocrine and/or oncological remission is not uniformly achieved. Moreover, of those patients in whom such 'cures' can be induced, the durability of the response is not absolute, as tumour recurrence will continue to threaten a small but significant proportion of patients over time. Finally, and notwithstanding the fact that trans-sphenoidal surgery remains one of the safest procedures in contemporary, neurosurgical practice, complications can occur, some of which can be associated with significant morbidity and, on rare occasions, mortality. Clearly, there continue to be areas in need of improvement, and it has been in response to these limitations of contemporary pituitary surgery that neurosurgeons have sought to develop alternative strategies to improve surgical outcome. As a result, a variety of important innovations have been introduced during recent years. Among others, the most important and effective of these have been the application of neuronavigational techniques, trans-sphenoidal endoscopy and intraoperative MR resection control to the standard trans-sphenoidal approach to pituitary tumours. Whereas some advances are conceptual and others are technical, all are helping to push the limits of pituitary surgery to new frontiers of efficacy and safety. In this chapter, the current state of the art of pituitary surgery is reviewed along with those important new developments that, in the foreseeable future, hope to improve the quality of surgical care available to the pituitary tumour patient.

Adenoma↗
PubMed1998

Localization of insulin-like growth factor-II mRNA in human pituitary adenomas.

Insulin-like growth factors (IGFs) have been reported to promote cell proliferation in many tumours, but their contribution to pituitary adenoma development and growth has not been characterized. We report the presence of insulin-like growth factor II (IGF-II) mRNA in pituitary adenomas using in situ hybridization (ISH). The intensity of IGF-II hybridization signal was correlated with adenoma type, and the presence of Ki-67. Among the 109 adenomas examined, 55 (50.4%) were positive for IGF-II mRNA. All acidophil stem cell, functioning corticotrophic and plurihormonal adenomas contained the message; a high incidence of signal was found among sparsely (7/8) and densely (4/6) granulated growth hormone (GH) cell adenomas, mixed GH cell-prolactin (PRL) cell adenomas (6/7), thyrotrophic (4/6) and null-cell (6/7) adenomas. Less frequently, IGF-II mRNA was localized in mammosomatotrophic, silent subtype 3, gonadotrophic, and oncocytic adenomas, whereas all sparsely granulated PRL cell adenomas and silent corticotrophic adenomas of subtypes 1 and 2 were negative. The MIB-I labelling index was significantly higher in adenomas with a moderate to intense IGF-II signal than in adenomas with weak or no signal. The results suggest that IGF-II, when highly expressed, may have a role in pituitary adenoma proliferation.

Adenoma↗
PubMed1998

Pituitary adenoma producing growth hormone and adrenocorticotropin: a histological, immunocytochemical, electron microscopic, and in situ hybridization study. Case report.

The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells--one somatotroph and one corticotroph--transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.

Acromegaly↗
PubMed1998

Transferrin and transferrin receptor in human hypophysis and pituitary adenomas.

Transferrin (Tf), a major transport protein for iron in the blood and an essential growth factor in some tissues, acts via specific transferrin receptor (TfR). We studied the cellular distribution of Tf and TfR gene expression in 50 human nontumorous autopsy pituitaries and 42 surgically removed pituitary adenomas. Tf and TfR mRNA accumulation was correlated with Ki-67 proliferation marker. In nontumorous pituitaries without iron deposits Tf immunoreactivity was localized in some growth hormone, prolactin, adrenocorticotropin, thyrotropin, and luteinizing hormone cells. Most adenohypophysial cells were immunopositive for TfR. In pituitaries with iron deposits, Tf and TfR were localized only in iron-free cells. Tf mRNA and protein were present in 27 and 32 adenomas, respectively; Ki-67 labeling index of tumors positive for Tf mRNA was significantly higher than in those without transcript (0.94% versus 0.51%; P < 0.025). A positive linear correlation between tumor growth fraction and Tf mRNA signal intensity was evident (r = 0.32; P = 0.04). TfR mRNA and encoded protein were demonstrated in 26 and 31 adenomas, respectively; Ki-67 immunoreactivities were not correlated with the presence of TfR transcripts and signal intensities. These data suggest that Tf may act as a growth-promoting factor for pituitary tumors.

Adenoma↗
PubMed1997

Antiproliferative effect of the somatostatin analogue octreotide on growth hormone-producing pituitary tumors: results of a multicenter randomized trial.

OBJECTIVE: To determine and quantify the in vivo effects of octreotide on the cell cycle kinetics of growth hormone-producing pituitary adenomas. DESIGN: A multicenter randomized trial had been conducted to assess the clinical efficacy of octreotide, and we studied tissue specimens from pituitary macroadenomas in 32 patients with acromegaly from that trial-16 of whom had received 4 months of octreotide therapy before surgical resection and 16 of whom had undergone surgical resection only. MATERIAL AND METHODS: All tumors had been fully characterized on the basis of their immunophenotypic profile and their ultrastructural morphologic features. Included were 16 densely and 16 sparsely granulated somatotroph adenomas. In each case, immunostaining for the cell cycle-specific nuclear antigen Ki-67 was performed with use of the MIB-1 antibody. The staining reaction was manually quantified, and a tumor growth fraction was derived in each case. RESULTS: The mean growth fraction of tumors exposed to octreotide was suppressed by 83% in comparison with untreated surgical controls (0.011+/-0.004% versus 0.065+/-0.016%, respectively; P = 0.0068). The association between octreotide treatment and lower tumor growth fractions was statistically independent of tumor subtype, being evident among both sparsely and densely granulated somatotroph adenomas. CONCLUSION: Octreotide exerts a significant antineoplastic effect on somatotroph adenomas, one readily reflected at the level of the cell cycle. This antiproliferative response provides insight into several clinicopathologic issues surrounding octreotide therapy for these neoplasms.

Acromegaly↗
PubMed1997

Immunocytochemical localization of macrophage migration inhibitory factor in human hypophysis and pituitary adenomas.

OBJECTIVE: To establish the presence of macrophage migration inhibitory factor (MIF) in human nontumorous and adenomatous pituitaries. DESIGN, SETTING, AND PATIENTS: Macrophage migration inhibitory factor was demonstrated by immunocytochemistry on paraffin sections with a polyclonal antirecombinant murine MIF using the streptavidin-biotin-peroxidase complex method. Nontumorous hypophyses (14 cases) obtained from autopsy and 54 surgically removed pituitary adenomas were studied. In nontumorous pituitaries, serial sections were immunostained for both pituitary hormones and MIF. RESULTS: Macrophage migration inhibitory factor was localized in all corticotrophs, including basophils extending into the posterior lobe, Crooke's cells, and a few thyrotrophs. The posterior lobe was immunonegative for MIF. Densely (five cases) and sparsely (six cases) granulated somatotroph and lactotroph (six cases) adenomas lacked MIF immunostaining. Macrophage migration inhibitory factor was found in 3 of 4 thyrotroph adenomas, 3 of 6 gonadotroph adenomas, 10 of 11 functioning corticotroph and 8 of 10 silent corticotroph adenomas, 3 of 3 null cell adenomas, and 3 of 3 oncocytic adenomas. The immunopositivity was diffuse or focal, and the intensity was variable. CONCLUSIONS: This study is the first to demonstrate the presence of MIF in human nontumorous and adenomatous pituitaries using an immunocytochemical staining technique.

Adenoma↗
PubMed1997

Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior.

The clinical behavior of growth hormone (GH)-producing pituitary tumors is known to vary greatly; however, the events underlying this variability remain poorly understood. Herein we demonstrate that tumor overexpression of the GH-releasing hormone (GHRH) gene is one prognostically informative event associated with the clinical aggressiveness of somatotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was demonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern analysis and reverse transcriptase polymerase chain reaction, and protein translation was confirmed by Western blotting. By comparison, transcript accumulation was absent or negligibly low in 30 normal pituitary glands. GHRH transcripts were found to preferentially accumulate among clinically aggressive tumors. Specifically, GHRH mRNA signal intensity was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0.71; P < 0.001), 2) linearly correlated with preoperative serum GH levels (r = 0.56; p = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a model of postoperative remission likelihood was derived wherein remission was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test. In this outcome model, GHRH mRNA signal intensity proved to be the most important explanatory variable overall, eclipsing any and all conventional clinicopathological predictors as the single most significant predictor of postoperative remission; increases in GHRH mRNA signal were associated with marked declines in remission likelihood. The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at another institution. These data indicate that overexpression of GHRH gene is an event associated with the neoplastic progression and clinical aggressiveness of somatotroph adenomas. More generally, these data merge essential elements of the hypothalamic and pituitary hypotheses of pituitary tumorigenesis, providing for a more unified concept of neoplastic progression in the pituitary.

Acromegaly↗
PubMed1996

Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody.

Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

Adult↗
PubMed1996

p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions.

Although most pituitary tumors are well differentiated, histologically benign neoplasms, their clinical behavior is known to vary greatly. These lesions are relentlessly aggressive in some instances yet biologically indolent in others, but these prognostically relevant differences in behavior are not reflected in their histopathological appearance. As a means of identifying intrinsically aggressive pituitary tumors, we evaluated 70 pituitary adenomas and 7 primary pituitary carcinomas for their expression of the p53 gene product, a nuclear phosphoprotein whose immunohistochemical accumulation has served as an unfavorable prognostic factor for a wide range of human neoplasms. All tumors were fully classified by immunohistochemistry and electron microscopy; adenomas were further stratified on the basis of their invasion status, the latter being defined as gross operatively or radiologically apparent infiltration of dura or bone. Conclusive nuclear immunopositivity for p53 was identified in a total of 12 tumors, all being either invasive adenomas or primary pituitary carcinomas. A clear and highly significant association was evident between p53 expression and tumor behavior, as the proportion of p53-positive cases among noninvasive adenomas, invasive adenomas, and pituitary carcinomas was 0, 15.2, and 100%, respectively (chi 2 = 44.72; degrees of freedom, 2; P << 0.001). A comparison of previously reported growth fraction data with p53 expression indicated that the mean Ki-67-derived growth fraction of p53-positive tumors was significantly higher than that of p53-negative tumors (10.41 +/- 2.20 versus 2.51 +/- 0.28%) (+/- standard error of the mean, two-sample t test for independent samples, P = 0.004). There was no apparent relationship between the functional status of the tumor and p53 expression; positivity was observed among somatotroph, lactotroph, corticotroph, and clinically nonfunctioning pituitary tumors. These data indicate that p53 expression, when conclusively present in pituitary tumors, may be of some diagnostic usefulness as a marker of biologically aggressive behavior.

Adenoma↗