Antisense oligonucleotide—induced inhibition of adrenocorticotropic hormone release from cultured human corticotrophs

1999 ◽  
Vol 91 (2) ◽  
pp. 261-267 ◽  
Author(s):  
Bruce Frankel ◽  
Sharon L. Longo ◽  
Gerard S. Rodziewicz ◽  
Charles J. Hodge
Keyword(s):  
Cushing’S Disease ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Adrenocorticotropic Hormone ◽  
Cushing's Disease ◽  
Hormone Release ◽  
Content Type ◽  
Novel Treatments ◽  
Fine Print

Object. Available therapies for Cushing's disease are often inadequate or involve the risk of significant morbidity. Accordingly, the need arises for the development of novel treatments, especially for cases caused by corticotroph hyperplasia, a condition difficult to treat using standard therapies. In this study, the authors investigated the use of phosphorothioate antisense oligonucleotides as a potential treatment for Cushing's disease.Methods. Corticotrophs, obtained from a patient with Cushing's disease in whom pathological findings showed multifocal areas of corticotroph adenoma and hyperplasia, were grown in tissue culture. By assessing cell viability and using immunoradiometric assay techniques, it was determined that these cells grew autonomously and secreted adrenocorticotropic hormone (ACTH) in vitro. A fully phosphorothioated antisense oligonucleotide was constructed to be complementary to the first 25 bp of the region coding for ACTH in exon 3 of the proopiomelanocortin precursor. After incubation of the corticotrophs with liposome-coated phosphorothioate antisense oligonucleotides, a greater than 90% decrease in ACTH release was noted on Days 3 and 6, compared with nonsense-treated controls (p < 0.05).Conclusions. Antisense oligonucleotides may prove to be a useful adjunct in treating Cushing's disease by targeting one of its fundamental problems, ACTH hypersecretion.

Surgical treatment of Cushing's disease

1987 ◽  
Vol 66 (2) ◽  
pp. 204-212 ◽  
Author(s):  
William F. Chandler ◽  
David E. Schteingart ◽  
Ricardo V. Lloyd ◽  
Paul E. McKeever ◽  
Gloria Ibarra-Perez
Keyword(s):  
Cushing’S Disease ◽  
Immunohistochemical Staining ◽  
Adrenocorticotropic Hormone ◽  
Cushing's Disease ◽  
Content Type ◽  
Acth Secreting ◽  
Endocrine Symptoms ◽  
Lung Carcinoid ◽  
Fine Print ◽  
Pharyngeal Pituitary

✓ The endocrinological, radiological, surgical, and pathological experience with 34 consecutive patients operated on for Cushing's disease is presented. Preoperative endocrine evaluation demonstrated that 19 patients had “typical” endocrine patterns for pituitary adrenocorticotropic hormone (ACTH)-dependent hypercortisolism and 11 had “atypical” testing. Pituitary pathology was found in 95% of the patients with typical preoperative endocrine testing but in only 55% of those with atypical testing. Eight of 34 preoperative computerized tomography scans demonstrated tumors, which correlated in all instances with the surgical findings. Microadenomas were removed from 25 patients, 22 of whom achieved postoperative remission of endocrine symptoms. Macroadenomas were found in three patients, only one of whom achieved remission after surgery. One patient had removal of an adenoma in the pharyngeal pituitary, and in another an ectopic lung carcinoid was excised; both of these patients were in postoperative remission. Four patients underwent transsphenoidal exploration but no definitive explanation was found for their hypercortisolism; these patients were not in remission. Immunohistochemical staining was performed on every specimen and all tumors showed excessive ACTH-secreting cells. A new rapid stain of the fibrovascular stroma is described.

Surgical management of adrenocorticotropic hormone—secreting macroadenomas: outcome and challenges in patients with Cushing's disease or Nelson's syndrome

2005 ◽  
Vol 103 (5) ◽  
pp. 825-830 ◽  
Author(s):  
Claudio De Tommasi ◽  
Mary Lee Vance ◽  
David O. Okonkwo ◽  
Alfa Diallo ◽  
Edward R. Laws
Keyword(s):  
Cushing’S Disease ◽  
Adrenocorticotropic Hormone ◽  
Signs And Symptoms ◽  
Disease Recurrence ◽  
Cushing's Disease ◽  
Nelson’S Syndrome ◽  
Content Type ◽  
Nelson's Syndrome ◽  
Acth Secreting ◽  
Fine Print

Object. Adrenocorticotropic hormone (ACTH)—secreting pituitary macroadenomas are an uncommon cause of Cushing's disease (CD) and, subsequently, Nelson's syndrome (NS). They have been associated with low postoperative remission rates. The outcome of modern surgical treatment is unclear and thus was assessed in a series of 43 patients, with the goal of improving therapeutic results in patients with ACTH-secreting macroadenomas. Methods. Thirty-seven patients presented with CD and six with NS. They represented 15% of the patients surgically treated at the authors' institution for ACTH-secreting adenomas. The median patient age was 38 years (range 14–71 years), and the mean duration of follow up was 37 months (range 1–108 months). Remission occurred in 25 (67.6%) of 37 patients with CD, whereas the disease persisted in 12 (32.4%) of 37 patients. After an initial remission, three (12%) of 25 patients demonstrated signs and symptoms indicative of disease recurrence. Among patients with NS, only one (16.6%) displayed remission. Invasion of the dura mater by tumor was histologically demonstrated in 10 patients with CD and in two patients with NS. Conclusions. Comprehensive management of CD caused by ACTH-secreting macroadenomas through the appropriate use of combination therapy, including surgery, radiotherapy, radiosurgery, and adrenalectomy, can lead to outcomes similar to those for microadenomas. Disease recurrence and persistence rates are higher, often because of the invasiveness associated with macroadenomas. Remission of NS-associated macroadenomas is difficult to achieve. Strategies for the characterization and treatment of invasive macroadenomas are needed.

Delayed cure of Cushing's disease after transsphenoidal surgery of pituitary microadenomas

1978 ◽  
Vol 49 (4) ◽  
pp. 593-596 ◽  
Author(s):  
Stephen D. McDonald ◽  
Stanley E. Von Hofe ◽  
Steven G. Dorfman ◽  
Richard M. Jordan ◽  
James R. LaMorgese ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Transsphenoidal Surgery ◽  
Normal Tissue ◽  
Adrenocorticotropic Hormone ◽  
Early Postoperative Period ◽  
Cushing's Disease ◽  
Content Type ◽  
Pituitary Microadenoma ◽  
Dexamethasone Suppression ◽  
Fine Print

✓ Transsphenoidal microdissection has been proposed as a preferred means of treating Cushing's disease. This procedure allows the surgeon to remove a pituitary microadenoma and at the same time to preserve normal tissue. Two cases described here were treated by this method. An interesting and important observation was that neither patient appeared to be cured for 2 to 6 weeks after surgery, as assessed by dexamethasone suppression. Later, normal suppressibility occurred and the course of each patient was compatible with cure. Patients treated by this method should not be automatically retreated because of adrenocorticotropic hormone (ACTH) non-suppressibility in the early postoperative period.

TISSUE CULTURE STUDIES ON HUMAN PITUITARY TUMOURS: RADIOIMMUNOASSAYABLE ANTERIOR PITUITARY HORMONES IN THE CULTURE MEDIUM

1978 ◽  
Vol 88 (2) ◽  
pp. 239-249 ◽  
Author(s):  
Loren G. Lipson ◽  
Inese Z. Beitins ◽  
Paul D. Kornblith ◽  
Janet W. Mc Arthur ◽  
Henry G. Friesen ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cushing’S Disease ◽  
Anterior Pituitary ◽  
Pituitary Hormones ◽  
Cushing's Disease ◽  
Hormone Release ◽  
Pituitary Tumours ◽  
Human Pituitary ◽  
Anterior Pituitary Hormones

ABSTRACT A tissue culture study was undertaken to determine if human non-functioning pituitary tumours secrete polypeptide anterior pituitary hormones in vitro and to study the spectrum of hormone release by functioning pituitary neoplasms. Fragments from 48 human pituitary tumours (from patients - 2 with Cushing's disease, 1 with Nelson's syndrome, 5 with amenorrhoea-galactorrhoea, 10 with acromegaly and 30 with non-functioning pituitary tumours) and three normal human anterior pituitary glands (controls) were placed in tissue culture immediately after surgery. The in vitro release of human growth hormone (HGH), prolactin (Prl), thyrotrophin (TSH), adrenocorticotrophin (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by radioimmunoassays at the end of one week in culture. Clinical and pathological data were compared to hormone release patterns. In the culture media from control pituitaries the concentrations of the six hormones tested were 100 to 10 000 times greater than in peripheral blood. The medium surrounding the fragments from functioning pituitary tumours contained the following: a) Acromegaly - high levels of HGH and variable concentrations of the other hormones. b) Cushing's disease - ACTH and Prl predominantly. c) Amenorrhcea-galactorrhoea syndrome - prolactin in 4 out of 5 patients, all six polypeptides in one patient. In the media from the 30 patients diagnosed as having non-functioning pituitary tumours, 60 % of the samples contained at least one hormone at a concentration similar to that of the controls and 100 % of the samples contained detectable quantities of at least one hormone.

Radiosurgery for Cushing's disease after failed transsphenoidal surgery

2000 ◽  
Vol 93 (5) ◽  
pp. 738-742 ◽  
Author(s):  
Jonas M. Sheehan ◽  
Mary L. Vance ◽  
Jason P. Sheehan ◽  
Dilantha B. Ellegala ◽  
Edward R. Laws
Keyword(s):  
Gamma Knife ◽  
Cushing’S Disease ◽  
Tumor Size ◽  
Transsphenoidal Surgery ◽  
Gamma Knife Radiosurgery ◽  
Magnetic Resonance Images ◽  
Cushing's Disease ◽  
Content Type ◽  
Fine Print

Object. Although transsphenoidal surgery has become the standard of care for Cushing's disease, it is often unsuccessful in normalizing cortisol production. In this study the authors investigate the safety and efficacy of gamma knife radiosurgery (GKRS) for Cushing's disease after failed transsphenoidal surgery.Methods. The records of all patients who underwent GKRS at the authors' institution after unsuccessful transsphenoidal surgery for Cushing's disease were retrospectively reviewed. Successful treatment was considered a normal or below-normal 24-hour urinary free cortisol (UFC) level. Records were also evaluated for relapse, new-onset endocrine deficiencies, interval change in tumor size, and visual complications.Forty-three patients underwent 44 gamma knife procedures with follow up ranging from 18 to 113 months (mean 39.1, median 44 months). Normal 24-hour UFC levels were achieved in 27 patients (63%) at an average time from treatment of 12.1 months (range 3–48 months). Three patients had a recurrence of Cushing's disease at 19, 37, and 38 months, respectively, after radiosurgery. New endocrine deficiencies were noted in seven patients (16%). Follow-up magnetic resonance images obtained in 33 patients revealed a decrease in tumor size in 24, no change in nine, and an increase in size in none of the patients. One patient developed a quadrantanopsia 14 months after radiosurgery despite having received a dose of only 0.7 Gy to the optic tract.Conclusions. Gamma knife radiosurgery appears to be safe and effective for the treatment of Cushing's disease refractory to pituitary surgery. Delayed recurrences and new hormone deficiencies may occur, indicating the necessity for regular long-term follow up.

Multiple pituitary adenomas in Cushing's disease

2000 ◽  
Vol 93 (5) ◽  
pp. 753-761 ◽  
Author(s):  
John K. Ratliff ◽  
Edward H. Oldfield
Keyword(s):  
Cushing’S Disease ◽  
Medical Records ◽  
Pituitary Adenomas ◽  
Cushing's Disease ◽  
Clinical Database ◽  
Null Cell ◽  
Content Type ◽  
Initial Surgery ◽  
Repeated Surgery ◽  
Fine Print

Object. Clinically evident multiple pituitary adenomas rarely occur. The authors assess the incidence and clinical relevance of multiple adenomas in Cushing's disease.Methods. A prospective clinical database of 660 pituitary surgeries was analyzed to assess the incidence of multiple pituitary adenomas in Cushing's disease. Relevant radiographic scans, medical records, and histopathological reports were reviewed.Thirteen patients with at least two separate histopathologically confirmed pituitary adenomas were identified. Prolactinomas (nine patients) were the most common incidental tumors. Other incidental tumors included secretors of growth hormone ([GH], one patient) and GH and prolactin (two patients), and a null-cell tumor (one patient). In two patients, early repeated surgery was performed because the initial operation failed to correct hypercortisolism, in one instance because the tumor excised at the initial surgery was a prolactinoma, not an adrenocorticotropic hormone—secreting tumor. One patient had three distinct tumors.Conclusions. Multiple pituitary adenomas are rare, but may complicate management of patients with pituitary disease.

Cushing's disease with pituitary apoplexy leading to hypopituitarism, empty sella, and spontaneous fracture of the dorsum sellae

1979 ◽  
Vol 51 (6) ◽  
pp. 866-869 ◽  
Author(s):  
Philip H. Gutin ◽  
William G. Cushard ◽  
Charles B. Wilson
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Disease ◽  
Plasma Cortisol ◽  
Pituitary Apoplexy ◽  
Empty Sella ◽  
Cushing's Disease ◽  
Content Type ◽  
Urinary Levels ◽  
Fine Print ◽  
Transsphenoidal Resection

✓ A patient with a pituitary adenoma secreting adrenocorticotropin hormone manifested panhypopituitarism after an episode of pituitary apoplexy. The previously elevated urinary levels of 17-ketogenic steroids dropped sharply, and plasma cortisol became undetectable. The apoplexy also resulted in a partially empty sella on which the dorsum sellae collapsed. Recurrent Cushing's disease developed and was cured by transsphenoidal resection of a microadenoma.

Localization of pituitary adenomas by using intraoperative ultrasoound pituitary in patients with Cushing's disease and no demonstrable tumor on magnetic resonance imaging

1998 ◽  
Vol 89 (6) ◽  
pp. 927-932 ◽  
Author(s):  
Joe C. Watson ◽  
Thomas H. Shawker ◽  
Lynnette K. Nieman ◽  
Hetty L. DeVroom ◽  
John L. Doppman ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Mr Imaging ◽  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Pituitary Surgery ◽  
Intraoperative Ultrasonography ◽  
Cushing's Disease ◽  
Content Type ◽  
Negative Findings ◽  
Fine Print

Object. Pituitary surgery has been reported to produce remission of Cushing's disease with preservation of pituitary function in only 60 to 70% of patients. The inability to identify an adenoma accounts for most failed sellar explorations. Most negative surgical explorations occur in patients in whom magnetic resonance (MR) imaging of the pituitary demonstrates normal findings, which happens in at least 35 to 45% of patients with Cushing's disease. Methods. To examine the usefulness of intraoperative ultrasonography (IOUS) for identifying an adenoma in patients with no demonstrable tumor (negative findings) on pituitary MR imaging, we prospectively assessed the results of IOUS in 68 patients with a negative (59 patients) or equivocal (nine patients) MR image from a consecutive series of 107 patients with Cushing's disease (64%). We compared surgical findings and outcomes in these 68 patients with a group of 68 patients with Cushing's disease and negative findings on MR imaging in whom IOUS was not available. Intraoperative ultrasonography localized a tumor in 47 (69%) of 68 patients with negative findings on MR imaging. Surprisingly, the size of the adenomas that were detected with IOUS compared with the size of those not detected did not differ (6.8 ± 3.4 mm compared with 6.1 ± 2.8 mm [mean ± standard deviation], respectively [p = 0.5]). In four patients, no adenoma was found at surgery or in the pathological specimen (“true negative”). In eight patients, nine abnormalities detected by IOUS that were suspected adenomas were negative on exploration (“false positive”). Thus, IOUS has a sensitivity of 73% and a positive predictive value of 84% for detecting pituitary adenomas in patients with Cushing's disease and negative findings on MR imaging. Compared with the 68 patients who did not undergo IOUS, remission after surgery was improved (61 patients [90%] compared with 57 patients [84%]), the number of tumors found on exploration was increased (61 tumors compared with 51 tumors; p = 0.02), and the number of hemihypophysectomies was decreased (five compared with 15; p = 0.02) with IOUS. When the groups were compared after excluding patients with prior pituitary surgery, tumors were found in 91% versus 72% (p = 0.008), and remission occurred in 95% versus 87% of patients, respectively, in the groups that had or did not have IOUS. Conclusions. The IOUS is a sensitive imaging modality when used in patients with Cushing's disease in whom findings on pituitary MR imaging are negative. The improved ability to detect and localize these tumors by using IOUS positively affects surgical outcome.

Cushing's disease: results of transsphenoidal microsurgery with emphasis on surgical failures

1990 ◽  
Vol 72 (3) ◽  
pp. 363-369 ◽  
Author(s):  
George T. Tindall ◽  
Carl J. Herring ◽  
Richard V. Clark ◽  
David A. Adams ◽  
Nelson B. Watts
Keyword(s):  
Cushing’S Disease ◽  
Preoperative Diagnosis ◽  
Adrenocorticotropic Hormone ◽  
Remission Rate ◽  
Cushing's Disease ◽  
Sustained Remission ◽  
Original Diagnosis ◽  
Content Type ◽  
Transsphenoidal Microsurgery

✓ From 1977 to 1988, 56 patients with a preoperative diagnosis of Cushingαs disease were treated by transsphenoidal microsurgical exploration of the pituitary gland. In 42 patients, a discrete tumor was found and a selective adenomectomy was performed. Total hypophysectomy was performed in nine patients. In an attempt to preserve pituitary function, a technique of subtotal hypophysectomy was utilized in the remaining five patients. Regular and adequate follow-up results were obtained in 53 patients. A sustained remission was obtained in 45 of these 53 patients for a remission rate of 84.9%. Eight patients were classified as therapeutic failures. The causes for failure included: 1) invasive tumor; 2) hyperplasia mistaken for an adenoma; 3) a presumed ectopic source of adrenocorticotropic hormone; 4) misdiagnosis; 5) atypical tumor; and 6) recurrence of disease after remission. In cases of therapeutic failure, the original diagnosis of Cushing's disease must be reevaluated and treatment continued until sustained remission is achieved. Necessary measures to help avoid surgical failures and an approach for further diagnostic and therapeutic maneuvers in these cases are discussed.

Intraoperative ultrasound-directed resection of pituitary tumors

1995 ◽  
Vol 83 (2) ◽  
pp. 225-230 ◽  
Author(s):  
Zvi Ram ◽  
Thomas H. Shawker ◽  
Mary H. Bradford ◽  
John L. Doppman ◽  
Edward H. Oldfield
Keyword(s):  
Mr Imaging ◽  
Cushing’S Disease ◽  
Intraoperative Ultrasound ◽  
Pituitary Tumors ◽  
Thyroid Stimulating Hormone ◽  
Cushing's Disease ◽  
Content Type ◽  
Normal Pituitary Gland ◽  
Intraoperative Localization ◽  
Fine Print

✓ Microadenomas of the pituitary vary in size, particularly those related to Cushing's disease. They are often not visualized on preoperative magnetic resonance (MR) imaging and may be difficult to find during surgical exploration of the pituitary. To enhance intraoperative localization of pituitary adenomas, we assessed the feasibility of using ultrasound to detect and localize pituitary tumors. Intraoperative ultrasound (IS) in the axial and sagittal planes was performed with an Intrascan system using a 12-MHz mechanically oscillating, end-firing transducer. Interpretation of the scans was performed by two individuals, who were usually blinded to the results of preoperative MR imaging or petrosal sinus sampling. Twenty-eight patients were examined. Eighteen of these patients had microadenomas (1.5–7 mm), all with Cushing's disease; nine had macroadenomas (10–20 mm), three of which were adrenocorticotropic hormone—secreting, three growth hormone—secreting, two thyroid-stimulating hormone—secreting, and one nonfunctioning; and one patient had an intrasellar craniopharyngioma. Normal sellar and parasellar structures, such as intrapituitary cysts, the intracavernous carotid arteries, and the diaphragma sella were easily visualized. Twenty-three of the 28 tumors, including 13 of the 18 microadenomas, were detected on IS (82% sensitivity). Tumors were seen as hyperechoic masses in 19 patients, mixed echogenicity in three, and isoechoic in one. In most macroadenomas IS allowed visualization of the interface between the tumor and the normal pituitary gland. These results indicate the potential of IS to aid the intraoperative localization and definition of pituitary tumors.

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