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Analysis of large versus small pheochromocytomas: operative approaches and patient outcomes.
Wilhelm SM, Prinz RA, Barbu AM, Onders RP, Solorzano CC
(2006) Surgery 140: 553-9; discussion 559-60
MeSH Terms: Adrenal Gland Neoplasms, Adrenalectomy, Adult, Female, Humans, Laparoscopy, Male, Middle Aged, Pheochromocytoma, Postoperative Complications, Retrospective Studies, Treatment Outcome
Show Abstract · Added March 5, 2014
BACKGROUND - Laparoscopic adrenalectomy for small pheochromocytomas, although challenging, is widely accepted. However, its application to pheochromocytomas larger than 6 cm is questioned due to concerns of malignancy and case complexity. Our aim was to examine the impact of pheochromocytoma tumor size (>/=6 cm vs <6 cm) on operative approach and postoperative patient outcomes.
METHODS - A retrospective review of adrenalectomies performed at 3 university hospitals over 1 decade was analyzed. All pheochromocytomas were identified and then divided based on size into large (>/=6 cm) and small (<6 cm) groups. We examined patient and tumor demographics, pathologic diagnosis, operative approach (laparoscopic vs open), postoperative complications, and biochemical cure rates. Data were analyzed using the Student t test and Fisher exact test with a P value <.05 considered significant.
RESULTS - From 1995 to 2005, 65 pheochromocytomas were resected. Of the total, 38% (n = 25) tumors were >/=6 cm and 62% (n = 40) were <6 cm. For the large tumors, 1 out of 25 (4%) was malignant, whereas no small tumors were malignant. There was no statistically significant increased risk of malignancy in tumors >/=6 cm in size (P = .31). Initial operative approach was based on surgeon preference. Of the adrenalectomies performed, 88% were laparoscopic, with 3 of 25 (12%) large tumors requiring conversion from laparoscopic to open for intraoperative bleeding. None of the small tumors required conversion. No major postoperative complications (eg, stroke or myocardial infarction) occurred in either group. Minor complications (eg, wound infections and hematomas) were noted in 16% of large tumors and 12.5% of small tumors (P = .45). A total of 96% (24 of 25) patients with large tumors and 100% with small tumors showed postoperative biochemical cure. Tumor recurrence was noted in 1 patient with a tumor <6 cm.
CONCLUSIONS - Pheochromocytomas >/=6 cm pose a challenge for laparoscopic resection, and concerns have been raised about the validity of this operative approach. This study demonstrates that there is no significant difference in the rate of malignancy for pheochromocytomas >/=6 cm versus <6 cm. There also were no significant differences identified in complication rates, postoperative biochemical cures, or tumor recurrence rates between these groups. Laparoscopic resection of pheochromocytomas can be safely accomplished regardless of size in centers with surgeons experienced in these procedures.
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12 MeSH Terms
Neurofibromatosis-associated pheochromocytoma.
Lew JI, Jacome FJ, Solorzano CC
(2006) J Am Coll Surg 202: 550-1
MeSH Terms: Adrenal Gland Neoplasms, Adrenalectomy, Adult, Diagnosis, Differential, Female, Follow-Up Studies, Humans, Laparoscopy, Neurofibromatosis 1, Pheochromocytoma, Positron-Emission Tomography, Tomography, X-Ray Computed
Added March 5, 2014
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12 MeSH Terms
Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.
Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG, Schlisio S
(2005) Cancer Cell 8: 155-67
MeSH Terms: Adrenal Gland Neoplasms, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, DNA-Binding Proteins, Dioxygenases, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Mutation, Nerve Growth Factor, Neurons, Pheochromocytoma, Procollagen-Proline Dioxygenase, Protein Kinase C, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction, Succinate Dehydrogenase, Sympathetic Nervous System, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added March 5, 2014
Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.
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26 MeSH Terms
Clinical experience over 48 years with pheochromocytoma.
Goldstein RE, O'Neill JA, Holcomb GW, Morgan WM, Neblett WW, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott HW
(1999) Ann Surg 229: 755-64; discussion 764-6
MeSH Terms: Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Pheochromocytoma, Postoperative Complications, Survival Rate, Time Factors, Treatment Outcome
Show Abstract · Added December 10, 2013
OBJECTIVE - To analyze the presentation, localization, surgical management, pathology, and long-term outcome of a large series of patients with pheochromocytomas.
SUMMARY BACKGROUND DATA - There are several areas of controversy pertaining to pheochromocytomas. Although many studies report a higher rate of malignancy for extraadrenal pheochromocytomas than for adrenal pheochromocytomas, the number of patients with the former tumor are small and statistical analysis is lacking. There has also been recent debate as to whether microscopic features of the tumor may be predictive of future behavior.
METHODS - From 1950 to 1998, the authors observed 108 pheochromocytomas in 104 patients. The outcome of these patients has been followed prospectively. The medical records of these patients were reviewed for data on the presentation, localization, surgical management, pathology, and outcome. Patient survival was analyzed using Kaplan-Meier survival distributions.
RESULTS - This study included 66 female patients and 38 male patients. The average age at surgery was 42.3 years. Sporadic cases accounted for 84% of the patients; the other 16% had multiple endocrine neoplasia type 2, von Recklinghausen's disease, von Hippel-Lindau disease, or Carney's syndrome. Of 64 adrenal tumors, 55 were initially considered benign, 6 had microscopic malignant features, and 3 had malignant disease. Mean patient follow-up was 12.6 years. To date, in five additional patients (none with microscopic disease) malignant disease developed (13% overall rate of malignancy). Recurrence occurred as late as 15 years after resection. Of 26 extraadrenal pheochromocytomas, 14 were initially considered benign, 8 had microscopic malignant features, and 4 had malignant disease. Thus, 46% of patients had either malignant disease or tumors with malignant features. Mean patient follow-up was 11.5 years. In one patient with benign disease and in one patient with malignant features, malignant disease developed (23% overall rate of malignancy). The difference in the rate of malignancy was not statistically significant between adrenal and extraadrenal pheochromocytomas. Patients with adrenal and extraadrenal pheochromocytomas also had similar rates of survival (p = NS).
CONCLUSIONS - The data suggest that patients with extraadrenal pheochromocytomas have the same risk of malignancy and the same overall survival as patients with adrenal pheochromocytomas. Lifelong follow-up of these patients is mandatory.
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14 MeSH Terms
Relation of blood volume and blood pressure in orthostatic intolerance.
Jacob G, Biaggioni I, Mosqueda-Garcia R, Robertson RM, Robertson D
(1998) Am J Med Sci 315: 95-100
MeSH Terms: Adolescent, Adrenal Gland Neoplasms, Adult, Blood Pressure, Blood Volume, Diastole, Female, Humans, Hypertension, Hypertension, Renovascular, Hypotension, Orthostatic, Male, Norepinephrine, Pheochromocytoma, Posture, Regression Analysis, Systole
Show Abstract · Added December 10, 2013
A complex but crucial relationship exists between blood volume and blood pressure in human subjects; it has been recognized that in essential hypertension, renovascular hypertension, and pheochromocytoma, the relationship between plasma volume and diastolic blood pressure is an inverse one. This phenomenon has not been studied in individuals with low normal and reduced blood pressures. Orthostatic intolerance is a commonly encountered abnormality in blood pressure regulation often associated with tachycardia in the standing position. Most of these patients have varying degrees of reduced blood volume. We tested the hypothesis that the relationship previously found between plasma volume and diastolic blood pressure in pressor states would also hold in orthostatic intolerance. We studied 16 patients with a history of symptomatic orthostatic intolerance associated with an elevation in plasma norepinephrine in the upright posture and hypovolemia in 9 patients and normovolemia in 7 patients. Our studies demonstrate an inverse relationship between plasma volume and diastolic blood pressure in patients with orthostatic intolerance. This finding also holds for the change in diastolic blood pressure in response to upright posture. In this relationship, patients with orthostatic intolerance with high plasma norepinephrine resemble those with essential hypertension, renovascular hypertension, and pheochromocytoma. We conclude that in a variety of conditions at both ends of the blood pressure spectrum, the seemingly paradoxical association of hypovolemia and diastolic blood pressure is preserved.
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17 MeSH Terms
Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP.
Morohashi K, Zanger UM, Honda S, Hara M, Waterman MR, Omura T
(1993) Mol Endocrinol 7: 1196-204
MeSH Terms: Adrenal Gland Neoplasms, Animals, Base Sequence, Cattle, Cell Line, Cytochrome P-450 Enzyme System, DNA-Binding Proteins, Fushi Tarazu Transcription Factors, Gene Expression Regulation, Enzymologic, Homeodomain Proteins, Molecular Sequence Data, Oligodeoxyribonucleotides, PC12 Cells, Plasmids, Promoter Regions, Genetic, Receptors, Cytoplasmic and Nuclear, Restriction Mapping, Steroid 11-beta-Hydroxylase, Steroidogenic Factor 1, Transcription Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured
Show Abstract · Added February 12, 2015
We have examined the transcriptional activity of four cis-elements, Ad1(CRE), Ad2, Ad3, and Ad4, that are present in the promoter of the bovine CYP11B (11 beta-hydroxylase P-450) gene using beta-globin reporter gene constructs and transient transfection into steroidogenic and nonsteroidogenic cell types. Only Ad1(CRE), a CRE homolog, showed forskolin-dependent transcriptional activity in adrenal tumor Y-1 cells, whereas the other elements were not able to stimulate transcription by themselves. As Ad3 and Ad4 had previously been identified as the cis-elements required for full cAMP-dependent transcription of this gene, we examined the effect of combinations of different cis-elements on the transcription of the reporter gene. In Y-1 cells, Ad1(CRE) and four tandem copies of any one of the other cis-elements substantially activated transcription in response to forskolin treatment. The template carrying Ad1(CRE) and Ad4 was also active in testicular Leydig cells, I-10, whereas it was inactive in nonsteroidogenic PC-12 cells. Transcriptional activation by the 4xAd4/Ad1(CRE) combination presumably depended on the presence of Ad4-binding protein (Ad4BP), which is absent in PC-12 cells, as shown by immunoblot analysis. This was confirmed by cotransfecting an expression vector for Ad4BP into PC-12 cells, which caused forskolin-dependent transcription to increase in proportion to the amount of expression vector. In Y-1 cells, transcriptional activation by forskolin was mimicked by cotransfection of an expression vector for the catalytic subunit of protein kinase-A.(ABSTRACT TRUNCATED AT 250 WORDS)
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23 MeSH Terms
A full-length cDNA encoding mouse adrenodoxin.
Stromstedt M, Waterman MR
(1995) Biochim Biophys Acta 1261: 126-8
MeSH Terms: Adrenal Gland Neoplasms, Adrenodoxin, Amino Acid Sequence, Animals, Base Sequence, DNA, Complementary, DNA, Neoplasm, Genes, Mammals, Mice, Molecular Sequence Data, Open Reading Frames, Sequence Alignment, Sequence Homology, Amino Acid, Species Specificity
Show Abstract · Added February 12, 2015
A full-length cDNA encoding mouse adrenodoxin was isolated from a Y1 adrenocortical tumor cell lambda ZAP cDNA library. The 883 bp cDNA contains a 567 bp open reading frame encoding a protein containing 188 amino acids. Mouse adrenodoxin shows high amino acid sequence identity with other mammalian adrenodoxins and the four cysteines involved in the formation of the iron-sulfur cluster are present.
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15 MeSH Terms
Clinical experience with malignant pheochromocytomas.
Scott HW, Reynolds V, Green N, Page D, Oates JA, Robertson D, Roberts S
(1982) Surg Gynecol Obstet 154: 801-18
MeSH Terms: Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Antineoplastic Agents, Catecholamines, Child, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Pheochromocytoma, Retrospective Studies
Show Abstract · Added December 10, 2013
In a 30 year period at Vanderbilt University Hospital, the affiliated Nashville General Hospital and the Nashville Veterans Administration Hospital, 64 patients with pheochromocytoma have been observed. In eight of these, the tumor proved to be malignant. Retrospective review of biologic characteristics of pheochromocytomas in this series included clinical, diagnostic imaging, chemical and histopathologic data. Aside from presence of distant metastases, none of these features had predictive value in indicating the biologic malignant nature of the primary tumor. One patient has been cured by radical surgical resection for 16 years. Three others have died with metastatic tumor and three patients are alive with metastatic tumor.
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14 MeSH Terms
Surgical experience with retrogastric and retropancreatic pheochromocytomas.
Scott HW, Dean RH, Lea JW, Waterhouse G, Sussman C, Robertson D, Oates JA
(1982) Surgery 92: 853-65
MeSH Terms: Adolescent, Adrenal Gland Neoplasms, Adult, Aortography, Choristoma, Female, Humans, Laparotomy, Male, Middle Aged, Pancreas, Pheochromocytoma, Stomach, Subtraction Technique, Tomography, X-Ray Computed
Show Abstract · Added December 10, 2013
From 1972 to 1981 at Vanderbilt University Hospital there were seven patients with midline retrogastric or retropancreatic pheochromocytomas. Each of these tumors arose between the aorta and the inferior vena cava. This report details the difficulties in localization before and at operation in the smaller tumors in these sites. Our experience suggests that small midline pheochromocytomas in these sites may be readily missed by computerized tomographic scan, aortography, or surgical search at laparotomy unless subtraction arteriograms are used and the Kocher maneuver is employed at operation routinely.
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15 MeSH Terms
Nonfunctioning adrenal tumors. Dilemmas in management.
Hubbard MM, Husami TW, Abumrad NN
(1989) Am Surg 55: 516-22
MeSH Terms: Adenoma, Adrenal Gland Neoplasms, Adult, Aged, Female, Humans, Male, Middle Aged
Show Abstract · Added December 10, 2013
A retrospective study conducted from 1975-1987 at Vanderbilt University Medical Center and affiliated hospitals identified 28 patients, ranging in age from 22 to 74 years, who were noted to have "nonfunctioning" adrenocortical tumors. Eighteen (64%) were men, and ten (36%) were women. A left adrenal mass was present in 16 (57%) patients, a right in 11 (39%) patients, and one (4%) patient had bilateral adrenal enlargements. Nineteen patients underwent an adrenalectomy. Ten were found to have adrenocortical adenomas, ranging is size from 2.5-4.0 cm in greatest diameter. Three were adrenocortical carcinomas (3.0, 5.5, and 8.0 cm). A necrotic mass (14.0 cm) was found in one patient. Two patients had myelolipoma, one had ganglioneuroma, and one had a suspected primary melanoma. Five patients were not operated upon and were followed by serial computed tomographic scans for variable periods; two died of unrelated cardiac problems, and one was lost to follow-up. Three patients underwent biopsy with benign pathology. The data indicate a high incidence of adenoma and carcinoma in patients with nonfunctioning adrenal tumors that measure more than 3.0 cm in diameter. These tumors have the potential to progress to malignant degeneration without any recognizable clinical or endocrine abnormalities. The authors thus conclude that all patients with "nonfunctioning" adrenal tumors that are larger than 3.0 cm in diameter should undergo surgical exploration and excision.
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8 MeSH Terms