National Cancer Institute®
Last Modified: January 1, 2002
UI - 11456263
AU - Midorikawa S; Sanada H; Hashimoto S; Suzuki T; Watanabe T; Sasano H
TI - Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas: study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes.
SO - Endocr J 2001 Apr;48(2):167-74
AD - Third Department of Internal Medicine, Fukushima Medical University School of Medicine, Japan.
Adrenal incidentalomas have recently increased in incidence, and thus it has become important to establish clinical management of these patients. It is also important to evaluate whether these tumors are different from preclinical or overt Cushing's syndrome in their steroidogenesis. In this study, we therefore examined steroidogenesis of hormonally inactive adrenal incidentalomas via short-term culture of tumor specimens, in addition to an immunohistochemical study of steroidogenic enzymes. Five patients (two men and three women) diagnosed with adrenocortical incidentaloma without any clinical signs of adrenocortical hormonal excess except for hypertension and disturbed glucose tolerance, were recruited for this study. Hormonal findings, including circadian rhythms for cortisol and ACTH secretion, the response of ACTH to CRH infusion and results of dexamethasone suppression test were all within normal limits in these patients. Immunoreactivity for all steroidogenic enzymes involved in cortisol production was detected in tumor cells in all cases examined. Results of in vitro steroidogenesis analysis using short-term culture revealed that levels of cortisol secretion varied among the cases. There were no differences in the immunolocalization of steroidogenic enzymes and/or the levels of cortisol secretion between these hormonally inactive tumors and preclinical and/or overt Cushing's syndrome. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity in nonneoplastic regions was suppressed in one case in which the tumor secreted cortisol similar to preclinical and/or overt Cushing's syndrome. These results demonstrate that the levels of in vitro steroid production and/or the immunolocalization of steroidogenic enzymes in hormonally inactive adrenocortical tumors vary markedly and are not overtly different from those of preclinical and/or overt Cushing's syndrome.
UI - 11572030
AU - Icard P; Goudet P; Charpenay C; Andreassian B; Carnaille B; Chapuis Y;
TI - Cougard P; Henry JF; Proye C Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group.
SO - World J Surg 2001 Jul;25(7):891-7
AD - Service de Chirurgie Viscerale et Urgences, Hopital General, 3 Rue du Faubourg-Raines, BP 1519, 21033 Dijon, France. email@example.com
Because of the rarity of adrenocortical carcinoma, survival rates and the prognosis for patients who have undergone operation are not well known. The purpose of the French Association of Endocrine Surgery was to evaluate these factors over an 18-year period. A trend study was associated to assess changes in the clinical and biochemical presentations as well as the surgical evolution. A total of 253 patients (158 women, 95 men) with a mean age of 47 years were included. Cushing syndrome was the main clinical presentation (30%), and hormonal studies revealed secreting tumors in 66% of the cases. Altogether, 72% (n = 182) of patients underwent resection for cure, and 41.5% (n = 105) of them had an extensive resection because of metastatic cancer. A lymphadenectomy was performed in 32.5% (n = 89) of the cases. The operative mortality was 5.5% (n = 14). Patients were given mitotane as adjuvant therapy in 53.8% of the cases (n = 135). The results of staging were stage I in 16 patients (6.3%), stage II (local disease) in 126 patients (49.8%), stage III (locoregional disease) in 57 patients (22.5%), and stage IV (metastases) in 54 patients (21.3%). Neither tumor staging nor the rate of curative surgery changed during the study period. More subcostal incisions were performed, and the use of mitotane increased significantly. The 5-year actuarial survival rates were 38% overall, 50% in the curative group, 66% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV. Multivariate analysis showed that mitotane benefited only the group of patients not operated on for cure. A better prognosis was found in patients operated on after 1988 (p = 0.04), in those with precursor-secreting tumors (p = 0.005), and in those at local stages of the disease (p = 0.0003). Thus mitotane benefited only patients not operated on for cure. Curative resection, precursor secretion, recent diagnosis, and local stage were favorably associated with survival.
UI - 11572033
AU - Dackiw AP; Lee JE; Gagel RF; Evans DB
TI - Adrenal cortical carcinoma.
SO - World J Surg 2001 Jul;25(7):914-26
AD - Department of Surgical Oncology, Section of Endocrine Tumor Surgery, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77033, USA.
Adrenal cortical carcinoma is a rare endocrine tumor for which complete surgical resection is the only potentially curative treatment. Accurate preoperative evaluation (biochemical and radiographic) of the patient who presents with an adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful prognostic variable for long-term survival. The response to chemotherapy or mitotane is modest in patients with advanced disease. Hopefully, an improved understanding of the molecular pathogenesis of this challenging tumor will lead to the development of more effective therapies in the future.
UI - 11572034
AU - Ahlman H; Khorram-Manesh A; Jansson S; Wangberg B; Nilsson O; Jacobsson
TI - CE; Lindstedt S Cytotoxic treatment of adrenocortical carcinoma.
SO - World J Surg 2001 Jul;25(7):927-33
AD - Department of Surgery, Sahlgrenska University Hospital, Goteborg University, S-413 45 Goteborg, Sweden. firstname.lastname@example.org
Adrenocortical carcinoma (ACC) is a rare, aggressive tumor that is often detected in an advanced stage. Medical treatment with the adrenotoxic drug mitotane has been used for decades, but critical prospective trials on its role in residual disease or as an adjuvant agent after surgical resection are still lacking. The concept of a critical threshold plasma level of the drug must be confirmed in controlled studies. Because individual responsiveness cannot be predicted, the use mitotane is still advised for nonresectable disease. In case of cortisol or other steroid overproduction, several drugs (e.g., ketoconazole or aminoglutethimide) may be used. Chemotherapy with single agents (e.g., doxorubicin or cisplatin) have been disappointing, with low response rates (< 30%) and a short response duration. Part of this refractoriness may be explained by the fact that ACC tumors express the multidrug-resistance gene MDR-1. Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. The best results were achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane, achieving a response rate of 54%, including individual complete responses. To be able to make progress in treating advanced ACC disease, adjuvant multicenter trials must be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.
UI - 11572037
AU - Kjellman M; Larsson C; Backdahl M
TI - Genetic background of adrenocortical tumor development.
SO - World J Surg 2001 Jul;25(7):948-56
AD - Department of Surgery, P9:03, Karolinska Hospital, S-17176, Stockholm, Sweden. email@example.com
The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place on the chromosomal and gene level in sporadic adrenocortical tumors.
UI - 11572038
AU - Enberg U; Farnebo LO; Wedell A; Grondal S; Thoren M; Grimelius L;
TI - Kjellman M; Backdahl M; Hamberger B In vitro release of aldosterone and cortisol in human adrenal adenomas correlates to mRNA expression of steroidogenic enzymes for genes CYP11B2 and CYP17.
SO - World J Surg 2001 Jul;25(7):957-66
AD - Department of Surgical Sciences, Section of Surgery, Karolinska Institute at Karolinska Hospital, P9:03, S-17176 Stockholm, Sweden.
Adenomas of the adrenal cortex cause different disorders depending on the main steroid synthesized and released. The aim of this research is to increase our understanding of the pathophysiology of steroidogenesis in adrenocortical disorders by comparing the release of steroids from adrenocortical adenomas in vitro with the messenger RNA (mRNA) expression of steroid synthesizing enzymes. Fourteen patients with adrenal tumors were included in the present study; nine were diagnosed with primary aldosteronism and three with Cushing's syndrome. Two patients had an adrenal tumor discovered on computed tomography (CT) during workup for an unrelated disease. Serum cortisol, plasma aldosterone, and urinary catecholamines were normal. Tissue was taken for in vitro steroid release, and aldosterone and cortisol in the medium after a 1-hour incubation were determined. Oligonucleotide probes with sequences complementary to mRNAs encoding for the steroid synthesizing enzymes 11 beta-hydroxylase (CYP11B1), 18-hydroxylase (CYP11B2), 17 alpha-hydroxylase (CYP17), and 21-hydroxylase (CYP21) were synthesized (Genset, Paris, France) and in situ hybridization was performed. Moderate expression of CYP11B2 and low expression of CYP11B1 were seen in the zona glomerulosa. The zona fasciculata of the control adrenals expressed a high signal of CYP11B1, whereas the expression of CYP11B2 was very low. There was considerable variation in aldosterone release from the aldosteronomas, whereas the tumors from the Cushing patients showed no detectable release of aldosterone. In contrast, tumors from patients with primary aldosteronism, Cushing's syndrome, and no hyperfunction all had the ability to synthesize and release cortisol in vitro. The highest cortisol release was found in tumors from patients with Cushing's syndrome, but also the nonhyperfunctioning tumors and some of the aldosteronomas released significant amounts of cortisol. The two patients with highest release of aldosterone in vitro showed the highest expression of CYP11B2 and the lowest expression of CYP11B1 and CYP17. The remaining aldosteronomas had low expression of CYP11B2, similar to the two other groups. Expression of CYP11B1 was high as expected in the Cushing adenomas, but also the two nonhyperfunctioning tumors and some of the aldosteronomas showed a moderate expression. Adenomas from Cushing's syndrome, nonhyperfunctioning adenomas, and some of the aldosterone-producing adenomas had moderate to high expression of CYP17. This paper presents new means for functional characterization of adrenocortical tumors. Diagnosis of an aldosteronoma is often difficult, and with the advent of these methods it is possible to determine the functional capacity of a tumor, once it is removed. This is of special interest if the patient remains hypertensive postoperatively, and it is not clear whether the patient indeed had a functioning tumor.
UI - 11562782
AU - Albertin G; Forneris M; Aragona F; Nussdorfer GG
TI - Expression of adrenomedullin and its receptors in the human adrenal cortex and aldosteronomas.
SO - Int J Mol Med 2001 Oct;8(4):423-6
AD - Department of Human Anatomy and Physiology (Section of Anatomy), School of Medicine, University of Padua, Via Gabelli 65, I-35121 Padua, Italy.
Adrenomedullin (ADM) is a hypotensive peptide, that derives from the proteolytic cleavage of pro(p)ADM and acts through at least two subtypes of receptors, called L1-receptor (L1-R) and calcitonin receptor-like receptor (CRLR). CRLR may function as a calcitonin gene-related peptide (CGRP) or a selective ADM receptor depending on the expression of the subtype 1 or the subtypes 2 and 3 of a family of proteins, referred to as receptor-activity-modifying proteins (RAMPs). Although adrenal cortex is known to be one of the main target organs of ADM, its expression of the ADM and its receptor has not yet been extensively investigated. Reverse transcription (RT)-polymerase chain reaction (PCR) revealed the expression of the pADM and peptidyl-glycine alpha-amidating monooxigenase (PAM) genes in four human adrenal cortexes and four aldosteronomas. Since PAM is the enzyme that converts immature ADM to the mature and active form, these findings suggest that the two tissues are able to produce ADM. RT-PCR also demonstrated high levels of L1-R mRNA and relatively low levels of CRLR mRNA, as well as the presence of specific mRNAs for the three RAMPs, thereby indicating that human adrenal cortex and aldosteronomas are provided with the two subtypes of classic ADM receptors. In conclusion, our investigation provides the first evidence that human adrenal cortex and aldosteronomas express the ADM system, that may play a role in the paracrine or autocrine control of their functions.
UI - 11592817
AU - Shibata H; Ikeda Y; Mukai T; Morohashi K; Kurihara I; Ando T; Suzuki T;
TI - Kobayashi S; Murai M; Saito I; Saruta T Expression profiles of COUP-TF, DAX-1, and SF-1 in the human adrenal gland and adrenocortical tumors: possible implications in steroidogenesis.
SO - Mol Genet Metab 2001 Sep-Oct;74(1-2):206-16
AD - Health Center, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan. firstname.lastname@example.org
Chicken ovalbumin upstream promoter-transcription factor (COUP-TF), DAX-1, and steroidogenic factor-1 (SF-1) are orphan members of the nuclear hormone receptor superfamily. COUP-TF and DAX-1 have been shown to negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P450 genes. We therefore examined the expression levels and immunolocalization of COUP-TF, DAX-1, and SF-1 in human adrenal gland (NL) and adrenocortical adenomas, and compared the results with CYP17 expression levels and its enzyme activities to study their potential correlation with adrenocortical steroidogenesis. In NL (n = 10), expressions of COUP-TF, DAX-1, and SF-1 were detected in the nuclei of adrenocortical cells, but not in the medulla. In cortisol-producing adenomas causing Cushing syndrome (CS, n = 20), CYP17 expression was upregulated (298 +/- 2% vs NL 98 +/- 4%), whereas expression levels of both COUP-TFs (COUP-TFI, 52 +/- 5% vs NL 98 +/- 4%; COUP-TFII, 18 +/- 4% vs NL 98 +/- 4%) and DAX-1 (42 +/- 4% vs NL 100 +/- 4%) were reduced. In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 +/- 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 +/- 4%). Expression levels of SF-1 did not differ between NL (100 +/- 8%) and CS (106 +/- 10%), but its expression appeared to be decreased in DOC (25 and 20%). These results showed CYP17 expression to be upregulated and downregulated in CS and DOC, respectively, in a manner reciprocal to that of its repressors, COUP-TF and/or DAX-1. In summary, the results indicate that co-localization of COUP-TF, DAX-1, and SF-1 in NL was lost in adrenocortical tumors and that these orphan receptors play an important role in the regulation of steroidogenesis in human adrenals. Copyright 2001 Academic Press.
UI - 11704201
AU - Segal S; Cytron S; Shenhav S; Gemer O
TI - Adrenocortical oncocytoma in pregnancy.
SO - Obstet Gynecol 2001 Nov;98(5 Pt 2):916-8
AD - Department of Obstetrics and Gynecology, Barzilai Medical Center, Ben-Gurion University of the Negev, Ashkelon, Israel.
BACKGROUND: Adrenal oncocytomas are uncommon, nonfunctioning tumors occurring most often in endocrine organs. CASE: A 32-year-old woman presented at 25 weeks' gestation complaining of right flank pain. Abdominal ultrasonography and computed tomography revealed a 9 x 10-cm solid right-sided adrenal mass. Endocrine evaluation was normal. At 36 weeks' gestation, she underwent cesarean followed by resection of the adrenal mass. Histopathologic and ultrastructural studies revealed a benign adrenocortical oncocytoma. CONCLUSION: Although rare, adrenocortical oncocytomas should be included in the differential diagnosis of solid, nonfunctioning, adrenal tumors in pregnancy.
UI - 11705136
AU - Schteingart DE
TI - Current perspective in the diagnosis and treatment of adrenocortical carcinoma.
SO - Rev Endocr Metab Disord 2001 Aug;2(3):323-33
AD - University of Michigan Medical School, Ann Arbor, MI, USA.
UI - 11701664
AU - Koch CA; Chrousos GP
TI - Editorial: Is the diminuto/dwarf1 gene involved in physiologic adrenocortical size regulation and tumor formation?
SO - J Clin Endocrinol Metab 2001 Nov;86(11):5127-9
UI - 11701720
AU - Peri A; Luciani P; Conforti B; Baglioni-Peri S; Cioppi F; Crescioli C;
TI - Ferruzzi P; Gelmini S; Arnaldi G; Nesi G; Serio M; Mantero F; Mannelli M Variable expression of the transcription factors cAMP response element-binding protein and inducible cAMP early repressor in the normal adrenal cortex and in adrenocortical adenomas and carcinomas.
SO - J Clin Endocrinol Metab 2001 Nov;86(11):5443-9
AD - Endocrine Unit, Department of Clinical Physiopathology, University of Florence, 50139 Florence, Italy.
The molecular mechanisms leading to adrenocortical tumorigenesis have been only partially elucidated so far. Because the pituitary hormone ACTH, via activation of the cAMP pathway, regulates both cell proliferation/differentiation and steroid synthesis in the adrenal cortex, in this study we focused on the cAMP-dependent transcription factors cAMP responsive element modulator (CREM) and cAMP responsive element binding protein (CREB). We studied CREM and CREB expression by RT-PCR in human normal adrenal cortex (n = 3), adrenocortical adenomas (n = 8), and carcinomas (n = 8). We found transcripts corresponding to the isoforms alpha, beta, gamma, and tau2 of the CREM gene in all of the normal adrenal tissues, in the adenomas, and in seven of eight carcinomas. On the other hand, mRNA for the inducible cAMP early repressor isoforms, which derive from an internal promoter of CREM gene, was detected in the normal adrenal and in seven of eight adenomas, but in only three of eight carcinomas. Similarly, CREB transcripts were readily detectable in all normal adrenals and adenomas, whereas they were not found in four of eight adrenal carcinomas. To further characterize the carcinomas, telomerase activity and the expression of the ACTH receptor gene were determined. Telomerase activity in the carcinomas resulted in levels significantly higher than in the adenomas, whereas the levels of ACTH receptor mRNA were lower in the carcinomas. No correlation was found in the carcinomas between the levels of the ACTH receptor transcript and the loss of expression of CREB/inducible cAMP early repressor, suggesting that this alteration is not secondary to an upstream disregulation at the receptor level. In conclusion, our results suggest that an alteration in cAMP signaling may be associated with malignancies of the adrenal cortex.
UI - 11711511
AU - Egidy G; Baviera E; Ciuffo G; Corvol P; Pinet F
TI - Localization of the endothelin system in aldosterone-producing adenomas.
SO - Hypertension 2001 Nov;38(5):1137-42
AD - INSERM Unit 36, College de France, Paris, France.
Endothelin-1 (ET-1) could play a role in the regulation of aldosterone secretion of the human adrenal gland. The presence of the endothelin-converting enzyme 1 (ECE-1) and ET-1 suggests that there is a local ET system in the adrenal cortex, but the in situ synthesis of ET-1 remains to be confirmed. The cellular distribution of the whole ET system was evaluated in 20 cases of aldosterone-producing adenomas. Polymerase chain reaction studies gave strong signals for ECE-1 mRNA and the mRNAs for endothelin type A (ET(A)) and B (ET(B)) receptors and faint signals for prepro-ET-1 mRNA. In situ hybridization showed ET(A) receptors scattered throughout the adenoma, in both secretory cells and vascular structures (score, +). There were more ET(B) receptors (score, ++), but they were restricted mainly to the endothelium. ECE-1 mRNA and protein were ubiquitous and abundant in secretory cells (score, +++) and vascular structures (score, ++); the enzyme was active on big ET-1. There was no prepro-ET-1 mRNA in the cortex, except in the thickened precapillary arterioles present in only 30% of the aldosterone-producing adenomas studied. ET-1 immunoreactivity was detected in vascular structures (score, +), probably bound to receptors, suggesting that ET-1 has an endocrine action. The low concentrations of ET-1 could also indicate that it acts in a paracrine-autocrine fashion to control adrenal blood flow. The discrepancy between the concentrations of ECE-1 and its substrate suggests that ECE-1 has another role in the adrenal secretory cells. Our data indicate that ET probably is not a primary cause of the development or maintenance of the adenoma.
UI - 11727263
AU - Diaz-Cano SJ; de Miguel M; Blanes A; Galera H; Wolfe HJ
TI - Contribution of the microvessel network to the clonal and kinetic profiles of adrenal cortical proliferative lesions.
SO - Hum Pathol 2001 Nov;32(11):1232-9
AD - Department of Pathology, Tufts University-New England Medical Center, Boston, MA, USA.
Monoclonal adrenocortical lesions have been characterized by an inverse correlation between proliferation and apoptosis, and polyclonal lesions show a direct correlation. Their relationship with the vascular pattern remains unknown in adrenocortical nodular hyperplasias (ACNHs), adenomas (ACAs), and carcinomas (ACCs). We studied 20 ACNHs, 25 ACAs, and 10 ACCs (World Health Organization classification criteria) from 55 women. The analysis included X-chromosome inactivation assay (on microdissected samples), slide and flow cytometry, and in situ end labeling. Endothelial cells were stained with anti-CD31, and the blood vessel area and density were quantified by image analysis in the same areas. Appropriate tissue controls were run in every case. Regression analyses between kinetic and vascular features were performed in both polyclonal and monoclonal lesions. Polyclonal patterns were observed in 14 of 18 informative ACNHs and 3 of 22 informative ACAs, and monoclonal patterns were seen in 4 of 18 ACNHs, 19 of 22 ACAs, and 9 of 9 ACCs. A progressive increase in microvessel area was observed in the ACNH-ACA-ACC transition but was statistically significant between benign and malignant lesions only (191.36 +/- 168.32 v 958.07 +/- 1279.86 microm(2); P < .0001). In addition, case stratification by clonal pattern showed significant differences between polyclonal and monoclonal benign lesions; 6% of polyclonal and 57% of monoclonal lesions had microvessel area >186 microm(2) (P = .0000008). Monoclonal lesions showed parallel trends (but with opposite signs) for microvessel area and density in comparison with proliferation and apoptosis, whereas polyclonal lesions showed inverse trends. In conclusion, the kinetic advantage of monoclonal adrenal cortical lesions (increased proliferation, decreased apoptosis) is maintained by parallel increases in microvessel area and density. Copyright 2001 by W.B. Saunders Company
UI - 11745214
AU - Baudin E; Pellegriti G; Bonnay M; Penfornis A; Laplanche A; Vassal G;
TI - Schlumberger M Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with adrenocortical carcinoma.
SO - Cancer 2001 Sep 15;92(6):1385-92
AD - Service de Medecine Nucleaire, Institut Gustave-Roussy, Villejuif, France. email@example.com
BACKGROUND: It has been suggested recently that 1,1-dichlorodiphenildichloroethane (o,p'DDD) elicits a dose effect relation in the treatment of patients with adrenocortical carcinoma (ACC). The authors performed a single-center, prospective study with two major objectives: 1) to confirm the interest of plasma o,p'DDD level measurement as a prognostic factor of response to o,p'DDD therapy; and 2) to look for parameters associated with a therapeutic plasma o,p'DDD level, especially the daily o,p'DDD dose. METHODS: Since 1995, patients with ACC who were referred to the Gustave-Roussy Institute have been enrolled prospectively in the study. Therapy with o,p'DDD was given as first-line therapy in 13 patients with metastatic disease or as adjuvant therapy in 11 patients. Oral o,p'DDD was given in three separate doses up to at least 6-12 g per day together with substitutive adrenal therapy. Plasma o,p'DDD levels were measured using high-performance liquid chromatography every 2 months. The o,p'DDD therapy was monitored to achieve plasma o,p'DDD levels within 14-20 mg/L. World Health Organization criteria were used to evaluate tumor response and toxicity. RESULTS: Twenty-four patients with ACC were studied, and a plasma o,p'DDD level > 14 mg/L was achieved in 14 patients (58%). An objective tumor response was observed in four patients with metastatic lesions (31%): One was response was complete, and three were objective hormonal responses. These tumor responses were observed among the six patients who achieved therapeutic plasma o,p'DDD levels. In contrast, no response was observed among the seven patients with plasma o,p'DDD levels that remained consistently low. Eight of 11 patients who received o,p'DDD as adjuvant therapy had disease recurrence, although the plasma o,p'DDD level was > 14 mg/L in 6 patients. Grade 3 or 4 neurologic toxicity was observed in three patients (12%), all with an o,p'DDD level > 20 mg/L. The daily o,p'DDD dose was the only parameter associated with the highest plasma o,p'DDD trough levels: It explained 35% of the variability in the plasma o,p'DDD level. A median interval of 3.7 months was found necessary to achieve the highest o,p'DDD trough levels. CONCLUSIONS: The results confirm the prognostic impact of the plasma o,p'DDD level in patients with metastatic ACC and its interest in avoiding toxicity. Copyright 2001 American Cancer Society.
UI - 11745237
AU - Bates S; Kang M; Meadows B; Bakke S; Choyke P; Merino M; Goldspiel B;
TI - Chico I; Smith T; Chen C; Robey R; Bergan R; Figg WD; Fojo T A Phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar).
SO - Cancer 2001 Sep 15;92(6):1577-90
AD - Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. firstname.lastname@example.org
BACKGROUND: PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS: Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS: The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS: PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies. Copyright 2001 American Cancer Society.
UI - 11720899
AU - Barzon L; Zucchetta P; Boscaro M; Marzola MC; Bui F; Fallo F
TI - Scintigraphic patterns of adrenocortical carcinoma: morpho-functional correlates.
SO - Eur J Endocrinol 2001 Dec;145(6):743-8
AD - Department of Medical and Surgical Sciences, Division of Endocrinology, University of Padova, Italy.
OBJECTIVE: Adrenocortical scintigraphy has demonstrated clinical utility in the morpho-functional characterization of adrenal tumors. The aim of this study was to identify possible relationships between the scintigraphic pattern and endocrine and/or morphological data in a series of adrenocortical carcinomas. DESIGN AND METHODS: Twenty-one patients with adrenocortical carcinoma (11 nonfunctioning and 10 hormone-secreting) were investigated with 75Se-methyl-nor-cholesterol scintigraphy. Clinical, hormonal, radiological, and pathological data were analyzed. RESULTS: The adrenal mass showed no radiocholesterol uptake in 18 cases (11 nonfunctioning and 7 functioning lesions). Contralateral normal adrenal gland was visualized in all patients with nonfunctioning tumors, whereas classic bilateral nonvisualization was observed in the 7 cases with hyperfunctioning masses. Three patients with cortisol-producing carcinomas showed radiotracer uptake by the mass, without visualization of the contralateral gland. At histology, the tumors were shown to be undifferentiated adrenocortical carcinomas; they had an aggressive clinical behavior. CONCLUSIONS: Radiocholesterol scintigraphy has an important role in diagnosing adrenocortical carcinomas, which typically are not visualized. However, 30% of hypersecreting adrenocortical carcinomas show an atypical increased tracer uptake, not predictive of the biochemical and histological features of the tumor.
UI - 7911125
AU - Gicquel C; Bertagna X; Schneid H; Francillard-Leblond M; Luton JP;
TI - Girard F; Le Bouc Y Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.
SO - J Clin Endocrinol Metab 1994 Jun;78(6):1444-53
AD - Laboratoire d'Explorations Fonctionnelles Endocriniennes, Hopital Trousseau, Paris, France.
Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly, in adrenocortical tumors, associated with the Beckwith-Wiedemann syndrome and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, we looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing's syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing's syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, an uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis.
UI - 8787355
AU - Gicquel C; Le Bouc Y
TI - [Insulin-like growth factor II (IGF II) and adrenocortical tumorigenesis]
SO - Ann Endocrinol (Paris) 1995;56(6):617-8
AD - Unite de biologie moleculaire, Hopital Armand Trousseau.
UI - 9204195
AU - Latronico AC; Chrousos GP
TI - Neoplasms of the adrenal cortex. Clinical and basic aspects.
SO - Cancer Treat Res 1997;89():217-37
AD - Developmental Endocrinology Branch, NIH Clinical Center, Bethesda, MD 20892, USA.
UI - 11518119
AU - Eguchi T; Tokuyama A; Tanaka Y; Takahashi Y; Kawahara G; Aiba M; Inishi
TI - Y; Minowa H Hypoglycemia associated with the production of insulin-like growth factor II in adrenocortical carcinoma.
SO - Intern Med 2001 Aug;40(8):759-63
AD - Department of Cardiology, Omori Red Cross Hospital, Tokyo.
A 78-year-old woman was hospitalized for congestive heart failure and repeated hypoglycemic attacks. The laboratory data showed a serum insulin level within the normal range and an increased level of serum insulin-like growth factor (IGF) II. Abdominal ultrasonogram and computed tomography scan revealed a huge mass lying above the left kidney. She was diagnosed as having an adrenocortical carcinoma. After the removal of the tumor, the plasma glucose level and the serum level of IGF-II were normalized. The tumor cells stained positively for IGF-II immunohistochemically. These findings suggested that the hypoglycemia was due to IGF-II produced by the adrenocortical carcinoma.
UI - 11753428
AU - DiGiammarino EL; Lee AS; Cadwell C; Zhang W; Bothner B; Ribeiro RC;
TI - Zambetti G; Kriwacki RW A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
SO - Nat Struct Biol 2002 Jan;9(1):12-6
AD - Department of Structural Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, Tennessee 38105, USA.
The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.
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