Table of Contents
1
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.
2
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.
pierre.goudet@chu-dijon.fr
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.
3
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.
4
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. hakan.ahlman@surgery.gu.se
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.
5
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. kmak@kir.ks.sc
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.
6
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.
7
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.
8
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. hiro-405@cb3.so-nat.ne.jp
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.
9
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.
10
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.
11
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
12
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.
13
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.
14
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
15
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. baudin@igr.fr
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.
16
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.
sebates@helix.nih.gov
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.
17
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.
18
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.
19
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.
20
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.
21
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.
22
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.
23
UI - 11786899
AU - Hainaut P
TI -
Tumor-specific mutations in p53: the acid test.
SO - Nat Med 2002 Jan;8(1):21-3
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