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NCBI: db=pubmed; Term=adrenal tumor
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Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion.

Fri, 10/13/2017 - 18:03
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Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion.

J Clin Endocrinol Metab. 2017 Sep 01;102(9):3461-3469

Authors: Debono M, Harrison RF, Chadarevian R, Gueroult C, Abitbol JL, Newell-Price J

Abstract
Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death.
Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers.
Design, Setting, and Participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed.
Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment.
Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.

PMID: 28911138 [PubMed - indexed for MEDLINE]

Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure.

Fri, 10/13/2017 - 18:03
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Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure.

PLoS One. 2017;12(8):e0181055

Authors: Suzuki D, Saito-Hakoda A, Ito R, Shimizu K, Parvin R, Shimada H, Noro E, Suzuki S, Fujiwara I, Kagechika H, Rainey WE, Kure S, Ito S, Yokoyama A, Sugawara A

Abstract
The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. NURR1 overexpression demonstrated that the decrease of NURR1 expression may contribute to the PA024-mediated suppression of CYP11B2 transcription. PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3β2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis. Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRα. Moreover, the combination of PPARγ agonist pioglitazone and PA024 caused synergistic suppressive effects on CYP11B2 mRNA expression. Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5). Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion.

PMID: 28800627 [PubMed - indexed for MEDLINE]

Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma.

Fri, 10/13/2017 - 18:03
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Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma.

J Clin Endocrinol Metab. 2017 Sep 01;102(9):3400-3405

Authors: Komada H, Hirota Y, So A, Nakamura T, Okuno Y, Fukuoka H, Iguchi G, Takahashi Y, Sakaguchi K, Ogawa W

Abstract
Context: Pheochromocytoma and paraganglioma are catecholamine-producing tumors that often impair glucose tolerance. The effects of these tumors on insulin sensitivity and insulin secretion in patients have remained unclear, however.
Objective: To characterize the influence of pheochromocytoma or paraganglioma on glucose tolerance, we comprehensively analyzed various parameters related to insulin secretion or insulin sensitivity in patients with these tumors.
Design: Hyperglycemic and hyperinsulinemic-euglycemic clamps, as well as an oral glucose tolerance test (OGTT), were performed in patients before and after tumor excision.
Setting: Patients underwent metabolic analyses on admission to Kobe University Hospital.
Patients: Eleven patients with pheochromocytoma and two with paraganglioma were examined.
Intervention: None.
Main Outcome Measures: We evaluated various parameters related to insulin secretion or insulin sensitivity as determined by an OGTT and by hyperglycemic and hyperinsulinemic-euglycemic clamp analyses.
Results: Surgical treatment of the tumor reduced urinary catecholamine excretion and improved glucose tolerance. The insulinogenic index, but not total insulin secretion, measured during the OGTT as well as the first phase, but not the second phase, of insulin secretion during the hyperglycemic clamp were improved after surgery. The insulin sensitivity index determined during the hyperinsulinemic-euglycemic clamp remained unchanged after surgery.
Conclusion: These results suggest pheochromocytoma and paraganglioma impair glucose tolerance primarily through impairment of insulin secretion-in particular, that of the early phase of the insulin secretory response. A prospective study with more patients is warranted to further confirm these results.

PMID: 28666346 [PubMed - indexed for MEDLINE]

THE PHYSIOLOGY BEHIND DIABETES MELLITUS IN PATIENTS WITH PHEOCHROMOCYTOMA: A REVIEW OF THE LITERATURE.

Fri, 10/13/2017 - 18:03
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THE PHYSIOLOGY BEHIND DIABETES MELLITUS IN PATIENTS WITH PHEOCHROMOCYTOMA: A REVIEW OF THE LITERATURE.

Endocr Pract. 2017 Aug;23(8):999-1005

Authors: Mesmar B, Poola-Kella S, Malek R

Abstract
OBJECTIVE: This paper reviews the physiologic mechanisms responsible for glucose intolerance and diabetes mellitus in patients with pheochromocytoma.
METHODS: Google Scholar and PubMed were searched using the following key words: "diabetes," "pheochromocytoma," "adrenoreceptors," and "hyperglycemia." All the articles that were retrieved and reviewed were in the English language.
RESULTS: Glucose intolerance and diabetes mellitus, resulting from high circulating levels of catecholamines, are mainly the product of compromised insulin secretion from the β-cells in the pancreas, decreased glucose uptake in the peripheral tissues, and increased insulin resistance.
CONCLUSION: As pheochromocytomas mainly present with cardiovascular and autonomic hyperfunctioning, it is important to understand the metabolic disorders associated with this rare disease. Hyperglycemia is an associated metabolic abnormality which can drastically improve after tumor resection, and significant downscaling of anti-hyperglycemic therapy is often required.
ABBREVIATIONS: GLUT4 = glucose transporter type 4 HbA1c = hemoglobin A1c IL = interleukin OGTT = oral glucose tolerance test.

PMID: 28613940 [PubMed - indexed for MEDLINE]

Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years.

Fri, 10/13/2017 - 18:03
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Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years.

J Clin Endocrinol Metab. 2017 Sep 01;102(9):3296-3305

Authors: Hamidi O, Young WF, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S, Bancos I

Abstract
Context: Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited.
Objective: We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival.
Design: Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016.
Setting: Referral center.
Patients: The group comprised 272 patients.
Main Outcome Measures: Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188).
Results: Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation.
Conclusions: The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.

PMID: 28605453 [PubMed - indexed for MEDLINE]

Clinical Relevance of Steroid Use in Neuro-Oncology.

Fri, 10/13/2017 - 18:03
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Clinical Relevance of Steroid Use in Neuro-Oncology.

Curr Neurol Neurosci Rep. 2017 Jan;17(1):5

Authors: Ly KI, Wen PY

Abstract
BACKGROUND: Corticosteroids are commonly used in the management of primary central nervous system (CNS) tumors and CNS metastases to treat cancer- and treatment-related cerebral edema and improve neurologic function. However, they are also associated with significant morbidity and mortality, given their wide range of adverse effects.
PURPOSE OF REVIEW: To review the mechanism of action, pharmacology, and toxicity profile of corticosteroids and to critically appraise the evidence that supports their use in neuro-oncologic practice based on the latest scientific and clinical data.
RECENT FINDINGS: Recent data suggest that corticosteroids may negatively impact survival in glioma patients. In addition, corticosteroids should be incorporated as a standard criterion to assess a patient's clinical and radiographic response to treatment. Corticosteroids should be used judiciously in neuro-oncologic patients, given the potential deleterious effects on clinical outcome and patient survival. Anti-angiogenic agents, which lack these adverse effects, may be a reasonable alternative to corticosteroids.

PMID: 28138871 [PubMed - indexed for MEDLINE]

Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

Fri, 10/13/2017 - 18:03
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Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

Clin Endocrinol (Oxf). 2017 Apr;86(4):499-505

Authors: Weigel M, Hahner S, Sherlock M, Agha A, Behan LA, Stewart PM, Arlt W, Beier D, Frey K, Zopf K, Quinkler M

Abstract
OBJECTIVE: Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet.
AIM: Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone.
DESIGN: Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0 mg, in nine patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens and ten healthy males were included.
METHODS: Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol.
RESULTS: Calculated free serum cortisol levels after 40 mg immediate release hydrocortisone in ACC patients (46 ± 14 nmol/l) were similar to those after 10 mg immediate release hydrocortisone intake in men with SAI (64 ± 16 nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31 ± 5 nmol/l). Compared to immediate release hydrocortisone, free cortisol levels after 40 mg modified release hydrocortisone in ACC patients were significantly lower (12 ± 3 nmol/l; P = 0·03) resulting in a generally lower AUC (98 ± 21 vs 149 ± 37 nmol h/l; P = 0·02).
CONCLUSIONS: 40-20-0 mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.

PMID: 28063163 [PubMed - indexed for MEDLINE]

Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up.

Fri, 10/13/2017 - 18:03
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Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up.

Clin Endocrinol (Oxf). 2017 04;86(4):488-498

Authors: Papanastasiou L, Alexandraki KI, Androulakis II, Fountoulakis S, Kounadi T, Markou A, Tsiavos V, Samara C, Papaioannou TG, Piaditis G, Kaltsas G

Abstract
OBJECTIVE: Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up.
DESIGN: Prospective study in a tertiary hospital.
PATIENTS AND MEASUREMENTS: Seventy-one patients with AI [51 nonfunctioning (NFAI) and 20 ACS] and 5·54 ± 1·7 years follow-up underwent testing for ACS and oral glucose tolerance test to determine IR indices and adrenal imaging.
RESULTS: At follow-up, 16/51 (31%) NFAI patients converted to ACS, while two with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary-free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9·8% NFAI and 15% ACS, respectively) and 14 IR (17·6% NFAI and 25% ACS, respectively). Adenoma size increased from 2·1 ± 0·8 to 2·3 ± 0·8 cm, whereas IR correlated with postdexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Ν-UFC), to H-UFC, C-ACS and ACS patients.
CONCLUSIONS: New-onset ACS developed in 31% patients with NFAI, whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients.

PMID: 27992961 [PubMed - indexed for MEDLINE]

Where does current and future pediatric asthma treatment stand? Remodeling and inflammation: Bird's eye view.

Fri, 10/13/2017 - 18:03
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Where does current and future pediatric asthma treatment stand? Remodeling and inflammation: Bird's eye view.

Pediatr Pulmonol. 2016 Dec;51(12):1422-1429

Authors: Yilmaz O, Yuksel H

Abstract
Airway remodeling is the chronic outcome of inflammation in asthma and a point of intervention between pediatric and adult ages. Pediatric asthma has been of great interest in the efforts to find a valuable time to interrupt remodeling. Various experimental and clinical research have assessed the effect of current therapeutic modalities on airway remodeling in asthma and many new agents are being developed with promising results. The heterogeneity in the results of these studies may lie in the heterogeneity of pathogenesis leading to asthma and remodeling; underlying the need for individualized treatment of the unique pathogenetic characteristics of each child's asthma. The aim of this review is to summarize the evidence about the influence of current and future therapeutic modalities in the concept of inflammation and remodeling in pediatric asthma. Pediatr Pulmonol. 2016;51:1422-1429. © 2016 Wiley Periodicals, Inc.

PMID: 27233079 [PubMed - indexed for MEDLINE]

IGF1-R inhibition and liposomal doxorubicin: Progress in preclinical evaluation for the treatment of adrenocortical carcinoma.

Fri, 10/13/2017 - 18:03
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IGF1-R inhibition and liposomal doxorubicin: Progress in preclinical evaluation for the treatment of adrenocortical carcinoma.

Mol Cell Endocrinol. 2016 Jun 15;428:82-8

Authors: Beuschlein F, Jakoby J, Mentz S, Zambetti G, Jung S, Reincke M, Süss R, Hantel C

Abstract
Adrenocortical carcinoma (ACC) is a tumor with poor prognosis and limited therapeutic options. Therefore, in addition to multi-chemotherapeutic regimens IGF-1 receptor (IGF-1R) targeting approaches have been evaluated including immunoliposomal (IL) preparations utilizing an IGF-1R inhibiting antibody. In the current study, we extended our experiments by long-term treatment regimens in the classical adrenocortical NCIH295R xenograft model as well as by short-term experiments in two novel xenograft models, which all displayed different levels of IGF-1R and IGF-2 expression. Interestingly, these experiments reveal sub-group dependent differences in therapeutic outcome, reflecting clinical observations and indicate, thus, that implementation of this panel of tumor models might be helpful for clinical translation of novel therapeutic regimens in the future.

PMID: 26994514 [PubMed - indexed for MEDLINE]

[Adrenal disease diagnosis: management of adrenal incidentaloma].

Fri, 10/06/2017 - 15:05

[Adrenal disease diagnosis: management of adrenal incidentaloma].

Rev Med Brux. 2017;38(4):325-333

Authors: Azzi AS, Driessens N

Abstract
Adrenal glands are specialized in biosynthesis of several hormones correlated to different clinical phenotypes in case of excess or lack of production. In addition to secretion disorders, tumors, secreting or not, can take place in adrenal glands. Incidentalomas are the most common adrenal diseases in clinical practice. The challenge of the management is to determine whether the lesion is benign or malignant and secreting or not in order to direct therapeutic management towards surgical option, pharmacotherapy or clinical follow-up. Several radiographic characteristics allow to predict the benign or malignant nature of a lesion (size and density of the tumor, fat content,...). Adrenal carcinoma is a very rare cancer but should be excluded because its extremely poor prognosis. If most incidentalomas are non-secreting, it is important to ensure that there is no Cushing syndrome, even subclinical (± 10 % of incidentalomas) or pheochromocytoma (± 10 % of incidentalomas), pathologies associated with a higher incidence of cardiovascular complications. Careful clinical evaluation for symptoms and signs related to excessive adrenal hormones production is recommended to prescribe appropriate hormone assays. Finally, the surgical indication will be guided by the probability of malignancy, the presence and the degree of hypersecretion but also the age, the general health and the choice of the patient.

PMID: 28981236 [PubMed - in process]

Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice.

Fri, 10/06/2017 - 15:05
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Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice.

Cell Physiol Biochem. 2017 Oct 04;43(3):1064-1076

Authors: Doroszko M, Chrusciel M, Stelmaszewska J, Slezak T, Rivero-Muller A, Padzik A, Anisimowicz S, Wolczynski S, Huhtaniemi I, Toppari J, Rahman NA

Abstract
BACKGROUND/AIMS: Physiological role of luteinizing hormone (LH) and its receptor (LHCGR) in adrenal remains unknown. In inhibin-α/Simian Virus 40 T antigen (SV40Tag) (inhα/Tag) mice, gonadectomy-induced (OVX) elevated LH triggers the growth of transcription factor GATA4 (GATA4)-positive adrenocortical tumors in a hyperplasia-adenoma-adenocarcinoma sequence.
METHODS: We investigated the role of LHCGR in tumor induction, by crossbreeding inhα/Tag with Lhcgr knockout (LuRKO) mice. By knocking out Lhcgr and Gata4 in Cα1 adrenocortical cells (Lhcgr-ko, Gata4-ko) we tested their role in tumor progression.
RESULTS: Adrenal tumors of OVX inhα/Tag mice develop from the hyperplastic cells localized in the topmost layer of zona fasciculata. OVX inhα/Tag/LuRKO only developed SV40Tag positive hyperplastic cells that were GATA4 negative, cleaved caspase-3 positive and did not progress into adenoma. In contrast to Lhcgr-ko, Gata4-ko Cα1 cells presented decreased proliferation, increased apoptosis, decreased expression of Inha, SV40Tag and Lhcgr tumor markers, as well as up-regulated adrenal- and down-regulated sex steroid gene expression. Both Gata4-ko and Lhcgr-ko Cα1 cells had decreased expression of steroidogenic genes resulting in decreased basal progesterone production.
CONCLUSION: Our data indicate that LH/LHCGR signaling is critical for the adrenal cell reprogramming by GATA4 induction prompting adenoma formation and gonadal-like phenotype of the adrenocortical tumors in inhα/Tag mice.

PMID: 28977799 [PubMed - as supplied by publisher]

Intermittent fasting could ameliorate cognitive function against distress by regulation of inflammatory response pathway.

Fri, 10/06/2017 - 15:05
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Intermittent fasting could ameliorate cognitive function against distress by regulation of inflammatory response pathway.

J Adv Res. 2017 Nov;8(6):697-701

Authors: Shojaie M, Ghanbari F, Shojaie N

Abstract
Undesirable and desirable effects of stressors on the body are assigned to distress and eustress, respectively. Immune system and brain are the most susceptible parts to stressful conditions, whereas long-lasting alterations in putative immune proteins involved in tension such as corticosterone (CORT), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) can impact learning and memory. Intermittent fasting (IF) is a repeated regular cycle of dietary restriction with well-known beneficial properties on the body. The aim of this study was to identify the eustress effects of IF on cognitive function by assessing the critical inflammatory factors in chronic distress. Forty male mice were divided into four groups (n = 10/group). Distress and control normally received food and water, whereas IF and IF with distress groups were daily deprived of food and water for two hours. In the second week, the electrical foot shock was induced to distress and IF with distress groups. Finally, the cognitive functions of all mice were evaluated by Barnes maze, their blood samples were taken to determine the plasma level of CORT, IL-6 and TNF-α, and the removed brain and adrenal glands were weighed in the third week. A significant gain in plasma level of CORT, IL-6 and TNF-α with a considerable brain hypotrophy and adrenal hypertrophy was found in distress group, whereas IF caused a remarkable reduction of the plasma inflammatory factors, especially in IF with distress mice (P ≤ 0.05). In conclusion, IF could improve cognitive function and preserve the brain against distress by regulation of inflammatory response pathway.

PMID: 28970945 [PubMed]

Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile.

Fri, 10/06/2017 - 15:05
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Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile.

Carcinogenesis. 2017 Sep 01;38(9):938-943

Authors: Franceschi S, Spugnesi L, Aretini P, Lessi F, Scarpitta R, Galli A, Congregati C, Caligo MA, Mazzanti CM

Abstract
Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

PMID: 28911001 [PubMed - indexed for MEDLINE]

Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma.

Fri, 10/06/2017 - 15:05
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Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma.

Eur J Endocrinol. 2017 Oct;177(4):361-367

Authors: Reimondo G, Puglisi S, Zaggia B, Basile V, Saba L, Perotti P, De Francia S, Volante M, Zatelli MC, Cannavò S, Terzolo M

Abstract
OBJECTIVE: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane.
DESIGN AND METHODS: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test.
RESULTS: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016).
CONCLUSIONS: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

PMID: 28780517 [PubMed - indexed for MEDLINE]

ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells.

Fri, 10/06/2017 - 15:05
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ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells.

Cancer Sci. 2017 Oct;108(10):2011-2021

Authors: Migita T, Takayama KI, Urano T, Obinata D, Ikeda K, Soga T, Takahashi S, Inoue S

Abstract
Long-chain acyl-coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen-responsive gene involved in the generation of fatty acyl-CoA esters. ACSL3 is expressed in both androgen-sensitive and castration-resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen-dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo-keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen-inactivating enzyme UDP-glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3-overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone-sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3-overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e. promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).

PMID: 28771887 [PubMed - indexed for MEDLINE]

Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma.

Fri, 10/06/2017 - 15:05
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Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma.

J Surg Res. 2017 Jul;215:204-210

Authors: Parikh PP, Rubio GA, Farra JC, Lew JI

Abstract
BACKGROUND: Adrenal adenomas are benign tumors often discovered incidentally, and >70% are hormonally inactive. The remaining subset may produce excess aldosterone, cortisol, or catecholamine. Perioperative outcomes after adrenalectomy for such "hormonally active" tumors remain unclear. This study examines in-hospital outcomes after unilateral adrenalectomy for hormonally active tumors.
METHODS: A retrospective review was performed using the Nationwide Inpatient Sample (2006-2011) to identify patients undergoing unilateral adrenalectomy for hormonally active or inactive tumors. Malignant adrenal tumors were excluded. Demographics, comorbidities, and postoperative complications were evaluated by univariate analysis, using two-tailed Chi-square and t-tests and multivariate logistic regression.
RESULTS: Of 27,312 patients who underwent adrenalectomy, 78% (n = 21,279) had hormonally inactive and 22% (n = 6033) had hormonally active adrenal tumors. Among the latter, 65% (n = 4000) had primary hyperaldosteronism (Conn's syndrome), 33% (n = 1996) had hypercortisolism (Cushing's syndrome), and 1.4% (n = 85) had pheochromocytoma. Patients with pheochromocytoma had higher rate of comorbidities including congestive heart failure, chronic lung disease, and malignant hypertension compared with remaining hormonally active tumors (12% versus 4%, 18% versus 11%, 6% versus 2%; P < 0.01). For patients with pheochromocytoma versus other hormonally active tumors, mean length of stay was 5 versus 3 d and total in-hospital cost was $50,000 versus $41,000 (P < 0.01). On multivariate analysis, pheochromocytoma had an independently higher risk for intraoperative blood transfusion (4.2, 95% confidence interval [CI] 2.4-7.2), postoperative cardiac (7.6, 95% CI 2.8-20.2), and respiratory (1.9, 95% CI 1.0-3.3) complications.
CONCLUSIONS: Patients with pheochromocytoma have high rates of preoperative comorbidities, postoperative cardiopulmonary complications, and longer and more costly hospitalizations. Such high-risk patients should undergo appropriate preoperative medical optimization in preparation for adrenalectomy.

PMID: 28688648 [PubMed - indexed for MEDLINE]

Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma.

Fri, 10/06/2017 - 15:05
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Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma.

J Clin Endocrinol Metab. 2017 Sep 01;102(9):3278-3287

Authors: Kong G, Grozinsky-Glasberg S, Hofman MS, Callahan J, Meirovitz A, Maimon O, Pattison DA, Gross DJ, Hicks RJ

Abstract
Purpose: Treatment options for unresectable paraganglioma (PGL)/pheochromocytoma (PCC), especially with uncontrolled secondary hypertension (HTN), are limited. Preliminary studies with peptide receptor radionuclide therapy (PRRT) suggest efficacy, but data on HTN control and survival are lacking. We assessed PRRT outcomes in such patients from two referral centers.
Methods: Twenty consecutive patients (13 men; age range, 21 to 77 years) with high somatostatin receptor (SSTR) expression treated with 177Lu-DOTA-octreotate, nine with radiosensitizing chemotherapy, were retrospectively reviewed. Median cumulative activity was 22 GBq (median 4 cycles). Fourteen patients were treated for uncontrolled HTN and six for progressive or symptomatic metastatic disease or local recurrence.
Results: Three months after PRRT, 8 of 14 patients treated for HTN required reduced medication doses, 5 had no change in anti-HTN doses, and 1 was lost to follow-up. Eighty-six percent had serum chromogranin-A reduction. Of the entire cohort, 36% had disease regression (29% partial and 7% minor response) on computed tomography, with stable findings in 50%. Three other patients had bony disease evaluable only on SSTR imaging (2 partial response and 1 stable). Median progression-free survival was 39 months; median overall survival was not reached (5 deaths; median follow-up, 28 months). Four patients had grade 3 lymphopenia; 2 had grade 3 thrombocytopenia. Renal impairment in 2 patients was attributed to underlying disease processes.
Conclusions: PRRT achieves worthwhile clinical and biochemical responses with low toxicity and encouraging survival in PGL/PCC. Because PRRT has logistic and radiation-safety advantages compared to 131I-MIBG therapy, further prospective evaluation is warranted.

PMID: 28605448 [PubMed - indexed for MEDLINE]

SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations.

Fri, 10/06/2017 - 15:05
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SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations.

J Cancer Res Clin Oncol. 2017 Aug;143(8):1421-1435

Authors: Jochmanova I, Wolf KI, King KS, Nambuba J, Wesley R, Martucci V, Raygada M, Adams KT, Prodanov T, Fojo AT, Lazurova I, Pacak K

Abstract
PURPOSE: Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is available concerning PHEO/PGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course.
METHODS: Asymptomatic relatives (N = 611) of 103 index patients were tested for SDHB mutations. Mutation carriers (N = 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016.
RESULTS: Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years).
CONCLUSIONS: Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location.

PMID: 28374168 [PubMed - indexed for MEDLINE]

Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells.

Fri, 10/06/2017 - 15:05
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Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells.

Endocr J. 2017 Mar 31;64(3):315-324

Authors: Li B, Baba T, Miyabayashi K, Sato T, Shima Y, Ichinose T, Miura D, Ohkawa Y, Suyama M, Morohashi KI

Abstract
Ad4-binding protein/steroidogenic factor 1 (Ad4BP/SF-1), a member of the nuclear receptor superfamily, is expressed in steroidogenic cells and regulates all steroidogenic gene expression. We recently employed mRNA and chromatin immunoprecipitation sequence (ChIP-seq) to demonstrate that Ad4BP/SF-1 directly regulates the expression of nearly all glycolytic genes. The pentose phosphate pathway (PPP) contributes to the production of nicotinamide adenine dinucleotide phosphate (NADPH). Although the expression of PPP genes and intracellular NADPH were decreased by Ad4BP/SF-1 knockdown, these genes were not the direct targets of Ad4BP/SF-1. This study therefore investigates whether Ad4BP/SF-1 directly regulates genes implicated in NADPH production. Examination of previously published data sets of mRNA sequence (mRNA-seq) and ChIP-seq strongly suggested a possibility that other NADPH-producing genes, such as malic enzyme 1 (Me1) and methylenetetrahydrofolate dehydrogenase 2 (Mthfd2), are the direct targets of Ad4BP/SF-1. Reporter gene assays and determination of intracellular NADPH concentration supported the notion that Ad4BP/SF-1 regulates NADPH production by regulating these genes. NADPH is required for macromolecule synthesis of compounds such as steroids, and for detoxification of reactive oxygen species. When synthesizing steroid hormones, steroidogenic cells consume NADPH through enzymatic reactions mediated by steroidogenic P450s. NADPH is also consumed through elimination of reactive oxygen species produced as the byproducts of the P450 reactions. Overall, Ad4BP/SF-1 potentially maintains the intracellular NADPH level through cooperative regulation of genes involved in the biological processes for consumption and supply.

PMID: 28202838 [PubMed - indexed for MEDLINE]

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