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Dendrimers, Carotenoids, and Monoclonal Antibodies.

Fri, 10/13/2017 - 18:03
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Dendrimers, Carotenoids, and Monoclonal Antibodies.

Monoclon Antib Immunodiagn Immunother. 2017 Oct 10;:

Authors: Bashmakov YK, Petyaev IM

Abstract
Dendrimers are unimolecular architectural nano- or microparticle entities that can accommodate various nutraceuticals and pharmaceuticals between their branches (dendrons) and provide targeted delivery of biomimetics into different tissues upon addition of functionalized groups to the dendrimer's surface. Covalent binding, hydrogen bonds, and electrostatic interactions between dendrimer-composing molecules are known to form and stabilize dendrimer structure. Carotenoids have recently been shown to form dendrimer-like structures and promote targeted delivery of "cargo" molecules into organs characterized by high-carotenoid uptake (adrenal glands, prostate, liver, and brain). The use of carotenoid dendrimers, in particular lycosome particles loaded with various xenobiotics (resveratrol, cocoa flavanols, and HMG-CoA reductase inhibitors), reportedly has a beneficial effect in diabetic foot syndrome, prehypertension, and cardiovascular disease. New applications for carotenoid dendrimers may arise from the use of complexes formed by carotenoid dendrimers and monoclonal antibodies (mAbs). The internalization of carotenoid dendrimer-mAb complexes through receptor-mediated mechanisms may prevent interactions of dendrimer-incorporated xenobiotics with membrane-associated P-glycoprotein, a major factor of drug resistance in tumor cells. The incorporation of mAb fragments with higher binding capacity to the membrane receptors and higher affinity to the target molecule may further increase the bioavailability of "cargo" molecules transported by the carotenoid dendrimer-mAb complexes and open new doors in nanodelivery technologies.

PMID: 28994638 [PubMed - as supplied by publisher]

Phrenicoabdominal venotomy for tumor thrombectomy in dogs with adrenal neoplasia and suspected vena caval invasion.

Fri, 10/13/2017 - 18:03
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Phrenicoabdominal venotomy for tumor thrombectomy in dogs with adrenal neoplasia and suspected vena caval invasion.

Vet Surg. 2017 Oct 09;:

Authors: Mayhew PD, Culp WTN, Balsa IM, Zwingenberger AL

Abstract
OBJECTIVE: To describe a technique for tumor thrombectomy by phrenicoabdominal venotomy in dogs with adrenal neoplasia and suspected caval invasion and to report complications and outcomes associated with the procedure.
STUDY DESIGN: Retrospective case series.
ANIMALS: Eight client-owned dogs with invasive adrenal tumors.
METHODS: Medical records of dogs diagnosed with adrenal tumors with extension of thrombus into the phrenicoabdominal vein (PAV) and vena cava were reviewed. Cases where phrenicoabdominal venotomy without cavotomy for thrombus resection was performed were included. Data collected from the medical records included signalment, clinical signs, physical examination findings, diagnostic imaging results, preoperative laboratory testing, surgical technique, surgical and postoperative complications and outcome.
RESULTS: Phrenicoabdominal venotomy was successful in removal of vena caval thrombosis in 7 of 8 dogs. In one case, an attempt was made to remove a large vena caval thrombus through a distended PAV resulting in fragmentation of the thrombus and the need to extend the incision into the vena cava. In all dogs, complete removal of tumor thrombus was achieved. Two dogs died in the perioperative period, one from cardiopulmonary arrest and a second from bronchopneumonia and pancreatitis. The remaining 6 dogs were discharged from the hospital.
CONCLUSION: Thrombectomy through a phrenicoabdominal venotomy may obviate the need for a cavotomy in a subset of dogs with invasive adrenal neoplasia.

PMID: 28990687 [PubMed - as supplied by publisher]

Diagnosis of Adrenocortical Tumors by Reticulin Algorithm.

Fri, 10/13/2017 - 18:03
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Diagnosis of Adrenocortical Tumors by Reticulin Algorithm.

Indian J Endocrinol Metab. 2017 Sep-Oct;21(5):734-737

Authors: Fonseca D, Murthy SS, Tagore KR, Rao BV, Thamminedi SR, Raju KVVN, Sharma R, Challa S

Abstract
AIMS: To apply reticulin algorithm (RA) to the diagnosis of adrenocortical tumors on adrenalectomy specimens and compare its efficacy to the modified Weiss criteria or Lin-Weiss-Bisceglia (LWB) criteria for oncocytic variant.
MATERIALS AND METHODS: Adrenocortical tumors (ACTs) diagnosed on resected specimens including the variants during January 2010-June 2016 were retrieved from the pathology records. The demographic and clinical data were obtained from medical records. The functional status of the tumor was noted based on clinical and biochemical evaluation. The location, size, and gross appearance of the tumor were noted. The corresponding hematoxylin and eosin-stained slides were independently assessed by two pathologists applying modified Weiss criteria and LWB criteria for the oncocytic variant as applicable. Reticulin stain was performed on representative sections in all cases. All the tumors were classified according to RA, and the diagnoses made by each system were correlated.
RESULTS: There were 15 ACTs in the study period. There were two adenomas including one oncocytoma which showed Weiss score (WS) of 2 and intact reticulin framework. There were 13 adrenal cortical carcinomas including two oncocytic variants with WS ranging from 4 to 7. There was disruption of reticulin and thick, irregular reticulin fibers in all tumors, irrespective of the histology. It correlated with modified Weiss and LWB criteria.
CONCLUSIONS: The RA was simple, easy to apply, and correlated well with modified Weiss criteria in the diagnosis of ACTs including the oncocytic variant.

PMID: 28989884 [PubMed]

Diagnosis of pediatric neuroblastoma by urine cytology: A case report.

Fri, 10/13/2017 - 18:03
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Diagnosis of pediatric neuroblastoma by urine cytology: A case report.

Diagn Cytopathol. 2017 Oct 06;:

Authors: Nishikawa S, Noguchi H, Tokumitsu T, Ohno A, Moriguchi-Goto S, Maekawa K, Asada Y, Moritake H, Kinoshita M, Yamada A, Takamura K, Sato Y

Abstract
Neuroblastomas are embryonal tumors arising from the neuronal crest cells of the synaptic nervous system. Findings from aspiration cytology have been reported, but there have been no reports of urine cytology findings. Here, we report a case of pediatric neuroblastoma characterized by urine cytology. A 2-year-old boy presented with abdominal pain, nausea, and loss of appetite. Computed tomography revealed a large tumor in the left suprarenal region with massive infiltration into the kidney. Urinary cytology showed highly cellular clusters composed of small, round, atypical cells with little cytoplasm and high nuclear/cytoplasmic ratio; nuclear molding was also noted in some places. Immunocytochemical staining was positive for synaptophysin and chromogranin A, and neuroblastoma was suggested by urine cytology. A biopsy of the left adrenal tumor later confirmed a diagnosis of poorly differentiated neuroblastoma. Urine cytology may be useful for rapid diagnosis and management of similar cases.

PMID: 28984419 [PubMed - as supplied by publisher]

MANAGEMENT OF ENDOCRINE DISEASE: Flushing: current concepts.

Fri, 10/13/2017 - 18:03
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MANAGEMENT OF ENDOCRINE DISEASE: Flushing: current concepts.

Eur J Endocrinol. 2017 Nov;177(5):R219-R229

Authors: Huguet I, Grossman A

Abstract
OBJECTIVE: Flushing can be defined as a sensation of warmth accompanied by erythema that most commonly is seen on the face and which occurs in episodic attacks. Such a problem can be clinically problematic, since many conditions and drugs can be related to flushing, and while often there appears to be no underlying organic disease, it is important to exclude disorders since they may be life-threatening conditions.
DESIGN AND METHODS: We performed a search in MEDLINE using the terms 'flushing' in combination with 'carcinoid syndrome', 'pheochromocytoma', 'mastocytosis', 'menopausal hot flush' and 'treatment'. European and American guidelines relating to neuroendocrine tumours, mastocytosis and menopause were reviewed.
RESULTS: In this review, we discuss the main causes of flushing and propose an algorithm based on pathogenesis, which can be used to guide the clinical evaluation process. We also review recent significant developments in the assessment and treatment of the carcinoid syndrome and menopausal hot flushes, which should guide the clinical practice regarding this common but sometimes confusing condition.
CONCLUSIONS: When evaluating flushing, a precise systematic approach is needed to exclude potentially serious underlying causes, although despite this, the cause of the disorder is not always found. If symptoms are not progressive, the patient should be advised about its apparently benign nature in order to avoid unnecessary studies or initiating treatments of minimal benefit.

PMID: 28982960 [PubMed - indexed for MEDLINE]

Robotic Radical Left Nephrectomy With Inferior Vena Cava Level III Thrombectomy.

Fri, 10/13/2017 - 18:03
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Robotic Radical Left Nephrectomy With Inferior Vena Cava Level III Thrombectomy.

Urology. 2017 Sep;107:269

Authors: Nelson RJ, Maurice MJ, Kaouk JH

Abstract
INTRODUCTION AND OBJECTIVE: We present our robotic approach and technique to manage a large left renal tumor with inferior vena cava (IVC) Level III thrombus. The superior mesenteric artery crossing the left renal vein requires robotic docking from the left, for dissection of the left kidney followed by repositioning and re-docking the robot from the right side for dissection of the right renal vein, distal and proximal IVC, and the remaining left renal vein insertion into the IVC.
METHODS: We present a 53-year-old man with a 10.9-cm left renal mass with IVC level III tumor thrombus. A robotic left radical nephrectomy with lymph node dissection was completed using 4 ports in a midline configuration. The dissection of the left renal vein was taken medially until the superior mesenteric artery. The patient was then repositioned in the right side flank position and the robot was re-docked using the previously placed midline ports. The right renal vein, distal and proximal IVC were then controlled using modified Rummel tourniquets.
RESULTS: Operative time was 530 minutes which included patient positioning, robot re-docking. The patient did not require a blood transfusion. Hospital stay was 4 days. Final pathology showed pT3bNoM1 renal cell carcinoma, clear cell type grade 4 with necrosis, and focal rhabdoid features measuring 11 cm. The tumor invaded the renal sinus and the renal vein and was metastatic to the ipsilateral adrenal gland. Margins were negative.
CONCLUSION: Herein we present a successful outcome of a left-sided robotic radical nephrectomy with IVC level III tumor thrombectomy.

PMID: 28982623 [PubMed - in process]

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]

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