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Old, New, and Emerging Immunohistochemical Markers in Pheochromocytoma and Paraganglioma.

Tue, 11/06/2018 - 21:05
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Old, New, and Emerging Immunohistochemical Markers in Pheochromocytoma and Paraganglioma.

Endocr Pathol. 2018 Jun;29(2):169-175

Authors: Cheung VKY, Gill AJ, Chou A

Abstract
The evolution of genetic research over the past two decades has greatly improved the understanding of pheochromocytomas and paragangliomas. It is now accepted that more than one third of pheochromocytoma and paragangliomas arise in the context of syndromic disease, usually hereditary. The genetic profile of these tumors also has important prognostic implications which may help guide treatment. Accompanying the changing molecular landscape is the development of new immunohistochemical markers. Initially used in assisting with diagnosis, immunohistochemical markers have now become an important adjunct to screening programs for inherited conditions and subsequently as prognostic markers. The accessibility and efficiency of immunohistochemistry bring pathologists to the forefront in triaging patients based on tumor genotype-phenotype. In this review, we provide an update on the role of immunohistochemistry in the diagnosis of pheochromocytomas and paragangliomas, as an adjunct to assessment for hereditary disease and finally as a potential tool to assist risk stratification.

PMID: 29779206 [PubMed - indexed for MEDLINE]

Immunohistochemical expression of glypican-3 in adrenocortical carcinoma: A potential cause of diagnostic pitfalls.

Tue, 11/06/2018 - 21:05
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Immunohistochemical expression of glypican-3 in adrenocortical carcinoma: A potential cause of diagnostic pitfalls.

Ann Diagn Pathol. 2018 08;35:92-93

Authors: Lionti S, Ieni A, Cannavò S, Barresi V

PMID: 29748062 [PubMed - indexed for MEDLINE]

Effectiveness and safety of anti-TNF therapy for inflammatory bowel disease in liver transplant recipients for primary sclerosing cholangitis: A nationwide case series.

Tue, 11/06/2018 - 21:05
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Effectiveness and safety of anti-TNF therapy for inflammatory bowel disease in liver transplant recipients for primary sclerosing cholangitis: A nationwide case series.

Dig Liver Dis. 2018 07;50(7):668-674

Authors: Altwegg R, Combes R, Laharie D, De Ledinghen V, Radenne S, Conti F, Chazouilleres O, Duvoux C, Dumortier J, Leroy V, Treton X, Durand F, Dharancy S, Nachury M, Goutorbe F, Lamblin G, Boivineau L, Peyrin-Biroulet L, Pageaux GP

Abstract
BACKGROUND: There is a lack of consensus regarding the treatment of inflammatory bowel disease (IBD) after liver transplantation (LT) forprimary sclerosing cholangitis (PSC).
AIM: To investigate the safety and effectiveness of anti-TNF therapy in patients with IBD after a LT for PSC.
METHODS: We reviewed the medical files of all of the IBD patients who underwent a LT for PSC and who were treated with anti-TNF therapy at 23 French liver transplantation centers between 1989 and 2012.
RESULTS: Eighteen patients (12 with ulcerative colitis and 6 who had Crohn's disease) were recruited at 9 LT centers. All of these patients received infliximab or adalimumab following their LT, and the median duration of their anti-TNF treatment was 10.4 months. The most frequent concomitant immunosuppressive treatment comprised a combination of tacrolimus and corticosteroids. Following anti-TNF therapy induction, a clinical response was seen in 16/18 patients (89%) and clinical remission in 10 (56%). At the end of the anti-TNF treatment or at the last follow-up examination (the median follow-up was 20.9 months), a clinical response was achieved in 12 patients (67%) and clinical remission in 7 (39%). A significant endoscopic improvement was observed in 9 out of 14 patients and a complete mucosal healing in 3 out of 14 patients (21%). Six patients experienced a severe infection. These were due to cholangitis, cytomegalovirus (CMV) infection, Clostridium difficile, cryptosporidiosis, or Enterococcus faecalis. Three patients developed colorectal cancer after LT, and two patients died during the follow-up period.
CONCLUSIONS: Anti-TNF therapy proved to be effective for treating IBD after LT for PSC. However, as 17% of the patients developed colorectal cancer during the follow-up, colonoscopic annual surveillance is recommended after LT, as specified in the current guidelines.

PMID: 29655972 [PubMed - indexed for MEDLINE]

Clock genes alterations and endocrine disorders.

Tue, 11/06/2018 - 21:05
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Clock genes alterations and endocrine disorders.

Eur J Clin Invest. 2018 Jun;48(6):e12927

Authors: Angelousi A, Kassi E, Nasiri-Ansari N, Weickert MO, Randeva H, Kaltsas G

Abstract
BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.
DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.
RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.
CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

PMID: 29577261 [PubMed - indexed for MEDLINE]

Immunohistochemical Biomarkers of Adrenal Cortical Neoplasms.

Tue, 11/06/2018 - 21:05
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Immunohistochemical Biomarkers of Adrenal Cortical Neoplasms.

Endocr Pathol. 2018 Jun;29(2):137-149

Authors: Mete O, Asa SL, Giordano TJ, Papotti M, Sasano H, Volante M

Abstract
Careful morphological evaluation forms the basis of the workup of an adrenal cortical neoplasm. However, the adoption of immunohistochemical biomarkers has added tremendous value to enhance diagnostic accuracy. The authors provide a brief review of immunohistochemical biomarkers that have been used in the confirmation of adrenal cortical origin and in the detection of the source of functional adrenal cortical proliferations, as well as diagnostic, predictive, and prognostic biomarkers of adrenal cortical carcinoma. In addition, a brief section on potential novel theranostic biomarkers in the prediction of treatment response to mitotane and other relevant chemotherapeutic agents is also provided. In the era of precision and personalized medical practice, adoption of combined morphology and immunohistochemistry provides a new approach to the diagnostic workup of adrenal cortical neoplasms, reflecting the evolution of clinical responsibility of pathologists.

PMID: 29542002 [PubMed - indexed for MEDLINE]

Genomic Landscape of Pheochromocytoma and Paraganglioma.

Tue, 11/06/2018 - 21:05
Related Articles

Genomic Landscape of Pheochromocytoma and Paraganglioma.

Trends Cancer. 2018 01;4(1):6-9

Authors: Jochmanova I, Pacak K

Abstract
Recent comprehensive molecular analysis allowed the identification of unique molecular signatures in pheochromocytomas (PHEOs) and paragangliomas (PGLs). Here we summarize the main pathway clusters activated by PHEO- and PGL-susceptibility genes: pseudohypoxic, kinase, and Wnt signaling. Molecular characterization and clustering of PHEOs and PGLs may help in the application of principles of personalized medicine and in decision making for targeted therapy of these tumors.

PMID: 29413423 [PubMed - indexed for MEDLINE]

Mutations of the Twik-Related Acid-Sensitive K+ Channel 2 Promoter in Human Primary Aldosteronism.

Tue, 11/06/2018 - 21:05
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Mutations of the Twik-Related Acid-Sensitive K+ Channel 2 Promoter in Human Primary Aldosteronism.

Endocrinology. 2018 03 01;159(3):1352-1359

Authors: Lenzini L, Prisco S, Gallina M, Kuppusamy M, Rossi GP

Abstract
Because blunted expression of the twik-related acid-sensitive K+ channel 2 (TASK-2) is a common feature of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA), we sequenced the promoter region of the TASK-2 gene (KCNK5) in APAs (n = 76), primary hypertensive patients (n = 98), and 20-year-old healthy volunteers (n = 71), searching for variants that could affect expression of this channel. We found TASK-2 promoter mutations in 25% of the APAs: C999T in 6.6%, G595A in 5.3%, G36A in 5.3%, and C562T, Gins468, G265C, C1247T, G1140T, and C1399T in 1.3% each. The C999T mutation was found in only one of the 98 primary hypertensive patients, but mutations were detected also in 12% of volunteers: 4 carried the C999T, 3 G1288C, 1 the G1140T mutation, and 1 the 468ins mutation. After a 16-year follow-up, none of these patients developed hypertension or PA. The effect of C999T mutation was investigated in H295R cells using reporter vectors with the mutated or the wild-type (WT) TASK-2 promoters. TASK-2 gene expression was decreased by 31% ± 18% (P = 0.01) in mutated compared with WT APA. Likewise, in transfected H295R cells, the C999T mutation decreased TASK-2 transcriptional activity by 35% (normalized luciferase signal fold change: 0.65 ± 0.25, P < 0.001). Thus, mutations in the promoter region of the TASK-2 gene can account for the low expression in ∼25% of APAs. As they did not result in hypertension or PA during long-term follow-up in healthy participants, these mutations do not seem to be a factor in causing PA by themselves.

PMID: 29293917 [PubMed - indexed for MEDLINE]

Effects of Perianal Involvement on Clinical Outcomes in Crohn's Disease over 10 Years.

Tue, 11/06/2018 - 21:05
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Effects of Perianal Involvement on Clinical Outcomes in Crohn's Disease over 10 Years.

Gut Liver. 2018 May 15;12(3):297-305

Authors: Yoon JY, Cheon JH, Park SJ, Kim TI, Kim WH

Abstract
Background/Aims: There was the assumption that Crohn's disease (CD) patients with perianal lesions might have different clinical courses compared to those without. However, quantifiable data comparing the long-term outcomes between the two groups are scarce.
Methods: We retrospectively reviewed 221 consecutive patients newly diagnosed with CD and registered at the IBD clinic of Severance Hospital, in Seoul, Korea, between January 1990 and October 2005. We compared patients with perianal CD (PCD) and non-perianal CD (NPCD) in terms of clinical outcomes over 10 years.
Results: PCD progressed more frequently from inflammatory to complicated behavior than NPCD. Moreover, corticosteroids were prescribed in 102 patients with PCD and only 57 with NPCD (82.9% vs 58.2%, p<0.001), immunosuppressants in 89 and 42 (72.4% vs 42.9%, p<0.001), and anti-tumor necrosis factor α (TNF-α) in 37 and 12 (30.1% vs 12.2%, p=0.002). Cumulative hospitalization rates were 82.1% in PCD and 72.4% in NPCD (p=0.086), and surgical intervention rates were 39.8% and 51.0%, respectively (p=0.097).
Conclusions: Patients with PCD were more likely than those with NPCD to be administered corticosteroids, immunosuppressants, and anti-TNF-α. However, there is no significant difference in the cumulative rates of surgical interventions or hospitalizations.

PMID: 29108399 [PubMed - indexed for MEDLINE]

Giant Bilateral Adrenal Myelolipoma.

Tue, 11/06/2018 - 21:05
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Giant Bilateral Adrenal Myelolipoma.

Balkan Med J. 2017 09 29;34(5):476-477

Authors: Gupta SS, Kupfer Y

PMID: 28990930 [PubMed - indexed for MEDLINE]

adrenal tumor; +33 new citations

Tue, 10/30/2018 - 21:36

33 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

adrenal tumor

These pubmed results were generated on 2018/10/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Treating canine Cushing's syndrome: Current options and future prospects.

Tue, 10/23/2018 - 18:42
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Treating canine Cushing's syndrome: Current options and future prospects.

Vet J. 2018 Nov;241:42-51

Authors: Sanders K, Kooistra HS, Galac S

Abstract
Naturally occurring hypercortisolism, also known as Cushing's syndrome, is a common endocrine disorder in dogs that can be caused by an adenocorticotrophic hormone (ACTH)-producing pituitary adenoma (pituitary-dependent hypercortisolism, PDH; 80-85% of cases), or by an adrenocortical tumor (ACT; 15-20% of cases). To determine the optimal treatment strategy, differentiating between these two main causes is essential. Good treatment options are surgical removal of the causal tumor, i.e. hypophysectomy for PDH and adrenalectomy for an ACT, or radiotherapy in cases with PDH. Because these options are not without risks, not widely available and not suitable for every patient, pharmacotherapy is often used. In cases with PDH, the steroidogenesis inhibitor trilostane is most often used. In cases with an ACT, either trilostane or the adrenocorticolytic drug mitotane can be used. Although mostly effective, both treatments have disadvantages. This review discusses the current treatment options for canine hypercortisolism, and considers their mechanism of action, efficacy, adverse effects, and effect on survival. In addition, developments in both adrenal-targeting and pituitary-targeting drugs that have the potential to become future treatment options are discussed, as a more selective and preferably also tumor-targeted approach could have many advantages for both PDH and ACTs.

PMID: 30340659 [PubMed - in process]

[Clinicopathological analysis of patients with papillary renal cell carcinoma].

Tue, 10/23/2018 - 18:42
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[Clinicopathological analysis of patients with papillary renal cell carcinoma].

Beijing Da Xue Xue Bao Yi Xue Ban. 2018 Oct 18;50(5):805-810

Authors: Ding ZS, Qiu M, Xu ZC, Xiao RT, Ge LY, Ma LL

Abstract
OBJECTIVE: To investigate the clinicopathological features,treatment and prognosis of patients with papillary renal cell carcinoma (PRCC) and PRCC-complicated with tumor thrombus.
METHODS: Single center retrospective analysis of 75 patients with PRCC treated from January 2012 to October 2017 was performed. There were 55 males and 20 females at an age range of 24-82 years. Sixteen PRCC patients were complicated with tumor thrombus. All the patients were with a surgery and had clear pathological diagnosis and detailed follow-up data. The clinicopathological features, prognosis and influencing factors of the patients with PRCC and PRCC complicated with tumor thrombus were analyzed and summarized.
RESULTS: The average age of the 75 patients was(56.05±11.59)years,the average body mass index (BMI) was (26±3) kg/m², and the average tumor maximum diameter was (5.17±3.85) cm. There were significant differences between tumor maximum diameter larger than 7 cm and less than 7 cm (69.6% vs. 94.4%, P<0.001), lymph node metastasis and no lymph node metastasis (<38% vs. 98%, P<0.001), adrenal metastasis and no adrenal metastasis (0% vs. 95.3%, P<0.001), pulmonary metastasis and no pulmonary metastasis (0% vs.90.7%, P<0.001), complicated with and without tumor thrombus (<66.4% vs. 93.5%, P<0.001) on the effect of 3-year survival rate of the PRCC patients. In this study, there were 16 patients with type 2 PRCC complicated with tumor thrombus. There were significant differences in concomitant symptoms (62.5% vs. 22.0%, P=0.005), maximum tumor diameter (68.8% vs.13.3%, P<0.001), adrenal metastasis (18.8% vs. 0.02%, P=0.029), pulmonary metastasis (18.8% vs. 0%, P=0.008), nuclear grade (P<0.001) and pathological type (100% vs. 44.1%, P<0.001) between the PRCC patients with and without tumor thrombus.
CONCLUSION: There were significant differences in tumor diameter,lymph node metastasis,adrenal metastasis, pulmonary metastasis,pathological type, nuclear grade and tumor thrombus in the effect of the 3-year survival rate of PRCC patients. PRCC patients with tumor thrombus were more commonly suffered from type 2 PRCC, for whom the tumor diameter was larger,the nuclear grade was higher,and the distance metastasis happened more easily.

PMID: 30337739 [PubMed - in process]

Association of Papillary Thyroid Carcinoma with Primary Aldosteronism.

Tue, 10/23/2018 - 18:42
Related Articles

Association of Papillary Thyroid Carcinoma with Primary Aldosteronism.

Intern Med. 2018 Oct 17;:

Authors: Nakamura S, Ishimori M, Yamakita N

Abstract
Objective The association of primary aldosteronism (PA) with thyroid disease has already been suggested. The aim of this study was to examine the presence of PA in patients with papillary thyroid carcinoma (PC) and to characterize such PC patients with PA Patients and Methods We examined the presence of PA in 81 consecutive patients with PC, whose random sitting blood pressure (BP) was ≥140/90 mmHg in the office (n= 68), who had an incidental adrenal tumor or adrenal enlargement (n=9), or who showed hypokalemia (n=4). Thirty-one of these 81 patients had been treated with anti-hypertensive drugs. The plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were first measured before operation in 16 patients and after operation in 65 patients. PA was diagnosed according to the guidelines of the Japan Endocrine Society. Results Forty patients with PC with a random PAC/PRA ratio of over 200 were subjected to a further study (12 of these patients had been treated with anti-hypertensive drugs). Ultimately, 15 patients with PC were diagnosed with PA. Adrenal venous sampling was done in 9 out of 15 patients with PC associated with PA. No patients were diagnosed as having unilateral lesions. Among the 15 patients, white -coat hypertension was observed in 5 patients, and normotension was observed in 1 patient. Conclusion These findings suggest that the prevalence of PA may be high among patients with PC. An active examination is needed to detect PA, as its signs and symptoms may be mild in patients with PC associated with hypertension.

PMID: 30333389 [PubMed - as supplied by publisher]

An Interesting Case of Hepatic Adrenocortical Carcinoma.

Tue, 10/23/2018 - 18:42
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An Interesting Case of Hepatic Adrenocortical Carcinoma.

Acta Med Indones. 2018 Jul;50(3):257-259

Authors: Permana H, Darmawan G, Ritonga E, Kusumawati M, Miftahurachman M, Soetedjo NN

Abstract
Adrenocortical carcinoma (ACC) is a rare solid tumor with an incidence of 0.5 to 2 cases per million per year. It affects women more commonly than men with a ratio of 1.5:1. Ectopic ACC are considered to be extremely rare with no exact incidence data yet. We report an interesting case of hepatic ACC in a young woman with clinical signs of virilization.A-21-year old Sundanese woman visited our endocrine clinic with progressive hirsutism over the face, body, and extremities starting 14 years previously. She had irregular, heavy periods when she was 7 years old. She also experienced pubertal development of her breasts. However, both menstrual cycle and breast development ceased when she was 8 years old. She noticed voice deepening and alopecia. Physical examination showed male-type alopecia and intense hirsutism. Tanner stage was 3 for breast tissue and 5 for pubic hair. There was no galactorrhea. Body mass index was 21.4 kg/m2. Hormonal evaluation revealed increased level of free testosterone (>1500 ng/dl; NV: 8.4-48.1 ng/dl), dehydroepiandrosterone sulfate (>1000 ug/ml; NV: 65.1-369 ug/ml), and estradiol (533.60 pg/ml; NV: 14-124 pg/ml), low level of LH (<0.07 mIU/ml; NV: 1.7-11 mIU/ml) and FSH (<0.30 mIU/ml; NV: 1.34-9.40 mIU/ml), slight increased in morning serum cortisol (26.61 ug/ml; NV: 4.3-22.4 ug/ml), normal serum thyroid stimulating hormone (3.2 mIU/l; NV: 0.34-4.25 mIU/l) and prolactin (14.70 ng/ml; NV: 3.30-15.80 ng/ml). Gynecological ultrasound and brain MRI examination showed no structural abnormality. Abdominal CT scan demonstrated contrast enhanced solid inhomogenous mass sized 11.6 x 14.2 x 15.6 cm in right liver lobe. Neither suprarenal mass nor paraaortic lymphadenopathy was seen in the abdominal CT scan. Chromosomal examination revealed normal female karyotype (46, XX). Further liver biopsy showed morphology and immunohistochemistry (positive for CD 56, HEP 1, and NSE) consistent with adrenocortical carcinoma. Surgical therapy with referral to other institution was offered to the patient as first line treatment. Meanwhile, the patient got spironolactone 100 mg OD.Virilizing tumors are rare and few of them are androgen-producing adrenal tumors. Ectopic adrenal tumors are even rarer. Ectopic adrenal tissue can be found close to the adrenal glands, or along the path of descent or in association with gonad. Moreover, they have ever been reported in nervous system, stomach, gall bladder, and liver. There have been several case reports of adrenal rest tumor of liver; however, our literature review found no report of ectopic ACC of liver. Cortical tissue, embrologically derived from mesoderm, seems to be the sole component of the tumor which can undergo malignant transformation or become hormonally functional. Functioning tumors are more frequent in women. Our case demonstrated virilization as chief complaint. The ectopically located functioning tumors display the same clinical picture as tumors located in adrenal gland, with Cushing's syndrome and virilization are the most frequent symptoms in order of frequency. The virilization, as shown in our case, is due to excessive androgen production of dehydroepiandrosterone sulfate and testosterone. The distinction of ACC from benign adrenocortical tumor is important. Since there is no previous report of hepatic ACC and surgery is the keystone of curative treatment modality for ACC at adrenal gland, we planned the patient for surgical resection. Adjuvant treatment with chemotherapy (mitotane and combination of cytotoxic drugs), irradiation might be considered in ACC treatment. To control androgen effects, spironolactone was administered in our patient. However, there was no significant improvement in symptoms.In conclusion, we present the first reported case of hepatic ACC. A thorough history, physical examination, and appropriate laboratory, imaging examination are critical in evaluating virilized female patients. Elevated serum concentration of  dehydroepiandrosterone sulfate and testosterone might direct clinician to functioning adrenal cortical tissue as etiology, with further investigation of exact tumor site.

PMID: 30333277 [PubMed - in process]

Withholding Perioperative Steroids in Patients Undergoing Transsphenoidal Resection for Pituitary Disease: Randomized Prospective Clinical Trial to Assess Safety.

Tue, 10/23/2018 - 18:42
Related Articles

Withholding Perioperative Steroids in Patients Undergoing Transsphenoidal Resection for Pituitary Disease: Randomized Prospective Clinical Trial to Assess Safety.

Neurosurgery. 2018 Oct 15;:

Authors: Sterl K, Thompson B, Goss CW, Dacey RG, Rich KM, Zipfel GJ, Chicoine MR, Kim AH, Silverstein JM

Abstract
BACKGROUND: Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution.
OBJECTIVE: To assess the safety of withholding glucocorticoids in patients undergoing TSS.
METHODS: Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected.
RESULTS: Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients.
CONCLUSION: Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.

PMID: 30325449 [PubMed - as supplied by publisher]

High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype.

Tue, 10/23/2018 - 18:42
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High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype.

Gene. 2018 Dec 30;679:219-231

Authors: Sucularli C, Thomas P, Kocak H, White JS, O'Connor BC, Keegan CE

Abstract
In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype. Loss of function of most shelterin proteins results in early embryonic lethality. Thus, study of the hypomorphic acd allele provides a unique opportunity to understand telomere dysfunction at an organismal level. The aim of this study was to identify transcriptome alterations in acd mutant and acd, p53 double mutant embryos to understand the p53-dependent and -independent factors that contribute to the mutant phenotypes in the context of the whole organism. Genes involved in developmental processes, cell cycle, metabolic pathways, tight junctions, axon guidance and signaling pathways were regulated by p53-driven mechanisms in acd mutant embryos, while genes functioning in immune response, and RNA processing were altered independently of p53 in acd, p53 double mutant embryos. To our best of knowledge, this is the first study revealing detailed transcriptomic alterations, reflecting novel p53-dependent and -independent pathways contributing to the acd phenotype. Our data confirm the importance of cell cycle and DNA repair pathways, and suggest novel links between telomere dysfunction and immune system regulation and the splicing machinery. Given the broad applicability of telomere maintenance in growth, development, and genome stability, our data will also provide a rich resource for others studying telomere maintenance and DNA damage responses in mammalian model systems.

PMID: 30189268 [PubMed - indexed for MEDLINE]

Perioperative management during laparoscopic resection of large pheochromocytomas: A single-institution retrospective study.

Tue, 10/23/2018 - 18:42
Related Articles

Perioperative management during laparoscopic resection of large pheochromocytomas: A single-institution retrospective study.

J Surg Oncol. 2018 Sep;118(4):709-715

Authors: Liu H, Li B, Yu X, Huang Y

Abstract
BACKGROUND AND OBJECTIVES: The safety of laparoscopic resection of very large pheochromocytomas is unclear, and preoperative preparation may benefit from refinement. This retrospective study was designed to determine the correlation between tumor size and perioperative characteristics by evaluating data from patients who underwent laparoscopic resection of pheochromocytomas.
METHODS: A total of 253 patients were grouped according to their tumor diameter: diameter ≥8 cm, Glarge (Glg ) (n = 30); diameter 6 to 8 cm, Gmedium (Gmd ) (n = 57); and diameter <6 cm, Gsmall (Gsm ) (n = 166). The perioperative data were compared among the three groups using the analysis of variance test, Wilcoxon's rank-sum test, and the chi-square test.
RESULTS: Patients in the Glg and Gmd groups had a higher preoperative phenoxybenzamine daily dose and 24-hour urine levels of noradrenaline and adrenaline than those in the Gsm group, as they needed longer vasopressor support. Transfusion of allogeneic blood products was found to be increased in patients of the Glg group compared with the other two groups and their intensive care unit stays were longer.
CONCLUSIONS: Compared with small-sized pheochromocytomas, laparoscopic resection of medium-sized pheochromocytomas requires vigilant monitoring and resolution of hemodynamic fluctuations. Patients with very large pheochromocytomas are at greater risk of intraoperative bleeding and may benefit from the ensured availability of blood products and intensive postoperative monitoring.

PMID: 30175399 [PubMed - indexed for MEDLINE]

Enzyme autoinduction by mitotane supported by population pharmacokinetic modelling in a large cohort of adrenocortical carcinoma patients.

Tue, 10/23/2018 - 18:42
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Enzyme autoinduction by mitotane supported by population pharmacokinetic modelling in a large cohort of adrenocortical carcinoma patients.

Eur J Endocrinol. 2018 10 16;179(5):287–297

Authors: Arshad U, Taubert M, Kurlbaum M, Frechen S, Herterich S, Megerle F, Hamacher S, Fassnacht M, Fuhr U, Kroiss M

Abstract
OBJECTIVE: Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1- 6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life, and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring.
METHODS: Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from therapeutic drug monitoring (TDM) of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules.
RESULTS: A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. Body mass index was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity.
CONCLUSION: The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

PMID: 30087117 [PubMed - indexed for MEDLINE]

Electrically conductive MEH-PPV:PCL electrospun nanofibres for electrical stimulation of rat PC12 pheochromocytoma cells.

Tue, 10/23/2018 - 18:42
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Electrically conductive MEH-PPV:PCL electrospun nanofibres for electrical stimulation of rat PC12 pheochromocytoma cells.

Biomater Sci. 2018 Aug 21;6(9):2342-2359

Authors: Borah R, Ingavle GC, Sandeman SR, Kumar A, Mikhalovsky S

Abstract
The purpose of this study was to prepare an electrically conducting poly[2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) based nanofibrous scaffold and to investigate the synergetic effect of nanofibre structure and electrical stimulation on neuronal growth for possible use in nerve repair. Nanofibres were produced by electrospinning of blended MEH-PPV with polycaprolactone (PCL) at a ratio of 20 : 80, 40 : 60, 50 : 50 and 60 : 40 (v/v). A better electrical conductivity was achieved by using core-sheath structured nanofibres of PCL (core) and MEH-PPV (sheath) produced using the coaxial electrospinning technique. The highest electrical conductivity was observed in the core-sheath nanofibres, while it increased with increasing concentration of MEH-PPV for the blended electrospun nanofibres. The biocompatibility of the electrospun nanofibres was confirmed by MTS and live-dead staining assays using 3T3 fibroblasts and a neuronal rat pheochromocytoma (PC12) cell line. Beta (III) tubulin immunochemistry showed that PC12 cells differentiated into sympathetic neurons on these porous and stiffer electrospun nanofibres coated with collagen I. Improved cell morphology and attachment on the collagen I coated electrospun meshes has been confirmed by SEM analysis. Significant enhancement in neurite formation and neurite outgrowth of PC12 cells on the conductive scaffolds under electrical potential of 500 mV cm-1 for 2 h day-1 suggests the potential use of these scaffolds for nerve repair.

PMID: 30019048 [PubMed - indexed for MEDLINE]

Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units.

Tue, 10/23/2018 - 18:42
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Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units.

Horm Res Paediatr. 2018;89(4):255-264

Authors: Zalas D, Reinehr T, Niedziela M, Borzikowsky C, Flader M, Simic-Schleicher G, Akkurt HI, Heger S, Hornig N, Holterhus PM, Kulle AE

Abstract
BACKGROUND/AIMS: The high complexity of pediatric reference ranges across age, sex, and units impairs clinical application and comparability of steroid hormone data, e.g., in congenital adrenal hyperplasia (CAH). We developed a multiples-of-median (MoM) normalization tool to overcome this major drawback in pediatric endocrinology.
METHODS: Liquid chromatography tandem mass spectrometry data comprising 10 steroid hormones representing 905 controls (555 males, 350 females, 0 to > 16 years) from 2 previous datasets were MoM transformed across age and sex. Twenty-three genetically proven CAH patients were included (21-hydroxylase deficiency [21OHD], n = 19; 11β-hydroxylase deficiency [11OHD], n = 4). MoM cutoffs for single steroids predicting 21OHD and 11OHD were computed and validated through new, independent patients (21OHD, n = 8; adrenal cortical carcinoma, n = 6; obesity, n = 40).
RESULTS: 21OHD and 11OHD patients showed disease-typical, easily recognizable MoM patterns independent of age, sex, and concentration units. Two single-steroid cutoffs indicated 21OHD: 3.87 MoM for 17-hydroxyprogesterone (100% sensitivity and 98.83% specificity) and 12.28 MoM for 21-deoxycortisol (94.74% sensitivity and 100% specificity). A cutoff of 13.18 MoM for 11-deoxycortisol indicated 11OHD (100% sensitivity and 100% specificity).
CONCLUSIONS: Age- and sex-independent MoMs are straightforward for a clinically relevant display of multi-steroid patterns. In addition, defined single-steroid MoMs can serve alone as predictors of 21OHD and 11OHD. Finally, MoM transformation offers substantial enhancement of routine and scientific steroid hormone data exchange due to improved comparability.

PMID: 29694956 [PubMed - indexed for MEDLINE]

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