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Immune Thrombocytopenia in a Child with Neuroblastoma.

Fri, 10/27/2017 - 23:11
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Immune Thrombocytopenia in a Child with Neuroblastoma.

Case Rep Pediatr. 2017;2017:1329489

Authors: Ikizoglu HT, Ayan I, Tokat F, Tecimer T, Topuzlu Tekant G

Abstract
Thrombocytopenia is a frequent finding in patients with solid tumors. It is usually caused by bone marrow infiltration or by myelosuppression due to anticancer therapy; however immune thrombocytopenia (ITP) associated with solid tumors is rare. Neuroblastoma is the most common extracranial solid tumor in children. Here we report the case of a two-year-nine-month-old patient with adrenal neuroblastoma who presented with ITP. Paraneoplastic ITP was considered in the differential diagnosis. Bone marrow infiltration and other causes of thrombocytopenia were excluded and the patient was treated with intravenous immunoglobulin and tumor resection. Platelet count increased rapidly after surgery and complete remission of ITP was achieved.

PMID: 29062578 [PubMed]

WNT signaling, the development of the sympathoadrenal-paraganglionic system and neuroblastoma.

Fri, 10/27/2017 - 23:11
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WNT signaling, the development of the sympathoadrenal-paraganglionic system and neuroblastoma.

Cell Mol Life Sci. 2017 Oct 22;:

Authors: Becker J, Wilting J

Abstract
Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11% of cancer deaths. It originates from highly migratory progenitor cells that leave the dorsal neural tube and contribute neurons and glial cells to sympathetic ganglia, and chromaffin and supportive cells to the adrenal medulla and paraganglia. Clinically, histologically and molecularly, NBs present as extremely heterogeneous, ranging from very good to very poor prognosis. The etiology of NB still remains unclear and needs to be elucidated, however, aberrant auto- and paracrine embryonic cell communications seem to be likely candidates to initiate or facilitate the emergence, progression and regression of NB. The wingless-type MMTV integration site (WNT) family of proteins represents an evolutionary highly conserved signaling system that orchestrates embryogenesis. At least 19 ligands in the human, numerous receptors and co-receptors are known, which control not only proliferation, but also cell polarity, migration and differentiation. Here we seek to interconnect aspects of WNT signaling with sympathoadrenal and paraganglionic development to define new WNT signaling cues in the etiology and progression of NB.

PMID: 29058015 [PubMed - as supplied by publisher]

Development and validation of a liquid chromatography tandem mass spectrometry method for the measurement of urinary catecholamines in diagnosis of pheochromocytoma.

Fri, 10/27/2017 - 23:11
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Development and validation of a liquid chromatography tandem mass spectrometry method for the measurement of urinary catecholamines in diagnosis of pheochromocytoma.

Biomed Chromatogr. 2017 Nov;31(11):

Authors: Shen Y, Cheng L, Guan Q, Li H, Lu J, Wang X

Abstract
The measurement of catecholamines in human body fluids is requested frequently for the differential diagnosis and monitoring of pheochromocytoma. The methods in most clinical laboratories focus on high-performance liquid chromatography coupled with electrochemical detection, which suffers from high background noise, low sensitivity, and poor separation. We reported and developed a robust high-throughput liquid chromatography tandem mass spectrometry method in routine clinical laboratories for the measurement of urinary catecholamines for diagnosis of pheochromocytoma. The method was validated for consistent linearity, good recovery (88-112%), excellent stability and low carryover. Intra- and inter-assay precision values for catecholamines were all below 3.35 and 4.83% respectively. Dilution linearity was investigated with satisfactory linearly dependent coefficients (r > 0.9988). The reference intervals were obtained from 310 results derived from patients in which the diagnosis of pheochromocytoma was excluded. This method was successfully used in our laboratory. The clinical characteristics of patients have been explored with satisfactory sensitivity and specificity. Therefore, we have developed a reliable assay for the liquid chromatography tandem mass spectrometry measurement of catecholamines in a routine clinical laboratory. The assay requires a small volume of urine, and all analytes are measured simultaneously. The assay is rapid and reliable to be executed, offering the potential for routine clinical laboratories.

PMID: 28481409 [PubMed - indexed for MEDLINE]

The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line.

Fri, 10/27/2017 - 23:11
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The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line.

Anticancer Drugs. 2017 Jul;28(6):634-644

Authors: Borges KS, Andrade AF, Silveira VS, Marco Antonio DS, Vasconcelos EJR, Antonini SRR, Tone LG, Scrideli CA

Abstract
Adrenocortical tumor (ACT) is a malignancy with a low incidence rate and the current therapy for advanced disease has a limited impact on overall patient survival. A previous study from our group suggested that elevated expression of aurora-A and aurora-B is associated with poor outcome in childhood ACT. Similar results were also reported for adult ACTs. The present in-vitro study shows that AMG 900 inhibits aurora kinases in adrenocortical carcinoma cells. AMG 900 inhibited cell proliferation in NCI-H295 cells as well as in the ACT primary cultures and caused apoptosis in the cell line NCI-H295. Furthermore, it potentialized the mitotane, doxorubicin, and etoposide effects on apoptosis induction and acted synergistically with mitotane and doxorubicin in the inhibition of proliferation. In addition, we found that AMG 900 activated Notch signaling and rendered the cells sensitive to the combination of AMG 900 and Notch signaling inhibition. Altogether, these data show that aurora kinases inhibition using AMG 900 may be an adjuvant therapy to treat patients with invasive or recurrent adrenocortical carcinomas.

PMID: 28410270 [PubMed - indexed for MEDLINE]

Failure of MIBG scan to detect metastases in SDHB-mutated pediatric metastatic pheochromocytoma.

Fri, 10/27/2017 - 23:11
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Failure of MIBG scan to detect metastases in SDHB-mutated pediatric metastatic pheochromocytoma.

Pediatr Blood Cancer. 2017 Nov;64(11):

Authors: Sait S, Pandit-Taskar N, Modak S

Abstract
(123) I-meta-iodo benzyl guanidine (MIBG) scans are considered the gold standard imaging in neuroblastoma; however, flouro deoxy glucose positron emission tomography (FDG-PET) scans have increased sensitivity in adults with pheochromocytoma/paraganglioma. We describe a pediatric patient initially considered to have localized neuroblastoma based on anatomical imaging and (123) I-MIBG scan, but subsequent investigations revealed germline succinate dehydrogenase complex iron sulfur subunit B (SDHB) mutation-associated pheochromocytoma with multiple FDG-avid skeletal metastases. We then compared (123) I-MIBG and FDG-PET scans in children with metastatic pheochromocytoma/paraganglioma. FDG-PET was superior to (123) I-MIBG scan for the detection of skeletal metastases (median number of skeletal lesions detected 10 [range 1-30] vs. 2 [range 1-26], respectively; P = 0.005 by t-test). FDG-PET should be considered the functional scan of choice in children with pheochromocytoma/paraganglioma.

PMID: 28409892 [PubMed - indexed for MEDLINE]

Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis.

Fri, 10/27/2017 - 23:11
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Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis.

BMC Gastroenterol. 2017 Apr 14;17(1):52

Authors: Wheat CL, Ko CW, Clark-Snustad K, Grembowski D, Thornton TA, Devine B

Abstract
BACKGROUND: The magnitude of risk of serious infections due to available medical therapies of inflammatory bowel disease (IBD) remains controversial. We conducted a systematic review and network meta-analysis of the existing IBD literature to estimate the risk of serious infection in adult IBD patients associated with available medical therapies.
METHODS: Studies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Randomized controlled trials comparing IBD medical therapies with no restrictions on language, country of origin, or publication date were included. A network meta-analysis was used to pool direct between treatment comparisons with indirect trial evidence while preserving randomization.
RESULTS: Thirty-nine articles fulfilled the inclusion criteria; one study was excluded from the analysis due to disconnectedness. We found no evidence of increased odds of serious infection in comparisons of the different treatment strategies against each other, including combination therapy with a biologic and immunomodulator compared to biologic monotherapy. Similar results were seen in the comparisons between the newer biologics (e.g. vedolizumab) and the anti-tumor necrosis factor agents.
CONCLUSIONS: No treatment strategy was found to confer a higher risk of serious infection than another, although wide confidence intervals indicate that a clinically significant difference cannot be excluded. These findings provide a better understanding of the risk of serious infection from IBD pharmacotherapy in the adult population.
PROSPERO REGISTRATION: The protocol for this systematic review was registered on PROSPERO ( CRD42014013497 ).

PMID: 28407755 [PubMed - indexed for MEDLINE]

Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas.

Fri, 10/27/2017 - 23:11
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Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas.

Horm Cancer. 2017 Apr;8(2):108-118

Authors: Asai S, Katabami T, Tsuiki M, Tanaka Y, Naruse M

Abstract
Evidence has not been established to support that combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) improves survival in patients with malignant pheochromocytoma and paraganglioma (M-PPGL). To investigate the efficacy of CVD for this disease, we retrospectively analyzed data of 23 patients with metastatic and unresectable M-PPGL (mean age, 41.7 ± 15.4 years) who received at least 2 cycles of this regimen. The follow-up period after initiation of CVD ranged from 0.3 to 13.7 years, with a median of 3.3 years. CVD therapy achieved a complete tumor response (CR) in 1 patient (4%), a partial response (PR) in 5 (22%), stable disease (SD) in 5 (22%), and progressive disease (PD) in 13 (52%), respectively. All of the responders (CR and PR) but 6% of the non-responders (SD and PD) showed substantial biochemical improvement. The progression-free survival period in the responders was significantly longer than in the non-responders (p < 0.01). Although the overall survival and survival after the diagnosis of M-PPGL were longer in the responders than the non-responders, the difference was not statistically significant (p = 0.08). The progression-free and overall survival period were significantly longer in the non-progression group (CR, PR, and SD) than in the progression group (PD) (1.7 ± 3.3 vs. 0.3 ± 0.3 years, p < 0.01, and 4.6 ± 3.6 vs. 2.0 ± 3.7 years, p = 0.01, respectively). It is therefore suggested that CVD chemotherapy could be useful in controlling tumor progression and improving survival in patients with metastatic and progressive M-PPGL.

PMID: 28108930 [PubMed - indexed for MEDLINE]

Regulation of hypothalamic-pituitary-adrenal axis activity and immunologic function contributed to the anti-inflammatory effect of acupuncture in the OVA-induced murine asthma model.

Fri, 10/27/2017 - 23:11
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Regulation of hypothalamic-pituitary-adrenal axis activity and immunologic function contributed to the anti-inflammatory effect of acupuncture in the OVA-induced murine asthma model.

Neurosci Lett. 2017 Jan 01;636:177-183

Authors: Wei Y, Dong M, Zhong L, Liu J, Luo Q, Lv Y, Mo S, Sun J, Liu F, Xu F, Yan C, Dong J

Abstract
Asthma is a complex inflammatory disease of the airways and acupuncture is one of the effective therapies widely used to treat asthma in China. The aim of the study was to evaluate the regulatory role of acupuncture in airway inflammation and the hypothalamic-pituitary-adrenal (HPA) axis activity in OVA-induced murine asthma model. Our results demonstrated that acupuncture was effective in suppression of AHR, inhibition of total leukocyte, neutrophil, lymphocyte and eosinophil counts in BALF, attenuation of airway inflammation and TNF-α, IL-1β, IL-5 and eotaxin secretion. Furthermore, the HPA axis activity was also regulated by acupuncture, which included promotion of adrenocorticotropic hormone and cortisol secretion in the plasma. Our findings revealed that acupuncture could attenuate airway inflammation and regulate HPA axis and immunologic function in the OVA-induced murine asthma model, which may provide support to better understand the contribution of acupuncture to the regulation of airway inflammation and HPA axis activity in asthma.

PMID: 27816549 [PubMed - indexed for MEDLINE]

Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells.

Fri, 10/27/2017 - 23:11
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Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells.

Horm Cancer. 2016 Dec;7(5-6):345-355

Authors: Kroiss M, Sbiera S, Kendl S, Kurlbaum M, Fassnacht M

Abstract
Mitotane is the only drug approved for treatment of the orphan disease adrenocortical carcinoma (ACC) and was recently shown to be the first clinically used drug acting through endoplasmic reticulum (ER)-stress induced by toxic lipids. Since mitotane has limited clinical activity as monotherapy, we here study the potential of activating ER-stress through alternative pathways. The single reliable NCI-H295 cell culture model for ACC was used to study the impact MG132, bortezomib (BTZ) and carfilzomib (CFZ) on mRNA and protein expression of ER-stress markers, cell viability and steroid hormone secretion. We found all proteasome inhibitors alone to trigger expression of mRNA (spliced X-box protein 1, XBP1) and protein markers indicative of the inositol-requiring enzyme 1 (IRE1) dependent pathway of ER-stress but not phosphorylation of eukaryotic initiation factor 2α (eIF2α), a marker of the PRKR-like endoplasmic reticulum kinase (PERK)-dependent pathway. Whereas mitotane alone activated both pathways, combination of BTZ and CFZ with low-dose mitotane blocked mitotane-induced eIF2α phosphorylation but increased XBP1-mRNA splicing indicating that proteasome inhibitors can commit signalling towards a single ER-stress pathway in ACC cells. By applying the median effect model of drug combinations using cell viability as a read out, we determined significant drug synergism between mitotane and both BTZ and CFZ. In conclusion, combination of mitotane with activators of ER-stress through the unfolded protein response is synergistic in an ACC cell culture model. Since proteasome inhibitors are readily available clinically, they are attractive candidates to study for ACC treatment in clinical trials in combination with mitotane.

PMID: 27631436 [PubMed - indexed for MEDLINE]

Synchronous vs. Metachronous Metastases in Adrenocortical Carcinoma: an Analysis of the Dutch Adrenal Network.

Fri, 10/27/2017 - 23:11
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Synchronous vs. Metachronous Metastases in Adrenocortical Carcinoma: an Analysis of the Dutch Adrenal Network.

Horm Cancer. 2016 Dec;7(5-6):336-344

Authors: Ettaieb MH, Duker JC, Feelders RA, Corssmit EP, Menke-van der Houven van Oordt CW, Timmers HJ, Kerstens MN, Wilmink JW, Zelissen PM, Havekes B, Haak HR

Abstract
Adrenal Cortical Carcinoma (ACC) is a rare malignancy with an incidence of 1.0 per million per year in the Netherlands. Median survival varies according to the European Network for the Study of Adrenal Tumours (ENS@T) tumour stage. It is unknown whether time until development of metastases is of influence on prognosis. To asses this, data were retrospectively obtained from centres of the Dutch Adrenal Network. Patients who presented with ACC between January 1, 2004 and October 31, 2013 were included. Date of detection of metastases, number of metastases and affected organs were registered. One hundred sixty patients were included in the analysis. Synchronous metastases were defined as diagnosis of metastasis ≤6 months after the initial diagnosis of ACC. Overall survival rate was calculated from the date of diagnosis of metastasis until death from any cause. At first presentation, 50 patients (31 %) had ACC with metastases (ENS@T stage IV). Another 67 (42 %) developed metastases during follow-up. Amongst the 117 patients with metastases, 84 (72 %) patients had synchronous metastases and 33 (28 %) developed metachronous metastases. Diagnosis of synchronous metastases (p = 0.046), more than one affected organ (p < 0.001) and four or more metastases (p < 0.001) were found to be associated with reduced overall survival. Limitations included retrospective design and limited details regarding pathological data. We conclude that synchronous metastases of ACC are associated with a poorer prognosis compared to metachronous metastases of ACC. The clinical characteristics associated with prognosis in this study support the view to refine the prognostic classification for patients with stage IV ACC.

PMID: 27422613 [PubMed - indexed for MEDLINE]

Different Types of Urinary Steroid Profiling Obtained by High-Performance Liquid Chromatography and Gas Chromatography-Mass Spectrometry in Patients with Adrenocortical Carcinoma.

Fri, 10/27/2017 - 23:11
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Different Types of Urinary Steroid Profiling Obtained by High-Performance Liquid Chromatography and Gas Chromatography-Mass Spectrometry in Patients with Adrenocortical Carcinoma.

Horm Cancer. 2016 Dec;7(5-6):327-335

Authors: Velikanova LI, Shafigullina ZR, Lisitsin AA, Vorokhobina NV, Grigoryan K, Kukhianidze EA, Strelnikova EG, Krivokhizhina NS, Krasnov LM, Fedorov EA, Sablin IV, Moskvin AL, Bessonova EA

Abstract
Urinary steroid profiling (USP) was studied using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) methods in 108 patients with adrenocortical adenoma (ACA) and in 31 patients with adrenocortical carcinoma (ACC). Thirteen ACC and Cushing's syndrome (ACC-CS) patients had two types of USP as well as 18 ACC patients without hypercortisolism. These four types differed by androgen and glucocorticoid secretion of the adrenal cortex. Fifteen main ACC features were observed by GC-MS. Urinary excretion of dehydroepiandrosterone (DHEA) was increased in 67.7 % of ACC patients and tetrahydro-11-deoxycortisol (THS) in 74.2 %. By combination of the following parameters: THS >900 μg/24 h and/or DHEA >1500 μg/24 h with ratios of 3α,16,20-pregnentriol/3β,16,20-pregnentriol (3α,16,20dP3/3β,16,20dP3) less than 6.0 and 3α,17,20dP3/3β,17,20dP3 less than 9.0 and the detection of "non-classical" 5-en-pregnens, not found in ACA and healthy persons, 100 % sensitivity and specificity of ACC and ACA differential diagnosis were achieved. Features of 21-hydroxylase and 11β-hydroxylase deficiency were observed by GC-MS in 32.2 and 61.3 % of the ACC patients, respectively. Additional features for ACC-CS diagnostic were increased urinary excretion of 6β-hydroxycortisol, 18-hydroxycorticosterone, the sum (UFF + UFE) obtained by HPLC, tetrahydrocorticosterone, and the sum (THF + THE + allo-THF) obtained by GC-MS.

PMID: 27370636 [PubMed - indexed for MEDLINE]

The landscape of bilateral adrenal incidentalomas associated with subclinical hypercortisolism.

Fri, 10/27/2017 - 23:11
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The landscape of bilateral adrenal incidentalomas associated with subclinical hypercortisolism.

Endocrine. 2016 09;53(3):621-3

Authors: Di Dalmazi G

PMID: 27369188 [PubMed - indexed for MEDLINE]

Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production.

Fri, 10/27/2017 - 23:11
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Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production.

J Mol Endocrinol. 2016 Jul;57(1):1-11

Authors: Hattangady NG, Karashima S, Yuan L, Ponce-Balbuena D, Jalife J, Gomez-Sanchez CE, Auchus RJ, Rainey WE, Else T

Abstract
Somatic and germline mutations in the inward-rectifying K(+) channel (KCNJ5) are a common cause of primary aldosteronism (PA) in aldosterone-producing adenoma and familial hyperaldosteronism type III, respectively. Dysregulation of adrenal cell calcium signaling represents one mechanism for mutated KCNJ5 stimulation of aldosterone synthase (CYP11B2) expression and aldosterone production. However, the mechanisms stimulating acute and chronic production of aldosterone by mutant KCNJ5 have not been fully characterized. Herein, we defined the effects of the T158A KCNJ5 mutation (KCNJ5(T158A)) on acute and chronic regulation of aldosterone production using an adrenal cell line with a doxycycline-inducible KCNJ5(T158A) gene (HAC15-TRE-KCNJ5(T158A)). Doxycycline incubation caused a time-dependent increase in KCNJ5(T158A) and CYP11B2 mRNA and protein levels. Electrophysiological analyses confirm the loss of inward rectification and increased Na(+) permeability in KCNJ5(T158A)-expressing cells. KCNJ5(T158A) expression also led to the activation of CYP11B2 transcriptional regulators, NURR1 and ATF2. Acutely, KCNJ5(T158A) stimulated the expression of total and phosphorylated steroidogenic acute regulatory protein (StAR). KCNJ5(T158A) expression increased the synthesis of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol, measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). All of these stimulatory effects of KCNJ5(T158A) were inhibited by the L-type Ca(2+) channel blocker, verapamil. Overall, KCNJ5(T158A)increases CYP11B2 expression and production of aldosterone, corticosterone and hybrid steroids by upregulating both acute and chronic regulatory events in aldosterone production, and verapamil blocks KCNJ5(T158A)-mediated pathways leading to aldosterone production.

PMID: 27099398 [PubMed - indexed for MEDLINE]

Paroxysmal hypertension due to paraganglioma.

Fri, 10/27/2017 - 23:11
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Paroxysmal hypertension due to paraganglioma.

Am J Surg. 1947 Jan;73(1):111-5

Authors: PHILLIPS JR

PMID: 20279390 [PubMed - indexed for MEDLINE]

An exceedingly rare adrenal collision tumor: adrenal adenoma-metastatic breast cancer-myelolipoma.

Fri, 10/20/2017 - 20:52
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An exceedingly rare adrenal collision tumor: adrenal adenoma-metastatic breast cancer-myelolipoma.

J Community Hosp Intern Med Perspect. 2017 Oct;7(4):241-244

Authors: Liu D, Kumar SA

Abstract
Adrenal collision tumors (ACTs), in which distinct tumors coexist without histological intermingling in the same adrenal gland, are rare and their actual prevalence is unknown. ACTs commonly consist of adrenal cortical adenoma, myelolipoma, or metastatic malignant tumor. We report a 58-year-old woman with a past history of breast cancer, who presented with a 1 month history of fevers, chills, and abdominal fullness. The physical examination and the laboratory data including endocrine studies were unremarkable. Computed tomography of the abdomen showed a right adrenal gland mass, and a laparoscopic right adrenalectomy was performed. Histological and immunohistochemical examinations revealed three distinct tumors: an adrenal cortical adenoma, a myelolipoma, and metastatic breast tumors. Breast cancer metastases are rare in the adrenal gland and exist as ACTs only in exceptionally rare cases. To our knowledge, this is the first reported case of coexisting metastatic breast tumors, adrenal adenoma, and myelolipoma in the same adrenal gland.

PMID: 29046752 [PubMed]

Intraparenchymal Hemorrhage due to Brain Metastasis of Hepatocellular Carcinoma.

Fri, 10/20/2017 - 20:52
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Intraparenchymal Hemorrhage due to Brain Metastasis of Hepatocellular Carcinoma.

Case Rep Gastroenterol. 2017 Sep-Dec;11(3):516-525

Authors: Sartori Balbinot R, Facco Muscope AL, Dal Castel M, Sartori Balbinot S, Angelo Balbinot R, Soldera J

Abstract
Although extrahepatic metastases from hepatocellular carcinoma (HCC) are present in only 5-15% of cases, they are certainly factors associated with poor prognosis. The main sites include lung, lymph nodes, bones, and adrenal glands, in descending order. Metastasis in the central nervous system is extremely rare, and the incidences vary from 0.6 to 1.7%. We report a case of a 54-year-old man previously diagnosed with alcohol-induced cirrhosis of the liver and HCC. The patient was admitted presenting progressive left hemiparesis and headache which started 2 days earlier, with no history of cranioencephalic trauma. After admission, cranial computed tomography revealed an intraparenchymal hemorrhage area with surrounding edema in the right frontal lobe. An angioresonance requested showed a large extra-axial mass lesion located in the right frontal region with well-defined contours and predominantly hypointense signal on T2 sequence. At first, the radiological findings suggested meningioma as the first diagnostic hypothesis. However, the patient underwent surgery. The tumor was completely removed, and the morphological and immunohistochemical findings were consistent with metastatic hepatocarcinoma associated with meningioma. In postoperative care, the patient did not recover from the left hemiparesis and manifested Broca's aphasia. He had a survival time of 24 weeks, presenting acute liver failure as his cause of death. There is a lack of evidence supporting a specific management of patients with brain metastasis from HCC. Furthermore, there are no studies that evaluate different modalities of therapeutics in brain metastasis of HCC due to the rarity of this condition. Therefore, management must be individualized depending on probable prognostic factors in these patients.

PMID: 29033772 [PubMed]

Retinal Degeneration Protein 3 (RD3) in normal human tissues: Novel insights.

Fri, 10/20/2017 - 20:52
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Retinal Degeneration Protein 3 (RD3) in normal human tissues: Novel insights.

Sci Rep. 2017 Oct 13;7(1):13154

Authors: Aravindan S, Somasundaram DB, Kam KL, Subramanian K, Yu Z, Herman TS, Fung KM, Aravindan N

Abstract
The 195-amino-acid-long human Retinal Degeneration Protein 3 (RD3) is critical in the regulation of guanylate cyclase (GC) signaling and photoreceptor cell survival. Recently, we identified significant loss of RD3 in high-risk neuroblastoma and the influential role of RD3 in tumor progression. However, the functional characterization of RD3 in tumor systems has been hampered by the dearth of information on its localization in normal tissue and by the lack of antibodies suitable for staining FFPE tissue, primarily due to the inaccessibility of the epitopes. In this study, we validated a custom-synthesized RD3 antibody and investigated the expression/localization of RD3 in assorted human tissues. We observed stratified expression of RD3 in different cell types and subcellular location of retina. We demonstrated extensive positive RD3 immunoreactivity in various normal tissues and particularly strong dot-like perinuclear staining in the lining epithelial cells, suggesting that RD3 may play an important role in the normal functioning of epithelial cells. RD3 expression is limited in the CNS. While neuroblastoma is often RD3-positive, the adrenal medulla, where many neuroblastomas originate, is RD3-negative. Meta-analysis of RD3 transcriptional expression across normal tissues confirmed tissue-specific RD3 mRNA levels. Our results revealed the tissue-specific expression/localization profile of RD3 for the first time.

PMID: 29030614 [PubMed - in process]

New insights in the clinical and translational relevance of miR483-5p in adrenocortical cancer.

Fri, 10/20/2017 - 20:52
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New insights in the clinical and translational relevance of miR483-5p in adrenocortical cancer.

Oncotarget. 2017 Sep 12;8(39):65525-65533

Authors: Salvianti F, Canu L, Poli G, Armignacco R, Scatena C, Cantini G, Di Franco A, Gelmini S, Ercolino T, Pazzagli M, Nesi G, Mannelli M, Pinzani P, Luconi M

Abstract
Adrenocortical cancer (ACC) is a rare aggressive malignancy. Recent ACC integrated genomics analysis contributed to redefine the risk groups on molecular basis, including tumor microRNAs (miRs), detectable also in the bloodstream. We developed a quantitative real-time (RT) assay for the measurement of miR483 and miR483-5p absolute levels in plasma samples. miR483/miR483-5p levels were evaluated in plasma samples of 27 patients with ACC before surgery and at follow-up. Statistically significant differences in miR483-5p and miR483 levels were found between stage 1/2 and stage 3/4 ACCs in pre-surgery and post-surgery samples. ROC curve analysis of miR483-5p levels gave a prediction of the clinical stage (accuracy 0.917±0.084), with the best cut-off value of 0.221 ng/ml, prognosticating overall and recurrence-free survival. In a multivariate Cox analysis (HR 16.2, 95%CI[1.39-188.6, P<0.026]), miR483-5p was the only variable that significantly predicted recurrence, but not overall survival. In addition, miR483 and miR483-5p levels correlated with the number of circulating tumor cells (CTCs) detected in the same blood samples, independently of the timing of sampling. In conclusion, we demonstrated that miR483-5p absolute plasma levels in ACC patients are powerful molecular markers that may help in the follow-up of patients after surgery and chemotherapy, and contribute to more accurately classify and predict tumor progression.

PMID: 29029450 [PubMed]

Advances in understanding the molecular underpinnings of adrenocortical tumors.

Fri, 10/20/2017 - 20:52
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Advances in understanding the molecular underpinnings of adrenocortical tumors.

Curr Opin Oncol. 2017 Oct 11;:

Authors: Nicolson NG, Man J, Carling T

Abstract
PURPOSE OF REVIEW: Adrenocortical tumors are divided into benign adenomas and malignant carcinomas. The former is relatively common and carries a favorable prognosis, whereas the latter is rare and frequently presents at an advanced stage, with poor outcomes. Advances in next-generation sequencing, genome analysis, and bioinformatics have allowed for high-throughput molecular characterization of adrenal tumorigenesis.
RECENT FINDINGS: Although recent genomic, epigenomic, and transcriptomic studies in large tumor cohorts have confirmed the central roles of aberrant Wnt/ß-catenin signaling, constitutive protein kinase A pathway activation, cell cycle dysregulation, and ion channelopathies in adrenal tumorigenesis, these studies also revealed novel signature events underlying malignant differentiation of adrenocortical carcinomas.
SUMMARY: Recent advances in understanding of the molecular mechanisms underlying adrenocortical tumorigenesis provide new molecular diagnostic and prognostic tools and opportunities for novel therapeutic approaches. These findings are particularly important in adrenocortical carcinoma, for which current treatment options are limited.

PMID: 29028646 [PubMed - as supplied by publisher]

Zebrafish as a model to study neuroblastoma development.

Fri, 10/20/2017 - 20:52
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Zebrafish as a model to study neuroblastoma development.

Cell Tissue Res. 2017 Oct 13;:

Authors: Casey MJ, Stewart RA

Abstract
Neuroblastoma is a pediatric solid tumor arising from embryonic neural crest progenitor cells that normally generate the peripheral sympathetic nervous system. As such, the location of neuroblastoma tumors is correlated with the distribution of major post-ganglionic clusters throughout the sympathetic chain, with the highest incidence in the adrenal medulla or lumbar sympathetic ganglia (~65%). Neuroblastoma is an enigmatic tumor that can spontaneously regress with minimal treatment or become highly metastatic and develop resistance to aggressive treatments, including radiation and high-dose chemotherapy. Age of diagnosis, stage of disease and cellular and genetic features often predict whether the tumor will regress or advance to metastatic disease. Recent efforts using molecular and genomic technologies have allowed more accurate stratification of patients into low-, intermediate- and high-risk categories, thereby allowing for minimal intervention in low-risk patients and providing potential new therapeutic targets, such as the ALK receptor tyrosine kinase, for high-risk or relapsed patients. Despite these advances, the overall survival of high-risk neuroblastoma patients is still less than 50%. Furthermore, next-generation sequencing has revealed that almost two-thirds of neuroblastoma tumors do not contain obvious pathogenic mutations, suggesting that epigenetic mechanisms and/or a perturbed cellular microenvironment may heavily influence neuroblastoma development. Understanding the mechanisms that drive neuroblastoma, therefore, will likely require a combination of genomic, developmental and cancer biology approaches in whole animal systems. In this review, we discuss the contributions of zebrafish research to our understanding of neuroblastoma pathogenesis as well as the potential for this model system to accelerate the identification of more effective therapies for high-risk neuroblastoma patients in the future.

PMID: 29027617 [PubMed - as supplied by publisher]

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