Science.gov

Sample records for adrenocortical tumors results

  1. Pathogenesis of benign adrenocortical tumors.

    PubMed

    Vezzosi, Delphine; Bertherat, Jérôme; Groussin, Lionel

    2010-12-01

    Most adrenocortical tumors (ACT) are benign unilateral adrenocortical adenomas, often discovered incidentally. Exceptionally, ACT are bilateral. However bilateral ACT have been very helpful to progress in the pathophysiology of ACT. Although most ACT are of sporadic origin, they may also be part of syndromic and/or hereditary disorders. The identification of the genetics of familial diseases associated with benign ACT has been helpful to define somatic alterations in sporadic ACT: for example, identification of PRKAR1A mutations in Carney complex or alterations of the Wnt/β-catenin pathway in Familial Adenomatous Polyposis Coli. Components of the cAMP signaling pathway-for example, adrenocorticotropic-hormone receptors and other membrane receptors, Gs protein, phosphodiesterases and protein kinase A-can be altered to various degrees in benign cortisol-secreting ACT. These progress have been important for the understanding of the pathogenesis of benign ACT, but already have profound implications for clinical management, for example in unraveling the genetic origin of disease in some patients with ACT. They also have therapeutic consequences, and should help to develop new therapeutic options. PMID:21115158

  2. Protein kinase A alterations in adrenocortical tumors.

    PubMed

    Espiard, S; Ragazzon, B; Bertherat, J

    2014-11-01

    Stimulation of the cAMP pathway by adrenocorticotropin (ACTH) is essential for adrenal cortex maintenance, glucocorticoid and adrenal androgens synthesis, and secretion. Various molecular and cellular alterations of the cAMP pathway have been observed in endocrine tumors. Protein kinase A (PKA) is a central key component of the cAMP pathway. Molecular alterations of PKA subunits have been observed in adrenocortical tumors. PKA molecular defects can be germline in hereditary disorders or somatic in sporadic tumors. Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) can be observed in patients with ACTH-independent Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic cortisol-secreting adrenocortical adenomas. Germline gene duplication of the catalytic subunits Cα (PRKACA) has been observed in patients with PPNAD. Furthermore, exome sequencing revealed recently activating somatic mutations of PRKACA in about 40% of cortisol-secreting adrenocortical adenomas. In vitro and in vivo functional studies help in the progress to understand the mechanisms of adrenocortical tumors development due to PKA regulatory subunits alterations. All these alterations are observed in benign oversecreting tumors and are mimicking in some way cAMP pathway constitutive activation. On the long term, unraveling these alterations will open new strategies of pharmacological treatment targeting the cAMP pathway in adrenal tumors and cortisol-secretion disorders. PMID:25105543

  3. ENDOCRINE TUMOURS: The genomics of adrenocortical tumors.

    PubMed

    Faillot, Simon; Assie, Guillaume

    2016-06-01

    The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone-producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches - including exome sequencing, transcriptome, miRNome, genome and methylome - converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine. PMID:26739091

  4. DNA Methylation Profiling Identifies Global Methylation Differences and Markers of Adrenocortical Tumors

    PubMed Central

    Rechache, Nesrin S.; Wang, Yonghong; Stevenson, Holly S.; Killian, J. Keith; Edelman, Daniel C.; Merino, Maria; Zhang, Lisa; Nilubol, Naris; Stratakis, Constantine A.; Meltzer, Paul S.

    2012-01-01

    Context: It is not known whether there are any DNA methylation alterations in adrenocortical tumors. Objective: The objective of the study was to determine the methylation profile of normal adrenal cortex and benign and malignant adrenocortical tumors. Methods: Genome-wide methylation status of CpG regions were determined in normal (n = 19), benign (n = 48), primary malignant (n = 8), and metastatic malignant (n = 12) adrenocortical tissue samples. An integrated analysis of genome-wide methylation and mRNA expression in benign vs. malignant adrenocortical tissue samples was also performed. Results: Methylation profiling revealed the following: 1) that methylation patterns were distinctly different and could distinguish normal, benign, primary malignant, and metastatic tissue samples; 2) that malignant samples have global hypomethylation; and 3) that the methylation of CpG regions are different in benign adrenocortical tumors by functional status. Normal compared with benign samples had the least amount of methylation differences, whereas normal compared with primary and metastatic adrenocortical carcinoma samples had the greatest variability in methylation (adjusted P ≤ 0.01). Of 215 down-regulated genes (≥2-fold, adjusted P ≤ 0.05) in malignant primary adrenocortical tumor samples, 52 of these genes were also hypermethylated. Conclusions: Malignant adrenocortical tumors are globally hypomethylated as compared with normal and benign tumors. Methylation profile differences may accurately distinguish between primary benign and malignant adrenocortical tumors. Several differentially methylated sites are associated with genes known to be dysregulated in malignant adrenocortical tumors. PMID:22472567

  5. Alterations of Phosphodiesterases in Adrenocortical Tumors.

    PubMed

    Hannah-Shmouni, Fady; Faucz, Fabio R; Stratakis, Constantine A

    2016-01-01

    Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs. PMID:27625633

  6. Alterations of Phosphodiesterases in Adrenocortical Tumors

    PubMed Central

    Hannah-Shmouni, Fady; Faucz, Fabio R.; Stratakis, Constantine A.

    2016-01-01

    Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.

  7. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed Central

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  8. Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith-Wiedemann syndrome as a sporadic adrenocortical tumor.

    PubMed

    H'mida Ben-Brahim, Dorra; Hammami, Sabeur; Haddaji Mastouri, Marwa; Trabelsi, Saoussen; Chourabi, Maroua; Sassi, Sihem; Mougou, Soumaya; Gribaa, Moez; Zakhama, Abdelfattah; Guédiche, Mohamed Neji; Saad, Ali

    2015-03-01

    Beckwith-Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith-Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith-Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith-Wiedemann syndrome presentation. PMID:26937341

  9. [Diagnostic benefits of adrenocortical scintigraphy in hepatic adrenal rest tumor].

    PubMed

    Ishida, Kosuke; Horii, Rika; Yamashita, Tatsuya; Arai, Kuniaki; Yamashita, Taro; Kagaya, Takashi; Sakai, Yoshio; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi

    2014-10-01

    An 81-year-old female was referred to our hospital for the examination of an S7 liver tumor. The tumor was suspected to be a hepatic adrenal rest tumor (HART) based on ultrasonography, dynamic CT, Gd-EOB-DTPA-enhanced MRI, and CT during abdominal angiography. After various hormonal tests, the tumor was confirmed as hormonally non-functional. The diagnosis of HART was confirmed based on (131)I-adosterol accumulation in the tumor by adrenocortical scintigraphy. The resected tumor was histologically compatible with HART, and it may have been able to produce cortisol based on the immunohistochemical findings of various adrenocortical hormone metabolic enzymes. Adrenocortical scintigraphy may thus be useful in diagnosing HART. PMID:25283230

  10. Adrenocortical tumors and insulin resistance: What is the first step?

    PubMed

    Altieri, Barbara; Tirabassi, Giacomo; Casa, Silvia Della; Ronchi, Cristina L; Balercia, Giancarlo; Orio, Francesco; Pontecorvi, Alfredo; Colao, Annamaria; Muscogiuri, Giovanna

    2016-06-15

    The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors. PMID:26637955

  11. Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors

    PubMed Central

    Longatto-Filho, Adhemar; Faria, André M.; Fragoso, Maria C. B. V.; Lovisolo, Silvana M.; Lerário, Antonio M.; Almeida, Madson Q.

    2015-01-01

    Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis. PMID:26587828

  12. Familial predisposition to adrenocortical tumors: clinical and biological features and management strategies.

    PubMed

    Ribeiro, Raul C; Pinto, Emilia M; Zambetti, Gerard P

    2010-06-01

    The incidence of adrenocortical tumors (ACTs) is increased in several familial cancer syndromes resulting from abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. These include P53, MEN1, APC, and PRKAR1A. Adenomas are the most common ACTs, but adrenocortical carcinomas occur rarely as well. The clinical manifestations of ACTs, which result from increased secretion of adrenocortical hormones, are similar in the familial and sporadic forms of the disease. However, their management may differ because of unique aspects of the constitutional syndromes. The analysis of gene expression profiles of ACTs in these constitutional syndromes have contributed to our understanding of adrenal tumorigenesis and revealed new molecular diagnostic and prognostic markers and candidate genes for targeted therapies. This chapter summarizes the clinical and biological features, pathogenesis, and management strategies for ACTs that develop in patients with familial cancer syndrome. PMID:20833338

  13. Adrenocortical carcinoma

    MedlinePlus

    ... JavaScript. Adrenocortical carcinoma is a cancer of the adrenal glands . Causes Adrenocortical carcinoma is most common in children ... tumor. Symptoms Symptoms of increased cortisol or other adrenal gland hormones: Fatty, rounded hump high on the back ...

  14. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

    PubMed Central

    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune–Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1–3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID:27512387

  15. PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors.

    PubMed

    Berthon, Annabel S; Szarek, Eva; Stratakis, Constantine A

    2015-01-01

    Cyclic-AMP (cAMP)-dependent protein kinase (PKA) is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH). More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα), were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA's role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway. PMID:26042218

  16. [Comparative clinical analysis of histological systems of adrenocortical tumors diagnosis].

    PubMed

    Bokhyan, V Yu; Stilidi, I S; Pavlovskaya, A I

    2015-01-01

    Differential diagnosis of adrenocortical cancer (ACC) and cortical adenoma presents certain difficulties since there is no specific histological criterion allowing to distinguish tumors of the adrenal cortex with malignant clinical course. Currently there are offered several systems, and the most widely spread have the index Weiss (IW) and the modified index Weiss (MIW). The accuracy of one or another of the proposed systems remains a matter of debate. There was analyzed own experience on the use of IW and MIW in the diagnosis of 91 cases of the ACC and 13 cases of cortex adenomas of the size at least 5 cm. For the diagnosis of large adenomas sensitivity IW was 77%, MIW--100%. For the diagnosis of metastatic and non-metastatic ACC--100% and 97%, 100% and 86%, respectively (p > 0.05). In multivariate analysis of life expectancy of patients the definition of IW and MIW had a prognostic significance. MIW was less subjective, more simple and convenient to be used and it showed a great informative value at the reclassification of certain "adenomas" into ACC. However to use it on their own, without IW, was impractical as MIW had wider gray area and did not reach the threshold value in some cases of ACC. For the diagnosis of tumors of the adrenal cortex IW remains a standard; when a value was equal of 2 or in cases of doubt it was necessary to calculate MIW as well. PMID:26995980

  17. Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors

    PubMed Central

    de Paula Mariani, Beatriz Marinho; Trarbach, Ericka Barbosa; Ribeiro, Tamaya Castro; Pereira, Maria Adelaide Albergaria; Mendonca, Berenice Bilharinho; Fragoso, Maria Candida Barisson Villares

    2012-01-01

    OBJECTIVE: Endostatin is a potent endogenous inhibitor of angiogenesis. It is derived from the proteolytic cleavage of collagen XVIII, which is encoded by the COL18A1 gene. A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis. This polymorphism has been previously analyzed in many types of cancer and has been considered a phenotype modulator in some benign and malignant tumors. However, these data are controversial, and different results have been reported for the same tumor types, such as prostate and breast cancer. The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors. METHODS: DNA samples were obtained from 38 pediatric and 56 adult patients (0.6–75 yrs) with adrenocortical tumors. The DNA samples were obtained from peripheral blood, frozen tissue or paraffin-embedded tumor blocks when blood samples or fresh frozen tissue samples were unavailable. Restriction fragment length polymorphism analysis was used to genotype the patients and 150 controls. The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed. RESULTS: Both the patient group and the control group were in Hardy–Weinberg equilibrium. The frequencies of the p.D104N polymorphism in the patient group were 81.9% (DD), 15.9% (DN) and 2.2% (NN). In the controls, these frequencies were 80.6%, 17.3% and 2.0%, respectively. We did not observe any association of this variant with clinical or histopathological features or oncologic outcome in our cohort of pediatric and adult patients with adrenocortical tumors. PMID:22358232

  18. Adrenocortical Tumors and Hyperplasias in Childhood - Etiology, Genetics, Clinical Presentation and Therapy

    PubMed Central

    Sutter, Jennifer A.; Grimberg, Adda

    2007-01-01

    Adrenocortical tumors are rare in children and are associated with a poor prognosis when malignant. The fund of knowledge regarding etiology, presentation and clinical outcomes remains limited. Evaluation of genetic disorders associated with the development of adrenocortical disorders has allowed researchers to identify a number of mutations that may be involved in tumorigenesis, including alterations in the GNAS1, PRKAR1A, TP53 and IGF2 genes. Clinical presentation in children is associated most commonly with young age, female gender and symptoms of virilization. Most children have localized disease at presentation which may be associated with a better prognosis when compared to adults. Surgical resection remains the only potentially curative treatment and mitotane, the most frequently used chemotherapeutic agent, has a poor response rate and is highly toxic. Broader participation in multi-center research, such as the International Pediatric Adrenocortical Tumor Registry, is needed to collect sufficient data to better guide our clinical management. PMID:17021581

  19. Adrenocortical tumor with precocious puberty in a 2-month-old girl.

    PubMed

    Marret, Jean-Baptiste; Raffoul, Lara; Ribault, Virginie; Ravasse, Philippe; Rod, Julien

    2015-10-01

    Adrenocortical tumor is a rare childhood tumor with a median age at onset of 3.2 years. Virilization is the most common sign. Laparotomy is the reference treatment and has a favorable course. The diagnosis of adrenal tumor can be difficult. The main parameters of malignant tumors are size and metastasis. Analysis of TP53 mutation can facilitate final diagnosis. We report a case of virilizing adrenal tumor that developed in a 2-month-old girl, and which was treated with laparoscopic adrenalectomy. PMID:26508188

  20. Need for Comprehensive Hormonal Workup in the Management of Adrenocortical Tumors in Children

    PubMed Central

    Gönç, E. Nazlı; Özön, Zeynep Alev; Çakır, Meltem Didem; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

    2014-01-01

    Ob­jec­ti­ve: Clinical findings do not reflect the excess hormonal status in adrenocortical tumors (ACTs) in children. Identification of abnormal hormone secretion may help provide the tumor marker and delineate those patients with a risk of adrenal suppression following tumor removal. To analyze the impact of complete hormonal assessment regardless of the clinical presentation in hormone-secreting ACTs in childhood. Methods: Association of hormonal workup at diagnosis with the clinical findings and frequency of adrenal suppression postoperatively were analyzed in 18 children with ACT. Results: Seventeen of the 18 patients had functional ACT. Clinical findings suggested isolated virilization and isolated Cushing’s syndrome in 38.8% and 17.6% of patients, respectively. Hormonal workup revealed a frequency of 83.3% for hyperandrogenism. The majority of the tumors (50%) had mixed type hormonal secretion. Hypercortisolism existed in 28.5% of children with isolated virilization and hyperandrogenism was found in 2/3 of children with isolated Cushing’s syndrome. Various androgens other than dehydroepiandrosterone sulfate were also determined to be high in hyperandrogenism. Increased testosterone was a highly prevalent tumor marker. Nine patients (3 with no signs of hypercortisolism) had adrenal suppression following tumor removal which lasted 1-24 months. Conclusion: Complete hormonal workup showed the predominance of mixed hormone-secreting type of tumor in the patients who lacked the appropriate clinical findings and also showed that patients lacking signs of Cushing’s syndrome could have postoperative adrenal suppression. Clinical findings may not reflect the abnormal hormone secretion in all cases and tumor markers as well as risk of postoperative adrenal suppression can best be determined by complete hormonal evaluation at the time of diagnosis. PMID:24932598

  1. Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells

    PubMed Central

    Chen, T-Y; Syu, J-S; Lin, T-C; Cheng, H-l; Lu, F-l; Wang, C-Y

    2015-01-01

    The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT. PMID:26690546

  2. Genome-wide paternal uniparental disomy as a cause of Beckwith-Wiedemann syndrome associated with recurrent virilizing adrenocortical tumors.

    PubMed

    Bertoin, F; Letouzé, E; Grignani, P; Patey, M; Rossignol, S; Libé, R; Pasqual, C; Lardière-Deguelte, S; Hoeffel-Fornes, C; Gaillard, D; Previderè, C; Delemer, B; Lalli, E

    2015-06-01

    Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by fetal macrosomia, macroglossia, and abdominal wall defects. BWS patients are at risk to develop Wilms tumor, neuroblastoma, hepatoblastoma, and adrenal tumors. A young woman with BWS features, but with inconclusive genetic evidence for the disease, came to clinical observation for signs of virilization at the age of 16 years. An adrenocortical tumor was diagnosed and surgically resected. The tumor underwent 2 local relapses that were also surgically treated. The patient was also operated to remove a breast fibroadenoma. SNP arrays were used to analyze chromosome abnormalities in normal and tumor samples from the patient and her parents. The patient presented genome-wide mosaic paternal uniparental disomy (patUPD) both in the adrenocortical and the breast tumors, with different degrees of loss of heterozygosity (LOH). The more recent relapses of the adrenocortical tumor showed a loss of part of chromosome 17p that was absent in the first tumor. Analysis of a skin biopsy sample also showed mosaic patUPD with partial LOH, while no LOH was detected in leukocyte DNA. This case shows that virilizing adrenocortical tumors may be a clinical feature of patients with BWS. The SNP array technology is useful to diagnose genome-wide patUPD mosaicism in BWS patients with an inconclusive molecular diagnosis and underlines the tumorigenic potential of the absence of the maternal genome combined with an excess of the paternal genome. PMID:25365508

  3. The reticulin algorithm for adrenocortical tumor diagnosis: a multicentric validation study on 245 unpublished cases.

    PubMed

    Duregon, Eleonora; Fassina, Ambrogio; Volante, Marco; Nesi, Gabriella; Santi, Raffaella; Gatti, Gaia; Cappellesso, Rocco; Dalino Ciaramella, Paolo; Ventura, Laura; Gambacorta, Marcello; Dei Tos, Angelo Paolo; Loli, Paola; Mannelli, Massimo; Mantero, Franco; Berruti, Alfredo; Terzolo, Massimo; Papotti, Mauro

    2013-09-01

    The pathologic diagnosis of adrenocortical carcinoma (ACC) still needs to be improved, because the renowned Weiss Score (WS) system has a poor reproducibility of some parameters and is difficult to apply in borderline cases and in ACC variants. The "reticulin algorithm" (RA) defines malignancy through an altered reticulin framework associated with 1 of the 3 following parameter: necrosis, high mitotic rate, and vascular invasion. This study aimed at validating the interobserver reproducibility of reticulin stain evaluation in an unpublished series of 245 adrenocortical tumors (61 adenomas and 184 carcinomas) from 5 Italian centers, classified according to the WS. Eight pathologists reviewed all reticulin-stained slides. After training, a second round of evaluation on discordant cases was performed 10 weeks later. The RA reclassified 67 cases (27%) as adenomas, including 44 with no reticulin alterations and 23 with an altered reticulin framework but lacking the subsequent parameters of the triad. The other 178 cases (73%) were carcinomas according to the above-mentioned criteria. A complete (8/8 pathologists) interobserver agreement was reached in 75% of cases (κ=0.702), irrespective of case derivation, pathologists' experience, and histologic variants, and was further improved when only those cases with high WS and clinically malignant behavior were considered. After the training, the overall agreement increased to 86%. We conclude that reticulin staining is a reliable technique and an easy-to-interpret system in adrenocortical tumors; moreover, it has a high interobserver reproducibility, which supports the notion of using such a method in the proposed 2-step RA approach for ACC diagnosis. PMID:23774167

  4. Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

    PubMed Central

    Lalli, Enzo; Figueiredo, Bonald C.

    2015-01-01

    Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal. PMID:25741319

  5. Origin and Molecular Pathology of Adrenocortical Neoplasms

    PubMed Central

    Bielinska, M.; Parviainen, H.; Kiiveri, S.; Heikinheimo, M.; Wilson, D.B.

    2008-01-01

    Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors have documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic AMP signaling, whereas key factors/signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/β-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies. PMID:19261630

  6. IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis.

    PubMed

    Peixoto Lira, Régia Caroline; Fedatto, Paola Fernanda; Marco Antonio, David Santos; Leal, Letícia Ferro; Martinelli, Carlos Eduardo; de Castro, Margaret; Tucci, Silvio; Neder, Luciano; Ramalho, Leandra; Seidinger, Ana Luiza; Cardinalli, Izilda; Mastellaro, Maria José; Yunes, José Andres; Brandalise, Silvia Regina; Tone, Luiz Gonzaga; Rauber Antonini, Sonir Roberto; Scrideli, Carlos Alberto

    2015-06-01

    Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth. PMID:27185872

  7. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors

    SciTech Connect

    Gicquel, C.; Schneid, H.; Le Bouc, Y.; Bertagna, X.; Francillard-Leblond, M.; Luton, J.P.; Girard, F.

    1994-06-01

    Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly in adrenocortical tumors associated with the Beckwith-Wiedemann syndrome, and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, the authors looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing`s syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing`s syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, a uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis. 58 refs., 6 figs., 4 tabs.

  8. Recurrence and mortality prognostic factors in childhood adrenocortical tumors: Analysis from the Brazilian National Institute of Cancer experience.

    PubMed

    Bulzico, Daniel; de Faria, Paulo Antônio Silvestre; de Paula, Marcela Pessoa; Bordallo, Maria Alice Neves; Pessoa, Cencita H C N; Corbo, Rossana; Ferman, Sima; Vaisman, Mario; Neto, Leonardo Vieira

    2016-05-01

    Prognostic markers that can help identifying precocious risk of unfavorable outcomes in patients with childhood adrenocortical tumors (ACTs) are still unclear. This observational and retrospective study aimed to identify clinical and pathology prognostic factors of recurrence and death in a tertiary cancer center population. Clinical, pathology, demographic, staging, and therapy data from patients with childhood ACT (median age: 3.6 years) treated at the Brazilian National Institute of Cancer between 1997 and 2015 were assessed. Univariate and bivariate analyses were used to study the association of clinical and pathology characteristics with recurrence and mortality. Recurrence and disease-related mortality were the main outcomes. Twenty-seven patients were included. Complete tumor resection was performed in 21 cases. The median tumor size was 8.2 cm. Mitotane was the most common adjuvant/palliative therapy (n = 13). Recurrence occurred in 6 patients, after a median time of 7.2 months, and was more common among those with larger tumors (P =.008), higher Weiss score (P =.001), and microscopic tumoral necrosis (P =.002). Ten patients died from the disease. Older age (P =.04), larger tumor size (P =.002), metastatic disease (P =.003), previous recurrence (P =.003), incomplete resection (P =.002), intraoperative tumor spillage (P =.005), higher Weiss score (P =.03), microscopic necrosis (P =.005), and capsular invasion (P =.02) were all associated with increased death risk. Even though complete tumor resection was performed in most cases, a considerable number of cases of childhood ACT resulted in recurrence and death. Early identification of unfavorable outcomes is essential to determine ideal therapy and appropriate surveillance. PMID:27246903

  9. Animal models of adrenocortical tumorigenesis

    PubMed Central

    Beuschlein, Felix; Galac, Sara; Wilson, David B.

    2011-01-01

    Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species – mouse, ferret, and dog – are reviewed, and their relevance to adrenocortical tumors in humans is discussed. PMID:22100615

  10. DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis.

    PubMed

    de Sousa, G R V; Soares, I C; Faria, A M; Domingues, V B; Wakamatsu, A; Lerario, A M; Alves, V A F; Zerbini, M C N; Mendonca, B B; Fragoso, M C B V; Latronico, A C; Almeida, M Q

    2015-08-01

    DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ(2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis. PMID:25985323

  11. microRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma

    PubMed Central

    Gill, Anthony J.; Weiss, Jocelyn; Mugridge, Nancy; Kim, Edward; Feeney, Alex L.; Ip, Julian C.; Reid, Glen; Clarke, Stephen; Soon, Patsy S.H.; Robinson, Bruce G.; Brahmbhatt, Himanshu; MacDiarmid, Jennifer A.; Sidhu, Stan B.

    2015-01-01

    Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7–5p (miR-7) reduces cell proliferation in vitro and induces G1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle (EGFREDVTM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDVTM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy. PMID:26452132

  12. Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: Relationship with cell proliferation

    SciTech Connect

    Mantovani, G.; Lania, A.G.; Bondioni, S.; Peverelli, E.; Pedroni, C.; Ferrero, S.; Pellegrini, C.; Vicentini, L.; Arnaldi, G.; Bosari, S.; Beck-Peccoz, P.; Spada, A.

    2008-01-01

    The four regulatory subunits (R1A, R1B, R2A, R2B) of protein kinase A (PKA) are differentially expressed in several cancer cell lines and exert distinct roles in growth control. Mutations of the R1A gene have been found in patients with Carney complex and in a minority of sporadic primary pigmented nodular adrenocortical disease (PPNAD). The aim of this study was to evaluate the expression of PKA regulatory subunits in non-PPNAD adrenocortical tumors causing ACTH-independent Cushing's syndrome and to test the impact of differential expression of these subunits on cell growth. Immunohistochemistry demonstrated a defective expression of R2B in all cortisol-secreting adenomas (n = 16) compared with the normal counterpart, while both R1A and R2A were expressed at high levels in the same tissues. Conversely, carcinomas (n = 5) showed high levels of all subunits. Sequencing of R1A and R2B genes revealed a wild type sequence in all tissues. The effect of R1/R2 ratio on proliferation was assessed in mouse adrenocortical Y-1 cells. The R2-selective cAMP analogue 8-Cl-cAMP dose-dependently inhibited Y-1 cell proliferation and induced apoptosis, while the R1-selective cAMP analogue 8-HA-cAMP stimulated cell proliferation. Finally, R2B gene silencing induced up-regulation of R1A protein, associated with an increase in cell proliferation. In conclusion, we propose that a high R1/R2 ratio favors the proliferation of well differentiated and hormone producing adrenocortical cells, while unbalanced expression of these subunits is not required for malignant transformation.

  13. Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis

    PubMed Central

    Leal, Letícia F.; Bueno, Ana Carolina; Gomes, Débora C.; Abduch, Rafael; de Castro, Margaret; Antonini, Sonir R.

    2015-01-01

    Background To date, there is no effective therapy for patients with advanced/metastatic adrenocortical cancer (ACC). The activation of the Wnt/beta-catenin signaling is frequent in ACC and this pathway is a promising therapeutic target. Aim To investigate the effects of the inhibition of the Wnt/beta-catenin in ACC cells. Methods Adrenal (NCI-H295 and Y1) and non-adrenal (HeLa) cell lines were treated with PNU-74654 (5–200 μM) for 24–96 h to assess cell viability (MTS-based assay), apoptosis (Annexin V), expression/localization of beta-catenin (qPCR, immunofluorescence, immunocytochemistry and western blot), expression of beta-catenin target genes (qPCR and western blot), and adrenal steroidogenesis (radioimmunoassay, qPCR and western blot). Results In NCI-H295 cells, PNU-74654 significantly decreased cell proliferation 96 h after treatment, increased early and late apoptosis, decreased nuclear beta-catenin accumulation, impaired CTNNB1/beta-catenin expression and increased beta-catenin target genes 48 h after treatment. No effects were observed on HeLa cells. In NCI-H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione secretion 24 and 48 h after treatment. Additionally, in NCI-H295 cells, PNU-74654 decreased SF1 and CYP21A2 mRNA expression as well as the protein levels of STAR and aldosterone synthase 48 h after treatment. In Y1 cells, PNU-74654 impaired corticosterone secretion 24 h after treatment but did not decrease cell viability. Conclusions Blocking the Tcf/beta-catenin complex inhibits the Wnt/beta-catenin signaling in adrenocortical tumor cells triggering increased apoptosis, decreased cell viability and impairment of adrenal steroidogenesis. These promising findings pave the way for further experiments inhibiting the Wnt/beta-catenin pathway in pre-clinical models of ACC. The inhibition of this pathway may become a promising adjuvant therapy for patients with ACC. PMID:26515592

  14. Adrenocortical endocrine disruption.

    PubMed

    Harvey, Philip W

    2016-01-01

    in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'. PMID:25460300

  15. Metastatic congenital adrenocortical carcinoma: a case report with tumor remission at 3 1/2 years.

    PubMed

    Godil, M A; Atlas, M P; Parker, R I; Priebe, C J; Zerah, M M; Kane, P; Tsung, J; Wilson, T A

    2000-11-01

    We describe a case of metastasizing congenital adrenocortical carcinoma and a follow-up of 3 1/2 yr. Treatment with surgery and mitotane was associated with multiple complications. The patient was in remission at 3 1/2 yr. Because of the rarity of this condition, we discuss step-by-step problems encountered during management. PMID:11095414

  16. 5th International ACC Symposium: Classification of Adrenocortical Cancers from Pathology to Integrated Genomics: Real Advances or Lost in Translation?

    PubMed

    de Krijger, Ronald E; Bertherat, Jérôme

    2016-02-01

    For the clinician, despite its rarity, adrenocortical cancer is a heterogeneous tumor both in term of steroid excess and tumor evolution. For patient management, it is crucial to have an accurate vision of this heterogeneity, in order to use a correct tumor classification. Pathology is the best way to classify operated adrenocortical tumors: to recognize their adrenocortical nature and to differentiate benign from malignant tumors. Among malignant tumors pathology also aims at prognosis assessment. Although progress has being made for prognosis assessment, there is still a need for improvement. Recent studies have established the value of Ki67 for adrenocortical cancer (ACC) prognostication, aiming also at standardization to reduce variability. The use of genomics to study adrenocortical tumors gives a very new insight in their pathogenesis and molecular classification. Genomics studies of ACC give now a clear description of the mRNA (transcriptome) and miRNA expression profile, as well as chromosomal and methylation alterations. Exome sequencing also established firmly the list of the main ACC driver genes. Interestingly, genomics study of ACC also revealed subtypes of malignant tumors with different pattern of molecular alterations, associated with different outcome. This leads to a new vision of adrenocortical tumors classification based on molecular analysis. Interestingly, these molecular classifications meet also the results of pathological analysis. This opens new perspectives on the development and use of various molecular tools to classify, along with pathological analysis, ACC, and guides patient management at the area of precision medicine. PMID:26676358

  17. Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor.

    PubMed

    Mitsui, Yozo; Yasumoto, Hiroaki; Nagami, Taichi; Hiraki, Miho; Arichi, Naoko; Ishikawa, Noriyoshi; Araki, Asuka; Maruyama, Riruke; Tanaka, Yuichiro; Dahiya, Rajvir; Shiina, Hiroaki

    2014-04-30

    Wnt/β-catenin signaling is considered to be an essential regulator of adrenocortical oncogenesis. Wnt inhibitory factor-1 (Wif-1), an extracellular regulator of Wnt signaling, is frequently down-regulated by hypermethylation of the promoter CpG. We investigated epigenetic regulation of Wif-1 and its association with adrenocortical (AC) tumor pathogenesis in light of Wnt activation. The AC tumors showed a high prevalence of Wif-1 promoter methylation and low prevalence of Wif-1 mRNA transcription as compared to the normal adrenal (NA) samples. Furthermore, a significant correlation was found between Wif-1 promoter methylation and mRNA transcription in the tumors. Either intracellular β-catenin accumulation or β-catenin mRNA transcription was significantly elevated in the AC tumors, which also showed an inverse correlation with Wif-1 mRNA transcription. Cyclin D1, a target gene of Wnt signaling, was also up-regulated in the AC tumors as compared with the NA samples. In addition, down-regulation of Wif-1 was correlated with increased cyclin D1 at both mRNA and protein levels. However, despite the proposed activation of Wnt signaling in AC tumors, only 2 of 20 with intracellular β-catenin accumulation showed β-catenin mutations. Thus, genetic alterations of β-catenin and epigenetics-related Wif-1 promoter hypermethylation may be important mechanisms underlying AC tumor formation though aberrant canonical Wnt/β-catenin signaling activation. PMID:24755523

  18. Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo).

    PubMed

    Chen, Sue

    2010-09-01

    Endocrine neoplasia is the most common tumor type in domestic ferrets, especially in middle-aged to older ferrets. Islet cell tumors and adrenocortical tumors constitute the major types of endocrine neoplasms. Insulinoma is a tumor that produces and releases excessive amounts of insulin. Evaluation of fasted blood glucose levels provides a quick diagnostic assessment for the detection of insulinomas. Use of glucocorticoids, diazoxide, and diet modification are some of the medical treatment options for insulinomas. Adrenocortical neoplasia in ferrets usually overproduces one or more sex hormones. Sex hormones which can result in progressive alopecia, vulvar swelling in females, and prostagomegaly in males. Abdominal ultrasonography and sex hormone assays can be used to diagnose adrenocortical neoplasms. Drugs such as leuprolide acetate, deslorelin acetate, and the hormone melatonin can be used to treat adrenocortical neoplasms in ferrets when surgery is not an option. PMID:20682429

  19. Adrenocortical Carcinoma

    PubMed Central

    Kim, Alex C.; Sabolch, Aaron; Raymond, Victoria M.; Kandathil, Asha; Caoili, Elaine M.; Jolly, Shruti; Miller, Barbra S.; Giordano, Thomas J.

    2014-01-01

    Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC. PMID:24423978

  20. POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells

    PubMed Central

    França, Monica Malheiros; Ferraz-de-Souza, Bruno; Lerario, Antonio Marcondes; Fragoso, Maria Candida Barisson Villares; Lotfi, Claudimara Ferini Pacicco

    2015-01-01

    POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers. PMID:26421305

  1. Adrenocortical carcinoma.

    PubMed

    Baudin, Eric

    2015-06-01

    Recent developments in the treatment of adrenocortical carcinoma (ACC) include diagnostic and prognostic risk stratification algorithms, increasing evidence of the impact of historical therapies on overall survival, and emerging targets from integrated epigenomic and genomic analyses. Advances include proper clinical and molecular characterization of all patients with ACC, standardization of proliferative index analyses, referral of these patients to large cancer referral centers at the time of first surgery, and development of new trials in patients with well-characterized ACC. Networking and progress in the molecular characterization of ACC constitute the basis for significant future therapeutic breakthroughs. PMID:26038209

  2. 5th International ACC Symposium: The New Genetics of Benign Adrenocortical Neoplasia: Hyperplasias, Adenomas, and Their Implications for Progression into Cancer.

    PubMed

    Kirschner, Lawrence S; Stratakis, Constantine A

    2016-02-01

    Genetic tools for the analysis of human tumors have developed rapidly over the past 20 years. Adrenocortical neoplasms have been subject to multiple analyses using these new genetic tools. Analysis of adrenocortical carcinomas (ACCs) has been complicated by the fact that these tumors tend to exhibit multiple somatic abnormalities, so that identifying driver mutations is complex task. In contrast, benign adrenocortical neoplasms have proven to be a fertile ground for the identification of the genetic causes of adrenocortical adenomas, as well as a variety of adrenocortical hyperplasia. Analysis of cortisol-producing adrenocortical adenomas has revealed alterations leading to enhanced signaling through the cAMP-dependent protein kinase (PKA) pathway. In contrast, macronodular cortisol-producing neoplasias have been shown to result from mutations in the ARMC5 gene, whose function is not yet quite so clear. In contrast, adrenal tumors resulting in excess production of the blood pressure hormone aldosterone almost always result from abnormalities of calcium handling, both in single adenomas and in bilateral hyperplasias. In both cases, there is elevation of a signaling pathway responsible both for hormone secretion and for gland growth and maintenance, thus confirming the linkage of these two output of cellular physiology. The connection between the benign hyperplasia observed in these states and adrenocortical carcinogenesis is not nearly as clear, although genetic studies are beginning to elucidate the relationship between benign and malignant tumors of this gland. PMID:26684645

  3. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  4. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

    PubMed

    Phan, Liem M; Fuentes-Mattei, Enrique; Wu, Weixin; Velazquez-Torres, Guermarie; Sircar, Kanishka; Wood, Christopher G; Hai, Tao; Jimenez, Camilo; Cote, Gilbert J; Ozsari, Levent; Hofmann, Marie-Claude; Zheng, Siyuan; Verhaak, Roeland; Pagliaro, Lance; Cortez, Maria Angelica; Lee, Mong-Hong; Yeung, Sai-Ching J; Habra, Mouhammed Amir

    2015-10-01

    Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. PMID:26282167

  5. Laparoscopic Adrenalectomy for Large Adrenocortical Carcinoma

    PubMed Central

    al Qadhi, Hani; al Wahaibi, Khalifa; Rizvi, Syed G.

    2015-01-01

    Background: Adrenocortical cancer (ACC) is a rare disease that is difficult to treat. Laparoscopic adrenalectomy (LA) is performed, even for large adrenocortical carcinomas. However, the oncological effectiveness of LA remains unclear. This review presents the current knowledge of the feasibility and oncological effectiveness of laparoscopic surgery for ACC, with an analysis of data for outcomes and other parameters. Database: A systematic review of the literature was performed by searching the PubMed and Medline databases for all relevant articles in English, published between January 1992 and August 2014 on LA for adrenocortical carcinoma. Discussion: The search resulted in retrieval of 29 studies, of which 10 addressed the outcome of LA versus open adrenalectomy (OA) and included 844 patients eligible for this review. Among these, 206 patients had undergone LA approaches, and 638 patients had undergone OA. Among the 10 studies that compared the outcomes obtained with LA and OA for ACC, 5 noted no statistically significant difference between the 2 groups in the oncological outcomes of recurrence and disease-free survival, whereas the remaining 5 reported inferior outcomes in the LA group. Using a paired t test for statistical analysis, except for tumor size, we found no significant difference in local recurrence, peritoneal carcinomatosis, positive resection margin, and time to recurrence between the LA and OA groups. The overall mean tumor size in patients undergoing LA and OA was 7.1 and 11.2 cm, respectively (P = .0003), and the mean overall recurrence was 61.5 and 57.9%, respectively. The outcome of LA is believed to depend to a large extent on the size and stage of the lesion (I and II being favorable) and the surgical expertise in the center where the patient undergoes the operation. However, the present review shows no difference in the outcome between the 2 approaches across all stages. A poor outcome is likely to result from inadequate surgery

  6. Effects of Type 1 Insulin-Like Growth Factor Receptor Silencing in a Human Adrenocortical Cell Line.

    PubMed

    Ribeiro, T C; Jorge, A A; Montenegro, L R; Almeida, M Q; Ferraz-de-Souza, B; Nishi, M Y; Mendonca, B B; Latronico, A C

    2016-07-01

    Type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed in a variety of human cancers, including adrenocortical tumors. The aim of the work was to investigate the effects of IGF-1R downregulation in a human adrenocortical cell line by small interfering RNA (siRNA). The human adrenocortical tumor cell line NCI H295R was transfected with 2 specific IGF1R siRNAs (# 1 and # 2) and compared with untreated cells and a negative control siRNA. IGF1R expression was determined by quantitative reverse-transcription PCR (qRTPCR) and Western blot. The effects of IGF-1R downregulation on cell proliferation and apoptosis were assessed. IGF-1R levels were significantly decreased in cells treated with IGF-1R siRNA # 1 or # 2. Relative expression of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein. Downregulation of this gene resulted in 40% reduction in cell growth in vitro and 45% increase in apoptosis using siRNA # 2. These findings demonstrate that decreasing IGF-1R mRNA and protein expression in NCI H295R cells can partially inhibit adrenal tumor cell growth in vitro. Targeting IGF1R is a promising therapy for pediatric malignant adrenocortical tumor and can still be an option for adult adrenocortical cancer based on personalized genomic tumor profiling. PMID:27246621

  7. Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression

    PubMed Central

    Ribeiro, Tamaya Castro; Jorge, Alexander Augusto; Almeida, Madson Q.; Mariani, Beatriz Marinho de Paula; Nishi, Mirian Yumi; Mendonca, Berenice Bilharinho; Fragoso, Maria Candida Barisson Villares

    2014-01-01

    Context. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors. PMID:25110710

  8. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD).

    PubMed

    de Joussineau, Cyrille; Sahut-Barnola, Isabelle; Tissier, Frédérique; Dumontet, Typhanie; Drelon, Coralie; Batisse-Lignier, Marie; Tauveron, Igor; Pointud, Jean-Christophe; Lefrançois-Martinez, Anne-Marie; Stratakis, Constantine A; Bertherat, Jérôme; Val, Pierre; Martinez, Antoine

    2014-10-15

    Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation. PMID:24865460

  9. Adrenocortical Stem and Progenitor Cells—Implications for Adrenocortical Carcinoma

    PubMed Central

    Simon, Derek P.; Hammer, Gary D.

    2012-01-01

    The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal and pluripotency. The adrenocortical capsule and underlying undifferentiated cortical cells are emerging as critical components of the stem/progenitor cell niche. Recent genetic analysis has identified various signaling pathways including Sonic Hedgehog (Shh) and Wnt as crucial mediators of adrenocortical lineage and organ homeostasis. Shh expression is restricted to the peripheral cortical cells that express a paucity of steroidogenic genes but give rise to the underlying differentiated cells of the cortex. Wnt/β-catenin signaling maintains the undifferentiated state and adrenal fate of adrenocortical stem/progenitor cells, in part through induction of its target genes Dax1 and inhibin-α, respectively. The pathogenesis of ACC, a rare yet highly aggressive cancer with an extremely poor prognosis, is slowly emerging from studies of the stem/progenitor cells of the adrenal cortex coupled with the genetics of familial syndromes in which ACC occurs. The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in β-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process. Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms. It is unclear whether other factors such as Pod1 and Pref1, which are implicated in stem/progenitor cell biology in the adrenal and/or other organs, are also implicated in the etiology of adrenocortical carcinoma. The rarity and heterogeneous presentation of ACC makes it difficult to identify the cellular origin and the molecular progression to cancer. A more

  10. Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer

    PubMed Central

    Legendre, Christophe R.; Demeure, Michael J.; Whitsett, Timothy G.; Gooden, Gerald C.; Bussey, Kimberly J.; Jung, Sungwon; Waibhav, Tembe; Kim, Seungchan; Salhia, Bodour

    2016-01-01

    Context Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options. Objective Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC. Design In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors. Results This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC. Conclusions DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors. PMID:26963385

  11. Stages of Adrenocortical Carcinoma

    MedlinePlus

    ... of Childhood Treatment for more information.) Having certain genetic conditions increases the risk of adrenocortical carcinoma. Anything ... can be a sign of disease. CT scan (CAT scan) : A procedure that makes a series of ...

  12. Untreated Congenital Adrenal Hyperplasia with 17-α Hydroxylase/17,20-Lyase Deficiency Presenting as Massive Adrenocortical Tumor

    PubMed Central

    Lee, Su Jin; Song, Je Eun; Hwang, Sena; Lee, Ji-Yeon; Park, Hye-Sun; Han, Seunghee

    2015-01-01

    Congenital adrenal hyperplasia (CAH) with 17α-hydroxylase/17,20-lyase deficiency is usually characterized by hypertension and primary amenorrhea, sexual infantilism in women, and pseudohermaphroditism in men. hypertension, and sexual infantilism in women and pseudohermaphroditism in men. In rare cases, a huge adrenal gland tumor can present as a clinical manifestation in untreated CAH. Adrenal cortical adenoma is an even more rare phenotype in CAH with 17α-hydroxylase/17,20-lyase deficiency. A 36-year-old female presented with hypertension and abdominal pain caused by a huge adrenal mass. Due to mass size and symptoms, left adrenalectomy was performed. After adrenalectomy, blood pressure remained high. Based on hormonal and genetic evaluation, the patient was diagnosed as CAH with 17α-hydroxylase/17,20-lyase deficiency. The possibility of a tumorous change in the adrenal gland due to untreated CAH should be considered. It is important that untreated CAH not be misdiagnosed as primary adrenal tumor as these conditions require different treatments. Adequate suppression of adrenocorticotropic hormone (ACTH) in CAH is also important to treat and to prevent the tumorous changes in the adrenal gland. Herein, we report a case of untreated CAH with 17α-hydroxylase/17,20-lyase deficiency presenting with large adrenal cortical adenoma and discuss the progression of adrenal gland hyperplasia due to inappropriate suppression of ACTH secretion. PMID:26248854

  13. A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells.

    PubMed

    Asakawa, Masahiro; Yoshimoto, Takanobu; Ota, Mitsutane; Numasawa, Mitsuyuki; Sasahara, Yuriko; Takeuchi, Takato; Nakano, Yujiro; Oohara, Norihiko; Murakami, Masanori; Bouchi, Ryotaro; Minami, Isao; Tsuchiya, Kyoichiro; Hashimoto, Koshi; Izumiyama, Hajime; Kawamura, Naoko; Kihara, Kazunori; Negi, Mariko; Akashi, Takumi; Eishi, Yoshinobu; Sasano, Hironobu; Ogawa, Yoshihiro

    2016-06-01

    A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case. PMID:26961704

  14. Human Adrenocortical Carcinoma Cell Lines

    PubMed Central

    Wang, Tao; Rainey, William E.

    2011-01-01

    Summary The human adrenal cortex secretes mineralocorticoids, glucocorticoids and adrenal androgens. These steroids are produced from unique cell types located within the three distinct zones of the adrenal cortex. Disruption of adrenal steroid production results in a variety of diseases that can lead to hypertension, metabolic syndrome, infertility and androgen excess. The adrenal cortex is also a common site for the development of adenomas, and rarely the site for the development of carcinomas. The adenomas can lead to diseases associated with adrenal steroid excess, while the carcinomas are particularly aggressive and have a poor prognosis. In vitro cell culture models provide an important tool to examine molecular and cellular mechanisms controlling both the normal and pathologic function of the adrenal cortex. Herein we discuss the human adrenocortical cell lines and their use as model systems for adrenal studies. PMID:21924324

  15. Treatment Option Overview (Adrenocortical Carcinoma)

    MedlinePlus

    ... of Childhood Treatment for more information.) Having certain genetic conditions increases the risk of adrenocortical carcinoma. Anything ... can be a sign of disease. CT scan (CAT scan) : A procedure that makes a series of ...

  16. Improved clonal and nonclonal growth of human, rat and bovine adrenocortical cells in culture.

    PubMed

    McAllister, J M; Hornsby, P J

    1987-10-01

    This report describes the development of a culture system for long-term growth and cloning of human fetal adrenocortical cells. Optimal conditions for stimulating clonal growth were determined by testing the efficacy of horse serum (HS), fetal bovine serum (FBS), fibroblast growth factor (FGF), epidermal growth factor (EGF), fibronectin, and a combination of growth factors, UltroSer G, in stimulating growth from low density. Optimal conditions for clonal growth were achieved using fibronectin-coated dishes and DME/F12 medium with 10% FBS, 10% HS, 2% UltroSer G, and 100 ng/ml FGF or 100 pM EGF. Conditions for growth at clonal density were found to be optimal for growth of early passage, nonclonal cultures at higher densities. The improved growth conditions used for cloning were shown to allow continued long-term growth of nonclonal human adrenocortical cells without fibroblast overgrowth. All cells in cultures grown in HS, FBS, and UltroSer G had morphologic characteristics of adrenocortical cells, whereas cells grown in FBS only rapidly became overgrown with fibroblasts. Clonal and nonclonal early passage human adrenocortical cells had similar mitogenic responses to FGF and EGF. Whereas FGF, EGF, and UltroSer G showed similar stimulation of DNA synthesis and clonal growth in human adrenocortical cells and human adrenal gland fibroblasts, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate stimulated growth only in adrenocortical cells and was strongly inhibitory to growth in fibroblasts. In both cell types, forskolin inhibited DNA synthesis. Human adrenocortical cell cultures were functional and synthesized cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. The improved growth conditions for clonal growth of human adrenocortical cells also provided optimal conditions for long-term growth of cultured rat adrenocortical cells and increased the cloning efficiency of cultured bovine adrenocortical cells. PMID:3667487

  17. Pubertal outcome in a female with virilizing adrenocortical carcinoma

    PubMed Central

    Breidbart, Emily; Cameo, Tamara; Garvin, James H.; Hibshoosh, Hanina

    2016-01-01

    Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months’ history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family. PMID:26812773

  18. Pubertal outcome in a female with virilizing adrenocortical carcinoma.

    PubMed

    Breidbart, Emily; Cameo, Tamara; Garvin, James H; Hibshoosh, Hanina; Oberfield, Sharon E

    2016-04-01

    Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months' history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family. PMID:26812773

  19. Methylation Status of Vitamin D Receptor Gene Promoter in Benign and Malignant Adrenal Tumors

    PubMed Central

    Pilon, Catia; Rebellato, Andrea; Urbanet, Riccardo; Guzzardo, Vincenza; Cappellesso, Rocco; Sasano, Hironobu; Fassina, Ambrogio

    2015-01-01

    We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5′ regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesis. PMID:26843863

  20. Plasma content of soluble fas antigen in patients with adrenal tumors and tumor-like pathologies.

    PubMed

    Kushlinskii, N E; Britvin, T A; Polyakova, G A; Abbasova, S G; Baronini, A A; Tishenina, R S; Molchanova, G S; Sel'chuk, V Yu; Pirogov, D A; Bogatyrev, O P; Lipkin, V M; Kalinin, A P

    2002-08-01

    We compared plasma content of soluble Fas antigen (sFas) in 59 patients with tumors and tumor-like pathologies of the adrenal cortex and medulla and 60 healthy donors (control). The incidence and content of sFas in the plasma from patients with adrenal tumors was significantly higher than in healthy donors. A direct correlation was found between sFas content and patient's age. The maximum sFas concentrations were found in patients with pheochromocytoma and aldosterone-producing adenoma. In patients with adrenocortical cancer plasma content of sFas was lower than in patients with tumors of other morphological types. Plasma sFas content in patients with adrenocortical cancer directly correlated with the size of tumors. Our results suggest that sFas plays a role in the pathogenesis of primary adrenal tumors. PMID:12459844

  1. Adrenocortical involution in rats during oestrus synchronisation with medroxyprogesterone.

    PubMed

    Fell, B F; Campbell, R M; Dinsdale, D

    1977-05-01

    Daily treatment of female rats with medroxyprogesterone acetate in aqueous suspension resulted in adrenocortical atrophy. The doses given were those used for oestrus synchronisation. Intramuscular injections of 2-0 mg medroxyprogesterone acetate were used to investigate the atrophic process. Adrenocortical involution was associated with extensive single cell deletion (apoptosis). It is suggested that theses changes were due to suppression of pituitary ACTH secretion. The cytological changes support the concept that single cell death plays an important role in organ remodelling. Biochemical determinations of DNA, RNA, protein and dry matter, and histological examination, did not reveal significant changes in the liver. PMID:560035

  2. Helsinki score-a novel model for prediction of metastases in adrenocortical carcinomas.

    PubMed

    Pennanen, Mirkka; Heiskanen, Ilkka; Sane, Timo; Remes, Satu; Mustonen, Harri; Haglund, Caj; Arola, Johanna

    2015-03-01

    Histopathologic diagnosis of adrenocortical tumors is based on adverse features that indicate malignant potential. Proliferation index has served as a supplemental tool in assessing the malignant potential of adrenocortical tumors. None of the current histologic classification systems can sufficiently accurately predict tumors' metastatic potential. We studied 177 consecutive adult patients with primary adrenocortical tumors operated on at Helsinki University Central Hospital between 1990 and 2003, all patients with a minimum follow-up of 5 years. We determined for each tumor the Weiss score and the Weiss revisited score by Aubert. Proliferation index was measured by computer-assisted image analysis. Each of the 9 Weiss criteria and the proliferation index were then used to establish a scoring system to predict the metastatic potential of adrenocortical tumors. Use of stepwise regression analysis led us to propose a calculation: 3 × mitotic rate (>5/50 high-power fields) + 5 × presence of necrosis + proliferation index in the most proliferative area of the tumor. Using a cutoff value of 8.5, the new scoring system was able to diagnose metastatic adrenocortical carcinoma with 100% sensitivity (confidence interval [CI], 76.8%-100%) and 99.4% specificity (CI, 96.6%-100%). The corresponding sensitivity of the Weiss system was 100% (CI, 76.8%-100%), and specificity, 90.2% (CI, 84.6%-94.3%), with sensitivity of the Weiss revisited system at 100% (CI, 76.8%-100%) and specificity at 96.9% (CI, 93.0%-99.0%). The new Helsinki score thus was accurate in predicting the metastatic potential of adrenocortical tumors. PMID:25582500

  3. Estrogen related receptor α (ERRα) a promising target for the therapy of adrenocortical carcinoma (ACC).

    PubMed

    Casaburi, Ivan; Avena, Paola; De Luca, Arianna; Chimento, Adele; Sirianni, Rosa; Malivindi, Rocco; Rago, Vittoria; Fiorillo, Marco; Domanico, Francesco; Campana, Carmela; Cappello, Anna Rita; Sotgia, Federica; Lisanti, Michael P; Pezzi, Vincenzo

    2015-09-22

    The pathogenesis of the adrenocortical cancer (ACC) involves integration of molecular signals and the interplay of different downstream pathways (i.e. IGFII/IGF1R, β-catenin, Wnt, ESR1). This tumor is characterized by limited therapeutic options and unsuccessful treatments. A useful strategy to develop an effective therapy for ACC is to identify a common downstream target of these multiple pathways. A good candidate could be the transcription factor estrogen-related receptor alpha (ERRα) because of its ability to regulate energy metabolism, mitochondrial biogenesis and signalings related to cancer progression. In this study we tested the effect of ERRα inverse agonist, XCT790, on the proliferation of H295R adrenocortical cancer cell line. Results from in vitro and in vivo experiments showed that XCT790 reduced H295R cell growth. The inhibitory effect was associated with impaired cell cycle progression which was not followed by any apoptotic event. Instead, incomplete autophagy and cell death by a necrotic processes, as a consequence of the cell energy failure, induced by pharmacological reduction of ERRα was evidenced. Our results indicate that therapeutic strategies targeting key factors such as ERRα that control the activity and signaling of bioenergetics processes in high-energy demanding tumors could represent an innovative/alternative therapy for the treatment of ACC. PMID:26312764

  4. Estrogen related receptor α (ERRα) a promising target for the therapy of adrenocortical carcinoma (ACC)

    PubMed Central

    Chimento, Adele; Sirianni, Rosa; Malivindi, Rocco; Rago, Vittoria; Fiorillo, Marco; Domanico, Francesco; Campana, Carmela; Cappello, Anna Rita; Sotgia, Federica; Lisanti, Michael P.; Pezzi, Vincenzo

    2015-01-01

    The pathogenesis of the adrenocortical cancer (ACC) involves integration of molecular signals and the interplay of different downstream pathways (i.e. IGFII/IGF1R, β-catenin, Wnt, ESR1). This tumor is characterized by limited therapeutic options and unsuccessful treatments. A useful strategy to develop an effective therapy for ACC is to identify a common downstream target of these multiple pathways. A good candidate could be the transcription factor estrogen-related receptor alpha (ERRα) because of its ability to regulate energy metabolism, mitochondrial biogenesis and signalings related to cancer progression. In this study we tested the effect of ERRα inverse agonist, XCT790, on the proliferation of H295R adrenocortical cancer cell line. Results from in vitro and in vivo experiments showed that XCT790 reduced H295R cell growth. The inhibitory effect was associated with impaired cell cycle progression which was not followed by any apoptotic event. Instead, incomplete autophagy and cell death by a necrotic processes, as a consequence of the cell energy failure, induced by pharmacological reduction of ERRα was evidenced. Our results indicate that therapeutic strategies targeting key factors such as ERRα that control the activity and signaling of bioenergetics processes in high-energy demanding tumors could represent an innovative/alternative therapy for the treatment of ACC. PMID:26312764

  5. Familial Adrenocortical Carcinoma in Association With Lynch Syndrome

    PubMed Central

    Challis, Benjamin G.; Kandasamy, Narayanan; Powlson, Andrew S.; Koulouri, Olympia; Annamalai, Anand Kumar; Happerfield, Lisa; Marker, Alison J.; Arends, Mark J.; Nik-Zainal, Serena

    2016-01-01

    Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes. PMID:27144940

  6. Adrenocortical Oncocytic Carcinoma: A Case Report and Review of the Histopathologic Diagnostic Criteria.

    PubMed

    Arik, Deniz; Canaz, Funda; Dündar, Emine

    2016-01-01

    Oncocytic tumors are rare in the adrenal gland. The histopathological diagnosis of adrenocortical carcinoma is difficult due to the lack of precise diagnostic criteria for malignancy. A 44-year-old man was admitted to our hospital with left flank pain. Radiologically an adrenal mass was detected. After the excision and histopathologic evaluation of the mass, a diagnosis of adrenocortical oncocytic carcinoma was made. At least one of the features of more than 5 mitoses in 50 high power fields, atypical mitotic figures or venous invasion is required for the diagnosis of malignancy in adrenocortical tumors. It has been suggested that tumors that have more than one of the minor criteria of large size ( > 10 cm or > 200 gr), necrosis, capsular or sinusoidal invasion, should be evaluated as having uncertain malignant potential. PMID:27562395

  7. Isolation of rat adrenocortical mitochondria

    SciTech Connect

    Solinas, Paola; Fujioka, Hisashi; Tandler, Bernard; Hoppel, Charles L.

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A method for isolation of adrenocortical mitochondria from the adrenal gland of rats is described. Black-Right-Pointing-Pointer The purified isolated mitochondria show excellent morphological integrity. Black-Right-Pointing-Pointer The properties of oxidative phosphorylation are excellent. Black-Right-Pointing-Pointer The method increases the opportunity of direct analysis of adrenal mitochondria from small animals. -- Abstract: This report describes a relatively simple and reliable method for isolating adrenocortical mitochondria from rats in good, reasonably pure yield. These organelles, which heretofore have been unobtainable in isolated form from small laboratory animals, are now readily accessible. A high degree of mitochondrial purity is shown by the electron micrographs, as well as the structural integrity of each mitochondrion. That these organelles have retained their functional integrity is shown by their high respiratory control ratios. In general, the biochemical performance of these adrenal cortical mitochondria closely mirrors that of typical hepatic or cardiac mitochondria.

  8. H295R Human Adrenocortical Carcinoma Cells as a Screening Platform for Steroidogenesis (NC SOT)

    EPA Science Inventory

    Proper biosynthesis and metabolism of steroid hormones is essential for development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carc...

  9. A Rare Case of Functioning Adrenocortical Oncocytoma Presenting as Cushing Syndrome

    PubMed Central

    Tartaglia, Nicola; Cianci, Pasquale; Altamura, Amedeo; Lizzi, Vincenzo; Vovola, Fernanda; Fersini, Alberto; Ambrosi, Antonio; Neri, Vincenzo

    2016-01-01

    Functioning adrenocortical oncocytoma is very rare neoplasm. It is usually nonfunctional and benign and incidentally detected. Generally, these tumors originate in the kidneys, thyroid, parathyroid, and salivary or pituitary glands; they have also been reported in other sites including choroid plexus, respiratory tract, and larynx. Histologically, they are characterized by cells with eosinophilic granular cytoplasm and numerous packed mitochondria. We reported a case of a 44-year-old female who presented with Cushing syndrome for hypersecretion of cortisol due to adrenocortical oncocytoma. Magnetic resonance of abdomen revealed a right adrenal mass. Laparoscopic adrenalectomy was performed and the tumor was pathologically confirmed as benign adrenocortical oncocytoma. After surgical treatment, Cushing's syndrome resolved. PMID:26989553

  10. A Rare Case of Functioning Adrenocortical Oncocytoma Presenting as Cushing Syndrome.

    PubMed

    Tartaglia, Nicola; Cianci, Pasquale; Altamura, Amedeo; Lizzi, Vincenzo; Vovola, Fernanda; Fersini, Alberto; Ambrosi, Antonio; Neri, Vincenzo

    2016-01-01

    Functioning adrenocortical oncocytoma is very rare neoplasm. It is usually nonfunctional and benign and incidentally detected. Generally, these tumors originate in the kidneys, thyroid, parathyroid, and salivary or pituitary glands; they have also been reported in other sites including choroid plexus, respiratory tract, and larynx. Histologically, they are characterized by cells with eosinophilic granular cytoplasm and numerous packed mitochondria. We reported a case of a 44-year-old female who presented with Cushing syndrome for hypersecretion of cortisol due to adrenocortical oncocytoma. Magnetic resonance of abdomen revealed a right adrenal mass. Laparoscopic adrenalectomy was performed and the tumor was pathologically confirmed as benign adrenocortical oncocytoma. After surgical treatment, Cushing's syndrome resolved. PMID:26989553

  11. Klatskin tumor--results of surgical therapy.

    PubMed

    Zovak, Mario; Doko, Marko; Glavan, Elizabet; Hochstädter, Hrvoje; Roić, Goran; Ljubicić, Neven

    2004-06-01

    Between January 1st 1990 and December 31st 1999, 24 patients affected by Klatskin tumor underwent operation in our department of surgery. According to Bismuth's classification, there were 0 (0%) type I, 5 (21%) type II, 6 (25%) type IIIa, 4 (17%) type IIIb and 9 (37%) type IV tumors. Five patients (21%) were treated by curative resection (group I) while in 14 patients (58%) palliative surgical procedure was performed (group II). In 5 cases (21%) the extension of malignancy did not allowed any procedure (group III). Curative resection for malignant tumors of the hepatic duct bifurcation included wide tumor excision and bile duct resection at the liver hilum (with wedge hepatic resection in one patient) and creation of biliary-enteric anastomosis. Palliative surgical procedure included stent insertion. Jaundice was completely relieved in all patients undergoing resection, since 3 patients (21%) after stenting hadn't satisfactory biliary drainage. There was 1 (20%) perioperative death in the group 1, while in group 2, 5 patients (36%) died postoperatively. In this series, the mean postoperative survival of all patients was 16 months. The mean postoperative survival of patients undergoing localized tumor resection with curative intent was 38 months, in contrast to 10 months for those undergoing operative stent insertion. in addition, only 1 patient from group III, in whom only exploratory surgery were performed survived 7 months, while other 4 patients died in the hospital. This retrospective review suggests that aggressive surgical treatment could improve survival and quality of life in patients suffering from Klatskin tumor. PMID:15636089

  12. Paracrine control of steroidogenesis by serotonin in adrenocortical neoplasms.

    PubMed

    Lefebvre, H; Duparc, C; Prévost, G; Zennaro, M C; Bertherat, J; Louiset, E

    2015-06-15

    Serotonin (5-hydroxytryptamine; 5-HT) is able to activate the hypothalamo-pituitary-adrenal axis via multiple actions at different levels. In the human adrenal gland, 5-HT, released by subcapsular mast cells, stimulates corticosteroid production through a paracrine mode of communication which involves 5-HT receptor type 4 (5-HT4) primarily located in zona glomerulosa. As a result, 5-HT is much more efficient to stimulate aldosterone secretion than cortisol release in vitro and administration of 5-HT4 receptor agonists to healthy individuals is followed by an increase in plasma aldosterone levels without any change in plasma cortisol concentrations. Interestingly, adrenocortical hyperplasias and tumors responsible for corticosteroid hypersecretion exhibit various cellular and molecular defects which tend to reinforce the intraadrenal serotonergic tone. These pathophysiological mechanisms, which are summarized in the present review, include an increase in adrenal 5-HT production and overexpression of 5-HT receptors in adrenal neoplastic tissues. Altogether, these data support the concept of adrenal serotonergic paracrinopathy and suggest that 5-HT and its receptors may constitute valuable targets for pharmacological treatments of primary adrenal diseases. PMID:25433205

  13. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants.

    PubMed

    de Krijger, Ronald R; Papathomas, Thomas G

    2012-01-01

    Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. According to WHO classification 2004, ACC variants include oncocytic ACCs, myxoid ACCs and ACCs with sarcomatous areas. Herein, we provide a comprehensive review of these rare subtypes of adrenocortical malignancy and emphasize their clinicopathological features with the aim of elucidating aspects of diagnostic categorization, differential diagnostics and biological behavior. The issue of current terminology, applied to biphasic tumors with pleomorphic, sarcomatous or sarcomatoid elements arising in adrenal cortex, is also discussed. We additionally present emerging evidence concerning the adrenal cortical tumorigenesis and the putative adenoma-carcinoma sequence as well. PMID:22086150

  14. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues.

    PubMed

    Ziegler, C G; Brown, J W; Schally, A V; Erler, A; Gebauer, L; Treszl, A; Young, L; Fishman, L M; Engel, J B; Willenberg, H S; Petersenn, S; Eisenhofer, G; Ehrhart-Bornstein, M; Bornstein, S R

    2009-09-15

    Peptide analogues targeting various neuropeptide receptors have been used effectively in cancer therapy. A hallmark of adrenocortical tumor formation is the aberrant expression of peptide receptors relating to uncontrolled cell proliferation and hormone overproduction. Our microarray results have also demonstrated a differential expression of neuropeptide hormone receptors in tumor subtypes of human pheochromocytoma. In light of these findings, we performed a comprehensive analysis of relevant receptors in both human adrenomedullary and adrenocortical tumors and tested the antiproliferative effects of peptide analogues targeting these receptors. Specifically, we examined the receptor expression of somatostatin-type-2 receptor, growth hormone-releasing hormone (GHRH) receptor or GHRH receptor splice variant-1 (SV-1) and luteinizing hormone-releasing hormone (LHRH) receptor at the mRNA and protein levels in normal human adrenal tissues, adrenocortical and adrenomedullary tumors, and cell lines. Cytotoxic derivatives of somatostatin AN-238 and, to a lesser extent, AN-162, reduced cell numbers of uninduced and NGF-induced adrenomedullary pheochromocytoma cells and adrenocortical cancer cells. Both the splice variant of GHRH receptor SV-1 and the LHRH receptor were also expressed in adrenocortical cancer cell lines but not in the pheochromocytoma cell line. The GHRH receptor antagonist MZ-4-71 and LHRH antagonist Cetrorelix both significantly reduced cell growth in the adrenocortical cancer cell line. In conclusion, the expression of receptors for somatostatin, GHRH, and LHRH in the normal human adrenal and in adrenal tumors, combined with the growth-inhibitory effects of the antitumor peptide analogues, may make possible improved treatment approaches to adrenal tumors. PMID:19717419

  15. Magnetic Resonance Elastography of Liver Tumors- Preliminary Results

    PubMed Central

    Venkatesh, Sudhakar K; Yin, Meng; Glockner, James F; Takahashi, Naoki; Araoz, Philip A; Talwalkar, Jayant A; Ehman, Richard L

    2010-01-01

    Aim To evaluate the potential value of magnetic resonance elastography (MRE) for characterizing solid liver tumors. Materials and Methods Forty-four liver tumors (metastases-14, hepatocellular carcinoma- 12, hemangioma-9, cholangiocarcinoma-5, focal nodular hyperplasia-3, and hepatic adenoma-1) were evaluated with MRE. MRE was performed on a 1.5 T scanner with a modified phase-contrast, gradient echo sequence to collect axial wave images sensitized along the through-plane motion direction. The tumors were identified in T2-, T1-weighted and gadolinium enhanced T1-weighted images and the MRE images were obtained through the tumor. A stiffness map (elastogram) was generated by an automated process using an inversion algorithm. The mean shear stiffness of the tumor was calculated using a manually specified region of interest placed over the tumor in the stiffness map. The stiffness value of non-tumor bearing hepatic parenchyma was also calculated. Statistical analysis was performed on the stiffness values for differentiation between normal liver, fibrotic liver, benign tumors and malignant tumors. Results Malignant liver tumors had significantly higher mean shear stiffness than benign tumors, fibrotic liver and normal liver (10.1kPa vs. 2.7kpa (p<0.001), vs. 5.9kPa (p<0.001) and vs. 2.3kPa (p<0.001) respectively). Fibrotic livers had stiffness values overlapping both the benign and malignant tumors. Cut-off values of 5kPa accurately differentiate malignant tumors from benign tumors and normal liver parenchyma in this preliminary investigation. Conclusions MR elastography is a promising, non-invasive technique for assessing solid liver tumors. MRE may provide new, quantitative tissue characterization parameters for differentiating benign and malignant liver tumors. PMID:18492904

  16. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model

    PubMed Central

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology. PMID:26885453

  17. Treatment Options by Stage (Adrenocortical Carcinoma)

    MedlinePlus

    ... of Childhood Treatment for more information.) Having certain genetic conditions increases the risk of adrenocortical carcinoma. Anything ... can be a sign of disease. CT scan (CAT scan) : A procedure that makes a series of ...

  18. Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

    PubMed Central

    Schillebeeckx, Maximiliaan; Pihlajoki, Marjut; Gretzinger, Elisabeth; Yang, Wei; Thol, Franziska; Hiller, Theresa; Löbs, Ann-Kathrin; Röhrig, Theresa; Schrade, Anja; Cochran, Rebecca; Jay, Patrick Y.; Heikinheimo, Markku; Mitra, Robi D.; Wilson, David B.

    2014-01-01

    Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both “male-specific” (Spinlw1) and “female-specific” (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing. PMID:25289806

  19. 2D-DIGE proteomic analysis identifies new potential therapeutic targets for adrenocortical carcinoma

    PubMed Central

    Armignacco, Roberta; Ercolino, Tonino; Canu, Letizia; Baroni, Gianna; Nesi, Gabriella; Galli, Andrea; Mannelli, Massimo; Luconi, Michaela

    2015-01-01

    Adrenocortical carcinoma (ACC) is a rare aggressive tumor with poor prognosis when metastatic at diagnosis. The tumor biology is still mostly unclear, justifying the limited specificity and efficacy of the anti-cancer drugs currently available. This study reports the first proteomic analysis of ACC by using two-dimensional-differential-in-gel-electrophoresis (2D-DIGE) to evaluate a differential protein expression profile between adrenocortical carcinoma and normal adrenal. Mass spectrometry, associated with 2D-DIGE analysis of carcinomas and normal adrenals, identified 22 proteins in 27 differentially expressed 2D spots, mostly overexpressed in ACC. Gene ontology analysis revealed that most of the proteins concurs towards a metabolic shift, called the Warburg effect, in adrenocortical cancer. The differential expression was validated by Western blot for Aldehyde-dehydrogenase-6-A1,Transferrin, Fascin-1,Lamin A/C,Adenylate-cyclase-associated-protein-1 and Ferredoxin-reductase. Moreover, immunohistochemistry performed on paraffin-embedded ACC and normal adrenal specimens confirmed marked positive staining for all 6 proteins diffusely expressed by neoplastic cells, compared with normal adrenal cortex. In conclusion, our preliminary findings reveal a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes, thus suggesting the Warburg effect also occurs in ACC. These proteins may represent promising novel ACC biomarkers and potential therapeutic targets if validated in larger cohorts of patients. PMID:25691058

  20. Effects of ToxCast Phase I Chemicals on Steroidogenesis in H295R Human Adrenocortical Carcinoma cells (SOT)

    EPA Science Inventory

    Steroid hormones are essential for proper development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carcinoma cells were used to evalu...

  1. Maternal dietary restriction during the periconceptional period in normal-weight or obese ewes results in adrenocortical hypertrophy, an up-regulation of the JAK/STAT and down-regulation of the IGF1R signaling pathways in the adrenal of the postnatal lamb.

    PubMed

    Zhang, Song; Morrison, Janna L; Gill, Amreet; Rattanatray, Leewen; MacLaughlin, Severence M; Kleemann, David; Walker, Simon K; McMillen, I Caroline

    2013-12-01

    Maternal dietary restriction during the periconceptional period results in an increase in adrenal growth and in the cortisol stress response in the offspring. The intraadrenal mechanisms that result in the programming of these changes are not clear. Activation of the IGF and the signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways regulate adrenal growth. We have used an embryo transfer model in sheep to investigate the impact of exposure to either dietary restriction in normal or obese mothers or to maternal obesity during the periconceptional period on adrenal growth and function in the offspring. We assessed the adrenal abundance of key signaling molecules in the IGF-I and Janus kinase/STAT/SOCS pathways including IGF-I receptor, IGF-II receptor, Akt, mammalian target of rapamycin, ribosomal protein S6, eukaryotic translation initiation factor 4E-binding protein 1, eukaryotic translation initiation factor 4E, STAT1, STAT3, STAT5, SOCS1, and SOCS3 in female and male postnatal lambs. Maternal dietary restriction in the periconceptional period resulted in the hypertrophy of the adrenocortical cells in the zona fasciculata-reticularis and an up-regulation in STAT1, phospho-STAT1, and phospho-STAT3 (Ser727) abundance and a down-regulation in IGF-I receptor, Akt, and phospho-Akt abundance in the adrenal cortex of the postnatal lamb. These studies highlight that weight loss around the time of conception, independent of the starting maternal body weight, results in the activation of the adrenal Janus kinase/STAT pathway and adrenocortical hypertrophy. Thus, signals of adversity around the time of conception have a long-term impact on the mechanisms that regulate adrenocortical growth. PMID:24108072

  2. Maternal Dietary Restriction During the Periconceptional Period in Normal-Weight or Obese Ewes Results in Adrenocortical Hypertrophy, an Up-Regulation of the JAK/STAT and Down-Regulation of the IGF1R Signaling Pathways in the Adrenal of the Postnatal Lamb

    PubMed Central

    Zhang, Song; Morrison, Janna L.; Gill, Amreet; Rattanatray, Leewen; MacLaughlin, Severence M.; Kleemann, David; Walker, Simon K.

    2013-01-01

    Maternal dietary restriction during the periconceptional period results in an increase in adrenal growth and in the cortisol stress response in the offspring. The intraadrenal mechanisms that result in the programming of these changes are not clear. Activation of the IGF and the signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways regulate adrenal growth. We have used an embryo transfer model in sheep to investigate the impact of exposure to either dietary restriction in normal or obese mothers or to maternal obesity during the periconceptional period on adrenal growth and function in the offspring. We assessed the adrenal abundance of key signaling molecules in the IGF-I and Janus kinase/STAT/SOCS pathways including IGF-I receptor, IGF-II receptor, Akt, mammalian target of rapamycin, ribosomal protein S6, eukaryotic translation initiation factor 4E-binding protein 1, eukaryotic translation initiation factor 4E, STAT1, STAT3, STAT5, SOCS1, and SOCS3 in female and male postnatal lambs. Maternal dietary restriction in the periconceptional period resulted in the hypertrophy of the adrenocortical cells in the zona fasciculata-reticularis and an up-regulation in STAT1, phospho-STAT1, and phospho-STAT3 (Ser727) abundance and a down-regulation in IGF-I receptor, Akt, and phospho-Akt abundance in the adrenal cortex of the postnatal lamb. These studies highlight that weight loss around the time of conception, independent of the starting maternal body weight, results in the activation of the adrenal Janus kinase/STAT pathway and adrenocortical hypertrophy. Thus, signals of adversity around the time of conception have a long-term impact on the mechanisms that regulate adrenocortical growth. PMID:24108072

  3. Molecular pathways of human adrenocortical carcinoma - translating cell signalling knowledge into diagnostic and treatment options.

    PubMed

    Szyszka, Paulina; Grossman, Ashley B; Diaz-Cano, Salvador; Sworczak, Krzysztof; Dworakowska, Dorota

    2016-01-01

    Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440). PMID:27387247

  4. Androgen receptor-mediated regulation of adrenocortical activity in the sand rat, Psammomys obesus.

    PubMed

    Benmouloud, Abdelouafi; Amirat, Zaina; Khammar, Farida; Patchev, Alexandre V; Exbrayat, Jean M; Almeida, Osborne F X

    2014-12-01

    The wild sand rat, Psammomys obesus, displays seasonal variations in adrenocortical activity that parallel those of testicular activity, indicating functional cross-talk between the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes. In the present study, we examined androgen receptor (AR)-mediated actions of testicular steroids in the regulation of adrenocortical function in the sand rat. Specifically, we examined the expression of AR in the adrenal cortex, as well as adrenal apoptosis in male sand rats that had been surgically castrated or castrated and supplemented with testosterone; biochemical indices of adrenocortical function and hormone profiles were also measured. Orchiectomy was followed by an increase in adrenocorticotropic hormone secretion from the anterior pituitary and subsequently, increased adrenocortical activity; the latter was evidenced by orchiectomy-induced increases in the adrenal content of cholesterol and lipids as well as adrenal hypertrophy (seen as an elevation of the RNA/DNA ratio). Further, androgen deprivation respectively up- and downregulated the incidence of apoptosis within the glucocorticoid-producing zona fasciculata and sex steroid-producing zona reticularis. Interestingly, orchiectomy resulted in increased expression of AR in the zona fasciculata. All of the orchiectomy-induced cellular and biochemical responses were reversible after testosterone substitution therapy. Together, these data suggest that adrenocortical activity in the sand rat is seasonally modulated by testicular androgens that act through AR located in the adrenal cortex itself. PMID:25179180

  5. Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma

    PubMed Central

    de Sousa, Gabriela Resende Vieira; Ribeiro, Tamaya C.; Faria, Andre M.; Mariani, Beatriz M.P.; Lerario, Antonio M.; Zerbini, Maria Claudia N.; Soares, Iberê C.; Wakamatsu, Alda; Alves, Venancio A.F.; Mendonca, Berenice B.; Fragoso, Maria Candida B.V.; Latronico, Ana Claudia; Almeida, Madson Q.

    2015-01-01

    Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas. PMID:26087193

  6. Carney complex presenting with a unilateral adrenocortical nodule: a case report

    PubMed Central

    2014-01-01

    Introduction Carney complex is an autosomal dominant syndrome with multiple neoplasms in different sites, including myxomas, endocrine tumors and lentigines lesions. To the best of our knowledge, this is the first report of Carney complex presenting with a unilateral adrenal adenoma associated with a pituitary incidentaloma. Case presentation A 27-year-old Iranian woman was referred to our endocrinology clinic with amenorrhea and hirsutism, further confirming a diagnosis of adrenocorticotropic hormone-independent Cushing’s syndrome. The cause was believed to be a right adrenocortical adenoma based on a computed tomography scan. Our patient underwent a right laparoscopic adrenalectomy and pathological examination revealed pigmented micronodular adrenal hyperplasia. Pituitary magnetic resonance imaging also documented a microadenoma that was considered to be an incidentaloma based on normal pituitary function tests. Recurrence of hypercortisolism led to a left laparoscopic adrenalectomy, providing further evidence for the diagnosis of primary pigmented nodular adrenocortical disease. Carney complex was established in light of her history of cardiac myxomas. Conclusion We present what we believe to be the first case of Carney complex presenting with a unilateral adrenocortical adenoma in association with a pituitary incidentaloma. Although primary pigmented nodular adrenocortical disease is rare as a component of Carney complex, it should be considered in the differential diagnosis of Cushing's syndrome. Rarely, adrenal and pituitary imaging can be misleading. PMID:24499519

  7. The role of mothers’ and fathers’ adrenocortical reactivity in spillover between interparental conflict and parenting practices

    PubMed Central

    Sturge-Apple, Melissa L.; Davies, Patrick T.; Cicchetti, Dante; Cummings, E. Mark

    2010-01-01

    Guided by the affective spillover hypothesis, the present study examined the mediational role of parental adrenocortical reactivity to interparental conflict in explaining associations between interparental conflict and subsequent changes in mothers’ and fathers’ parenting practices over a 2 year period in a sample of 202 parents and their six year old children. Results of autoregressive, path models indicated that marital withdrawal was associated with increases in adrenocortical reactivity to conflict for mothers but not fathers. Furthermore, elevated adrenocortical reactivity in turn predicted greater psychologically controlling parenting practices and inconsistent discipline over time for mothers, but was not associated with changes in maternal warmth. Implications for clinicians and therapists working with maritally distressed parents and families are discussed. PMID:19364215

  8. No Detectable Hypoxia in Malignant Salivary Gland Tumors: Preliminary Results

    SciTech Connect

    Wijffels, Karien; Hoogsteen, Ilse J.; Lok, Jasper; Rijken, Paulus F.J.W.; Marres, Henri A.M.; Wilde, Peter C.M. de; Kogel, Albert J. van der; Kaanders, Johannes H.A.M.

    2009-04-01

    Purpose: Hypoxia is detected in most solid tumors and is associated with malignant progression and adverse treatment outcomes. However, the oxygenation status of malignant salivary gland tumors has not been previously studied. The aim of this study was to investigate the potential clinical relevance of hypoxia in this tumor type. Methods and Materials: Twelve patients scheduled for surgical resection of a salivary gland tumor were preoperatively injected with the hypoxia marker pimonidazole and the proliferation marker iododeoxyuridine. Tissue samples of the dissected tumor were immunohistochemically stained for blood vessels, pimonidazole, carbonic anhydrase-IX, glucose transporters-1 and -3 (Glut-1, Glut-3), hypoxia-inducible factor-1{alpha}, iododeoxyuridine, and epidermal growth factor receptor. The tissue sections were quantitatively assessed by computerized image analysis. Results: The tissue material from 8 patients was of sufficient quality for quantitative analysis. All tumors were negative for pimonidazole binding, as well as for carbonic anhydrase-IX, Glut-1, Glut-3, and hypoxia-inducible factor-1{alpha}. The vascular density was high, with a median value of 285 mm{sup -2} (range, 209-546). The iododeoxyuridine-labeling index varied from <0.1% to 12.2% (median, 2.2%). Epidermal growth factor receptor expression levels were mostly moderate to high. In one-half of the cases, nuclear expression of epidermal growth factor receptor was observed. Conclusion: The absence of detectable pimonidazole binding, as well as the lack of expression of hypoxia-associated proteins in all tumors, indicates that malignant salivary gland tumors are generally well oxygenated. It is unlikely that hypoxia is a relevant factor for their clinical behavior and treatment responsiveness.

  9. Steroidogenic enzyme profile in an androgen-secreting adrenocortical oncocytoma associated with hirsustism

    PubMed Central

    Tetsi Nomigni, Milène; Ouzounian, Sophie; Benoit, Alice; Vadrot, Jacqueline; Tissier, Frédérique; Renouf, Sylvie; Lefebvre, Hervé; Christin-Maitre, Sophie; Louiset, Estelle

    2015-01-01

    Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH. PMID:26034121

  10. Paediatric Nonfunctioning Adrenocortical Carcinoma with Extension up to Right-Side Heart: Cardiac Surgery Approach

    PubMed Central

    Quarti, Andrea; Surace, Chiara; Pozzi, Marco

    2016-01-01

    Adrenocortical carcinoma is a rare malignancy. Due to late diagnosis and no adequate effective adjuvant treatment, prognosis remains poor. Only approximately 30% of these malignancies are confined to the adrenal gland when they are diagnosed, as these tumors tend to be found years after their genesis. Cardiac involvement of adrenal carcinoma is very rare. We report a rare case of a 7-year-old female with right adrenal cortical carcinoma, involving the right-side heart. PMID:27493811

  11. Effects of centrifugation on gonadal and adrenocortical steroids in rats

    NASA Technical Reports Server (NTRS)

    Kakihana, R.; Butte, J. C.

    1980-01-01

    Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.

  12. Adrenocortical suppression in cats given megestrol acetate.

    PubMed

    Chastain, C B; Graham, C L; Nichols, C E

    1981-12-01

    Megestrol acetate was given orally to 8 cats at a dose of 2.5 mg every other day for 2 weeks and to 8 cats at a dose of 5.0 mg every day for 2 weeks. Four cats were designated nontreated controls. Pre-ACTH-stimulated plasma concentrations of cortisol (hydrocortisone) and ACTH-stimulated cortisol and tolerance to large-dose glucose infusion (IV) were determined on each of the 20 cats given megestrol acetate. Cats were restrained with acepromazine maleate and ketamine hydrochloride during blood sample collection and large-dose glucose infusion. Adrenocortical function and tolerance to large-dose glucose infusion were reevaluated for 4 weeks--after 1st and 2nd weeks of megestrol acetate treatment of the treated groups, and after 1st and 2nd weeks when treatment was stopped (ie, experiment weeks 3 and 4). Each week a cat from the control group and 2 cats from the 2 treated groups were selected to determine the changes occurring during the experiment for that week; after collection of plasma samples, each week's 5 selected cats were euthanatized and necropsied. Significant impairment of adrenocortical function and alteration of adrenocortical morphology occurred with both treated groups. The most severe adrenocortical alterations occurred in the cats 1 week after megestrol acetate was no longer given (ie, experiment week 3). Megestrol acetate-induced adrenocortical suppression contributed to the death of 1 cat. It was concluded that if stress occurs to cats on treatment or soon after treatment with megestrol acetate, glucocorticoids should be supplemented. The effects of megestrol acetate on glucose tolerance were overshadowed by the unforeseen intolerance caused by chemical restraint with acepromazine maleate and ketamine hydrochloride. PMID:6280517

  13. The Effects of Morning Naps, Car Trips, and Maternal Separation on Adrenocortical Activity in Human Infants.

    ERIC Educational Resources Information Center

    Larson, Mary C.; And Others

    1991-01-01

    Three studies examined adrenocortical activity in infants. Morning naps were associated with decreases in salivary cortisol. Riding for 40 minutes in a car lowered salivary cortisol concentrations. Thirty minutes of maternal separation in the laboratory resulted in higher salivary cortisol concentrations than did 30 minutes of play with the mother…

  14. Percutaneous Ablation of Adrenal Tumors

    PubMed Central

    Venkatesan, Aradhana M.; Locklin, Julia; Dupuy, Damian E.; Wood, Bradford J.

    2010-01-01

    Adrenal tumors comprise a broad spectrum of benign and malignant neoplasms, and include functional adrenal adenomas, pheochromocytomas, primary adrenocortical carcinoma and adrenal metastases. Percutaneous ablative approaches that have been described and used in the treatment of adrenal tumors include percutaneous radiofrequency ablation (RFA), cryoablation, microwave ablation and chemical ablation. Local tumor ablation in the adrenal gland presents unique challenges, secondary to the adrenal gland’s unique anatomic and physiologic features. The results of clinical series employing percutaneous ablative techniques in the treatment of adrenal tumors are reviewed in this article. Clinical and technical considerations unique to ablation in the adrenal gland are presented, including approaches commonly used in our practices, and risks and potential complications are discussed. PMID:20540918

  15. Bilateral Adrenocortical Masses Producing Aldosterone and Cortisol Independently

    PubMed Central

    Lee, Seung-Eun; Lee, You-Bin; Seok, Hyeri; Shin, In Seub; Eun, Yeong Hee; Kim, Jung-Han; Oh, Young Lyun

    2015-01-01

    A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol-producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses. PMID:26248855

  16. Bilateral Adrenocortical Masses Producing Aldosterone and Cortisol Independently.

    PubMed

    Lee, Seung Eun; Kim, Jae Hyeon; Lee, You Bin; Seok, Hyeri; Shin, In Seub; Eun, Yeong Hee; Kim, Jung Han; Oh, Young Lyun

    2015-12-01

    A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol-producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses. PMID:26248855

  17. Giant adrenal pseudocyst harbouring adrenocortical cancer

    PubMed Central

    Wilkinson, Michael; Fanning, Deirdre Mary; Moloney, James; Flood, Hugh

    2011-01-01

    The authors report a very rare case of adreno-cortical carcinoma arising in a giant adrenal pseudocyst. A 64-year-old woman presented to the emergency department with a 6 week history of progressively worsening severe left abdominal pain, anorexia, anergia and constipation. On examination, she was cachectic with tenderness over the left abdomen and flank. Medical history was significant for gastritis and anaemia. During her investigation, a well-defined para-renal 12×6 centimetre multi-loculated cyst, of uncertain origin was identified on CT. Ultrasound-guided biopsy was not diagnostic. MRI showed the cyst to be likely adrenal in origin. Serum and urinary catecholamines were unremarkable. At laparotomy an unresectable large, tense, fixed, cystic mass was seen to occupy the left side of the abdomen. The cyst was de-roofed. Pathology showed a high-grade poorly differentiated adreno-cortical carcinoma with a pseudo-capsule. She died 2 months postoperatively. PMID:22679267

  18. Open adrenalectomy for medium sized adrenocortical tumour: How I do it?

    PubMed Central

    Sameh, Wael M.; Kotb, Ahmed Fouad

    2015-01-01

    Introduction: The aim of our work was to report our experience in managing cases with medium-sized adrenocortical carcinoma by the high retroperitoneal extra pleural approach. Methods: During the past 2 years, 10 patients with suspected adrenocortical carcinoma were managed by our technique: the high supra 10th rib, retroperitoneal extra pleural approach. We included cases with 5 to 10 cm adrenal masses, suspected as adrenocortical carcinoma. Results: The mean patient age was 38 years (range: 26–44), the median tumour volume was 7 cm (range: 5–8). Of the 10 patients, 7 were female. Of the patients, 6 had right- and 4 had left-sided tumours. Intraoperatively, all cases had proper surgical removal, with no apparent residual tumour tissue. No single patient required a chest tube or developed respiratory problems. There were no major vascular injuries during surgery. We did not compare our findings to the standard lateral or subcostal approaches, as in our institution we adopt this high lateral approach for medium-sized tumours, while managing larger tumours with transperitoneal subcostal approach and smaller tumours laparoscopically. Conclusion: The high supra 10th lateral retroperitoneal, extra pleural approach is a safe, doable technique, allowing easy access to medium-sized suprarenal tumours and its vasculature, for cases suspected to be adrenocortical carcinoma. PMID:26029297

  19. Mechanism of adrenocortical toxicity induced by quinocetone and its bidesoxy-quinocetone metabolite in porcine adrenocortical cells in vitro.

    PubMed

    Wang, Xu; Wan, Dan; Ihsan, Awais; Liu, Qianying; Cheng, Guyue; Li, Juan; Liu, Zhenli; Yuan, Zonghui

    2015-10-01

    Quinocetone (QCT) is a new feeding antibacterial agent in the QdNOs family. The mechanism of its adrenal toxicity is far from clear. This study was conducted to estimate the adrenal cell damage induced by QCT and its bidesoxy-quinocetone (B-QCT) metabolite and to further investigate their mechanisms. Following doses of QCT increasing from 5 to 50 μM, cell apoptosis and necrosis, mitochondrial dysfunction and redox imbalance were observed in porcine adrenocortical cells. The mRNA levels of the six components of intermediary enzymes and the adrenal renin-angiotensin-aldosterone system (RAAS) displayed a dysregulation induced by QCT, indicating that QCT might influence aldosterone secretion not only through the upstream of the production but also through the downstream of the adrenal RAAS pathway. In contrast, B-QCT had few toxic effects on the cell apoptosis, mitochondrial dysfunction and redox imbalance. Moreover, LCMS-IT-TOF analysis showed that no desoxy metabolites of QCT were found in either cell lysate or supernatant samples. In conclusion, we reported on the cytotoxicity in porcine adrenocortical cells exposed to QCT via oxidative stress, which raised awareness that its toxic effects resulted from N→O groups, and its toxic mechanism might involve the interference of the steroid hormone biosynthesis pathway. PMID:26296292

  20. microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges

    PubMed Central

    Cherradi, Nadia

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors, such as the IGF2 pathway, the Wnt pathway, and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation, and microRNA (miRNA) profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. miRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated miRNAs to the pathogenesis of ACC is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some miRNAs have been shown to carry potential diagnostic and prognostic values, while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne miRNAs signatures, analyses of small cohorts of patients with ACC suggest that circulating miRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating miRNAs in ACC patients, while emphasizing their potential significance in pathogenic pathways in light of recent insights into the role of miRNAs in shaping the tumor microenvironment. PMID:26834703

  1. Syndromes resulting from ectopic hormone-producing tumors.

    PubMed

    Gomez-Uria, A; Pazianos, A G

    1975-03-01

    Among the malignant tumors of nonendocrine origin that are capable of producing polypeptide hormones and of manifesting as different endocrine syndromes discussed here are ectopic ACTH syndrome, SIADH, and ectopic gonadotropin-producing tumors. PMID:163945

  2. High-density lipoprotein is a potential growth factor for adrenocortical cells

    SciTech Connect

    Murao, Koji . E-mail: mkoji@kms.ac.jp; Imachi, Hitomi; Cao, Wenming; Yu, Xiao; Li, Junhua; Yoshida, Kazuya; Ahmed, Rania A.M.; Matsumoto, Kensuke; Nishiuchi, Takamasa; Ishida, Toshihiko; Wong, Norman C.W.

    2006-05-26

    The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [{sup 3}H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor.

  3. Mechanical Disruption of Tumors by Iron Particles and Magnetic Field Application Results in Increased Anti-Tumor Immune Responses

    PubMed Central

    Bouchlaka, Myriam N.; Sckisel, Gail D.; Wilkins, Danice; Maverakis, Emanual; Monjazeb, Arta M.; Fung, Maxwell; Welniak, Lisbeth; Redelman, Doug; Fuchs, Alan; Evrensel, Cahit A.; Murphy, William J.

    2012-01-01

    The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF) consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+)T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer. PMID:23133545

  4. Molecular Profiling of Refractory Adrenocortical Cancers and Predictive Biomarkers to Therapy

    PubMed Central

    Millis, Sherri Z.; Ejadi, Samuel; Demeure, Michael J.

    2015-01-01

    PURPOSE Current first-line chemotherapy for patients with metastatic adrenocortical cancer (ACC) includes doxorubicin, etoposide, cisplatin, and mitotane with a reported response rate of only 23.2%. New therapeutic leads for patients with refractory tumors are needed; there is no standard second-line treatment. METHODS Samples from 135 ACC tumors were analyzed by immunohistochemistry, in situ hybridization (FISH or CISH), and/or gene sequencing at a single commercial reference laboratory (Caris Life Sciences) to identify markers associated with drug sensitivity and resistance. RESULTS Overexpression of proteins related to demonstrated chemotherapy sensitivity or resistance included topoisomerase 1, progesterone receptor, and topoisomerase 2-alpha in 46%, 63%, and 42% of cases, respectively. Loss of excision repair cross-complementary group 1 (ERCC1), phosophatase and tensin homolog, O(6)-methylguanine-methyltransferase, and ribonucleotide reductase M1 (RRM1) was identified in 56%, 59%, 71%, and 58% of cases, respectively. Other aberrations included overexpression of programmed death-ligand 1 or programmed cell death protein 1 tumor-infiltrating lymphocytes in >40% of cases. In all, 35% of cases had a mutation in the canonical Wnt signaling pathway (either CTNNB1 or APC) and 48% had a mutation in TP53. No other genomic alterations were identified. CONCLUSION Biomarker alterations in ACC may be used to direct therapies, including recommendations for and potential resistance of some patients to traditional chemotherapies, which may explain the low response rate in the unselected population. Limited outcomes data support the use of mitotane and platinum therapies for patients with low levels of the proteins RRM1 and ERCC1. PMID:26715866

  5. ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo.

    PubMed

    Cheng, Yunhui; Kerppola, Raili Emilia; Kerppola, Tom Klaus

    2016-04-01

    Adrenocortical carcinoma (ACC) generally has poor prognosis. Existing treatments provide limited benefit for most patients with locally advanced or metastatic tumors. We investigated the mechanisms for the cytotoxicity, xenograft suppression, and adrenalytic activity of ATR-101 (PD132301-02), a prospective agent for ACC treatment. Oral administration of ATR-101 inhibited the establishment and impeded the growth of ACC-derived H295R cell xenografts in mice. ATR-101 induced H295R cell apoptosis in culture and in xenografts. ATR-101 caused mitochondrial hyperpolarization, reactive oxygen release, and ATP depletion within hours after exposure, followed by cytochrome c release, caspase-3/7 activation, and membrane permeabilization. The increase in mitochondrial membrane potential occurred concurrently with the decrease in cellular ATP levels. When combined with ATR-101, lipophilic free radical scavengers suppressed the reactive oxygen release, and glycolytic precursors prevented the ATP depletion, abrogating ATR-101 cytotoxicity. ATR-101 directly inhibited F1F0-ATPase activity and suppressed ATP synthesis in mitochondrial fractions. ATR-101 administration to guinea pigs caused oxidized lipofuscin accumulation in thezona fasciculatalayer of the adrenal cortex, implicating reactive oxygen release in the adrenalytic effect of ATR-101. These results support the development of ATR-101 and other adrenalytic compounds for the treatment of ACC. PMID:26843528

  6. Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

    PubMed Central

    Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

    2016-01-01

    Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

  7. Radiation-guided drug delivery to tumor blood vessels results in improved tumor growth delay.

    PubMed

    Geng, Ling; Osusky, Katherine; Konjeti, Sekhar; Fu, Allie; Hallahan, Dennis

    2004-10-19

    Tumor blood vessels are biological targets for cancer therapy. In this study, a tumor vasculature targeting system that consisted of liposomes and lectin (WGA) was built. Liposomes were used to carry a number of liposome-friendly anti-tumoral agents along with WGA, a lectin which posseses a specific affinity for binding to inflamed endothelial cells. In order to target tumor vasculature, inflammation of endothelial cells was induced by radiation. Because ionizing radiation induces an inflammatory response in tumor vasculature, lectin-conjugates were utilized to determine whether radiation can be used to target drug delivery to tumor vessels. Wheat germ agglutinin (WGA) is one such lectin that binds to inflamed microvasculature. WGA was conjugated to liposomes containing cisplatin and administered to tumor bearing mice. Tumor growth delay was used to analyze the efficacy of cytotoxicity. FITC-conjugated WGA accumulated within irradiated tumor microvasculature. WGA was conjugated to liposomes and labeled with 111In. This demonstrated radiation-inducible tumor-selective binding. WGA-liposome-conjugates were loaded with Cisplatin and administered to mice bearing irradiated tumors. Tumors treated with a combination of liposome encapsulated cisplatin together with radiation showed a significant increase in tumor growth delay as compared to radiation alone. These findings demonstrate that ionizing radiation can be used to guide drug delivery to tumor microvasculature. PMID:15451595

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

    PubMed

    Beuschlein, Felix; Jakoby, Judith; Mentz, Susanne; Zambetti, Gerard; Jung, Sara; Reincke, Martin; Süss, Regine; Hantel, Constanze

    2016-06-15

    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

  9. Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

    PubMed Central

    Costa, Marcia Helena Soares; Domenice, Sorahia; Toledo, Rodrigo Almeida; Lourenço, Delmar Muniz; Latronico, Ana Claudia; Pinto, Emilia Modolo; Toledo, Sergio Pereira Almeida; Mendonca, Berenice Bilharinho; Fragoso, Maria Candida Barisson Villares

    2011-01-01

    BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the ΔΔCT method, and β-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical

  10. Ultrastructure of the adrenocortical homologue in dexamethasone-treated eels.

    PubMed Central

    Bhattacharyya, T K; Butler, D G

    1980-01-01

    The ultrastructural modifications of the adrenocortical homologue (AH) in the North American eel (Anguilla rostrata) were studied following a 10 day treatment with dexamethasone (20 mg/day). The principal changes were: disorganization of smooth endoplasmic reticlum, regression and fragmentation of the Golgi apparatus, and a lowering of matrix density in the mitochondria. Steroid treatment also induced the appearance of numerous cytoplasmic inclusions: (a) lamellated bodies with electron-lucent cores; (b) membranous whorls isolating cytoplasmic regions containing smooth endoplasmic reticulum and mitochondria and (c) complex aggregates showing whorls of membranes, residues of cytoplasmic organelles, and dense matrix. The non-accumulation of lipid droplets in repressed AH cells was noteworthy. These subcellular changes indicate endogenous cellular autophagy in the AH as a result of steroid-induced suppression of ACTH production by the pituitary. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:7400039

  11. Exposure to the three structurally different PCB congeners (PCB 118, 153, and 126) results in decreased protein expression and altered steroidogenesis in the human adrenocortical carcinoma cell line H295R.

    PubMed

    Tremoen, Nina Hårdnes; Fowler, Paul A; Ropstad, Erik; Verhaegen, Steven; Krogenæs, Anette

    2014-01-01

    Polychlorinated biphenyls (PCB), synthetic, persistent organic pollutants (POP), are detected ubiquitously, in water, soil, air, and sediments, as well as in animals and humans. PCB are associated with range of adverse health effects, such as interference with the immune system and nervous system, reproductive abnormalities, fetotoxicity, carcinogenicity, and endocrine disruption. Our objective was to determine the effects of three structurally different PCB congeners, PCB118, PCB 126, and PCB 153, each at two concentrations, on the steroidogenic capacity and proteome of human adrenocortical carcinoma cell line cultures (H295R) . After 48 h of exposure, cell viability was monitored and estradiol, testosterone, cortisol and progesterone secretion measured to quantify steroidogenic capacity of the cells. Two-dimensional (2D) gel-based proteomics was used to screen for proteome alterations in H295R cells in response to the PCB. Exposure to PCB 118 increased estradiol and cortisol secretion, while exposure to PCB 153 elevated estradiol secretion. PCB 126 was the most potent congener, increasing estradiol, cortisol, and progesterone secretion in exposed H295R cells. Seventy-three of the 711 spots analyzed showed a significant difference in normalized spot volumes between controls (vehicle only) and at least one exposure group. Fourteen of these protein spots were identified by liquid chromatography with mass spectroscopy (LC-MS/MS). Exposure to three PCB congeners with different chemical structure perturbed steroidogenesis and protein expression in the H295R in vitro model. This study represents an initial analysis of the effects on proteins and hormones in the H295R cell model, and additional studies are required in order to obtain a more complete understanding of the pathways disturbed by PCB congeners in H295R cells. Overall, alterations in protein regulation and steroid hormone synthesis suggest that exposure to PCB disturbs several cellular processes, including

  12. Knockdown of SF-1 and RNF31 Affects Components of Steroidogenesis, TGFβ, and Wnt/β-catenin Signaling in Adrenocortical Carcinoma Cells

    PubMed Central

    Ehrlund, Anna; Jonsson, Philip; Vedin, Lise-Lotte; Williams, Cecilia; Gustafsson, Jan-Åke; Treuter, Eckardt

    2012-01-01

    The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma. PMID:22427816

  13. Interstitial laser photocoagulation therapy for liver tumors: clinical results

    NASA Astrophysics Data System (ADS)

    Amin, Zahir; Donald, J. J.; Masters, A.; Kant, R.; Lees, William R.; Bown, Stephen G.

    1993-07-01

    Interstitial laser photocoagulation is a new technique of tumor ablation using low power (2 W) laser light over a long time (500 s) via thin (0.2 mm) optical fibers. We have treated 26 patients with 70 liver metastases measuring 1 to 15 cm (median 2.5 cm). There were 1 to 8 treatment sessions per patient (median 3). Each tumor was treated via 1 to 4 optical fibers. The median energy used was 16000 J (range 3000 to 34000 J). Treatment effects were monitored in real-time with ultrasound, and the extent of tumor necrosis evaluated 1 to 3 days later using dynamic enhanced CT which showed laser-induced necrosis as well-defined new areas of non-enhancement. Greater than 50% necrosis of tumor volume was achieved in 86% (60 out of 70) of the tumors treated, and 100% necrosis in 53% (37 out of 70). Metastases under 4 cm were treated more effectively and required fewer treatment sessions than those over 4 cm. In eleven patients there was evidence of disease progression (follow-up 14 months or longer) and in 15 patients there has been overall tumor reduction (follow-up less than 1 year, median 4 months). Conclusion: With further development, ILP may offer a practical and minimally invasive alternative to major surgery for eradicating small, deep seated tumors, and debulking larger ones.

  14. Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.

    PubMed

    Creemers, S G; van Koetsveld, P M; van Kemenade, F J; Papathomas, T G; Franssen, G J H; Dogan, F; Eekhoff, E M W; van der Valk, P; de Herder, W W; Janssen, J A M J L; Feelders, R A; Hofland, L J

    2016-09-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients. PMID:27535174

  15. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    PubMed Central

    Qin, Liang; Xu, Tianyuan; Xia, Leilei; Wang, Xianjin; Zhang, Xiang; Zhang, Xiaohua; Zhu, Zhaowei; Zhong, Shan; Wang, Chuandong; Shen, Zhoujun

    2016-01-01

    Background It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo. Methods The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy. Results The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice. Conclusion The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an

  16. Molecular Imaging in the Management of Adrenocortical Cancer: A Systematic Review.

    PubMed

    Wong, Ka Kit; Miller, Barbra S; Viglianti, Benjamin L; Dwamena, Ben A; Gauger, Paul G; Cook, Gary J; Colletti, Patrick M; Rubello, Domenico; Gross, Milton D

    2016-08-01

    Adrenocortical cancer (ACC) is an uncommon primary neoplasm of the adrenal cortex with dismal prognosis. It often presents with symptoms and signs of adrenal cortical hormone hypersecretion and abdominal mass effect or is incidentally detected as an adrenal mass on imaging performed for other indications. Endocrine evaluation, comprehensive staging, and meticulous resection are crucial to ensure the best possible outcome. Despite extensive initial surgical resection, local and distant metastases are not uncommon with disappointing 5-year survival, although progress is being made at high-volume centers. Accurate restaging of recurrent disease is important to guide further management. Mitotane, external beam radiation and chemotherapy, and newer anticancer systemic treatments are used as adjunctives for inoperable disease and distant metastases. Contrast-enhanced CT and MRI are first-line imaging modalities for evaluation of ACC to characterize adrenal masses and to determine tumor resectability. Emerging literature supports F-FDG PET/CT use to determine the malignant potential of adrenal masses. In patients with a diagnosis of ACC, FDG PET/CT is sensitive for detecting metastatic disease, and its tumor accumulation has been correlated to pathology, Weiss scores, and prognosis. Metomidate, labeled with C for PET or with I for SPECT/CT, allows characterization of an adrenal mass as being of adrenocortical origin with high specificity. Taking advantage of its adrenocortical avidity, metomidate has been labeled with I for radionuclide therapy in a subset of ACC. In this review, we describe how nuclear medicine imaging, and specifically PET, can assist surgical management of ACC. PMID:26825212

  17. Hypofractionation Results in Reduced Tumor Cell Kill Compared to Conventional Fractionation for Tumors With Regions of Hypoxia

    SciTech Connect

    Carlson, David J.; Keall, Paul J.; Loo, Billy W.; Chen, Zhe J.; Brown, J. Martin

    2011-03-15

    Purpose: Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation. Methods and Materials: A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions. Results: Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10{sup 5} over a distance of 130 {mu}m. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of {approx}10{sup 3} as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively. Conclusions: Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.

  18. PTTG1 Over-expression in Adrenocortical Cancer is Associated with Poor Survival and Represents a Potential Therapeutic Target

    PubMed Central

    Demeure, Michael J.; Coan, Kathryn E.; Grant, Clive S.; Komorowski, Richard A.; Stephan, Elizabeth; Sinari, Shripad; Mount, David; Bussey, Kimberly J.

    2014-01-01

    Background Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. Methods 44 ACC and 4 normal adrenals were profiled on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. Results Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). Analysis of a previously published data set confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of two ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively). Conclusion Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target. PMID:24238056

  19. A genetic and molecular update on adrenocortical causes of Cushing syndrome.

    PubMed

    Lodish, Maya; Stratakis, Constantine A

    2016-05-01

    Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP-PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP-PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder. PMID:26965378

  20. Classification and surgical treatment for 180 cases of adrenocortical hyperplastic disease

    PubMed Central

    Zhang, Yushi; Li, Hanzhong

    2015-01-01

    Objective: To review and discuss the diagnostic and surgical therapeutic methods of adrenocortical hyperplastic disease. Methods: A retrospective analysis was done to 180 adrenocortical hyperplasia patients (74 males, 109 females, aged 6~76 (average 40.1). Studies were done to the relationship between patients’ clinical characteristics, biochemical, endocrinological and imaging examination results, the therapeutic effects. Results: Among all 180 cases, there are 107 Cushing disease (CD), 19 ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 28 adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 4 primary pigmented nodular adrenocortical hyperplasia (PPNAH), and 28 Idiopathic Hyperaldosteronism (IHA). Twenty-four-hour urinary free cortisol (24 h UFC) excretion of CD, EAAH, AIMAH and PPNAH patients were 95.2~535.7 µg (average 287.6 µg), 24.8~808.2 µg (average 307.9 µg), 102.5~3127.0 µg (average 852.5 µg), and 243.8~1124.6 µg (average 564.3 µg). Both low and high-dose dexamethasone suppression tests (DDST) were not suppressed in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. CT thin scanning results of 180 patients all showed enlargements in the affected side adrenal gland. Unilateral adrenalectomies were performed in 102 hypercortisolism cases. Local lesion excisions were done to 21 IHA patients. 57 patients had surgeries in both sides of the adrenal glands (39 bilateral total adrenalectomies, 16 total adrenalectomy in one side andsubtotal adrenalectomy in the other, 2 bilateral subtotal adrenalectomies). 106 (59%) patients were followed up for 4~158 (average 32) months. Conclusion: Unilateral adrenalectomy was the first choice for operable adrenocortical hyperplasia patients. The operation mode for the other adrenal gland should be based on the type of hyperplasia and clinical observation. PMID:26770569

  1. Primary tumors of the trachea. Results of radiation therapy

    SciTech Connect

    Fields, J.N.; Rigaud, G.; Emami, B.N.

    1989-06-15

    From 1959 to 1986, 24 patients with primary malignant tumors of the trachea received radiotherapy as all or part of treatment. Common presentations included respiratory symptoms in 20 patients and hemoptysis in 15. Thirteen patients had squamous carcinomas with undifferentiated and adenoid cystic cancers in five and four patients, respectively. Overall actuarial survival was 45% at 1 year, 25% at 5 years, and 13% at 10 years. Survival was significantly correlated to histologic type (adenoid cystic versus squamous, P less than 0.03), but not to tumor extent or to patient age or sex. Local control was attained in 10 of 24 patients overall and was more frequent for patients with tumors localized to the trachea and for patients who were treated with combined surgery and radiotherapy. For the 18 patients treated with radiotherapy alone, complete response (CR) was seen to be significantly (P less than 0.001) related to dose: six of seven (86%) patients receiving greater than or equal to 6000 cGy attained CR versus one of 11 (9%) receiving less than 6000 cGy. Three patients developed complications related to radiotherapy. Radiotherapy can provide durable local control of localized tracheal tumors and should be considered for medically inoperable patients with localized tumors and for patients with high risk of recurrence after resection.

  2. Adrenocortical Gap Junctions and Their Functions

    PubMed Central

    Bell, Cheryl L.; Murray, Sandra A.

    2016-01-01

    Adrenal cortical steroidogenesis and proliferation are thought to be modulated by gap junction-mediated direct cell–cell communication of regulatory molecules between cells. Such communication is regulated by the number of gap junction channels between contacting cells, the rate at which information flows between these channels, and the rate of channel turnover. Knowledge of the factors regulating gap junction-mediated communication and the turnover process are critical to an understanding of adrenal cortical cell functions, including development, hormonal response to adrenocorticotropin, and neoplastic dedifferentiation. Here, we review what is known about gap junctions in the adrenal gland, with particular attention to their role in adrenocortical cell steroidogenesis and proliferation. Information and insight gained from electrophysiological, molecular biological, and imaging (immunocytochemical, freeze fracture, transmission electron microscopic, and live cell) techniques will be provided. PMID:27445985

  3. High-throughput screening of chemical effects on steroidogenesis using H295R human adrenocortical carcinoma cells

    EPA Science Inventory

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2,060 chemical samples...

  4. Serum and growth factor requirements for proliferation of human adrenocortical cells in culture: comparison with bovine adrenocortical cells.

    PubMed

    Hornsby, P J; Sturek, M; Harris, S E; Simonian, M H

    1983-11-01

    Although bovine adrenocortical cells proliferate readily in cell culture, proliferation of fetal or adult human adrenocortical cells has been observed to be limited and preparation of pure proliferating cultures of human adrenocortical cells has not been reported. The growth requirements of fetal human definitive zone adrenocortical cells in culture were compared to the established requirements of bovine adrenocortical cells. The medium used was 1:1 Ham's F12 and Dulbecco's modified Eagle's medium supplemented with transferrin and insulin. Earlier experiments showed that human cells had a greater proliferative response to horse serum than to fetal bovine serum, whereas the opposite was true for bovine cells. When plated on fibronectin-coated dishes and exposed to varying concentrations of horse serum in the presence of 100 ng/ml fibroblast growth factor (FGF), increasing cell growth was observed up to a serum concentration of 50%. When 50% fetal bovine serum was used instead of horse serum proliferation was less. In contrast, bovine adrenocortical cells showed a maximal proliferative response to either fetal bovine serum or horse serum at 10%. Human adrenocortical cells thus have a very high requirement for serum; 50% is the highest level that may be practically used, but the shape of the dose-response curve suggests that this concentration is still suboptimal. Growth was less in the absence of FGF. Epidermal growth factor can partially substitute for FGF. No response to 100 nM placental lactogen was observed. Less growth was observed when dishes were not coated with fibronectin. The factors present in horse serum that are evidently needed in high amounts by human cells are unknown. Despite this lack of knowledge, use of 50% horse serum enabled long-term growth of human adrenocortical cells that are pure by the criterion of retraction in response to ACTH. Nonadrenocortical cells do not show a retraction response. Such long-term cultures may be useful in studies of

  5. Ultrastructural Localization of Endogenous Exchange Factor for ARF6 in Adrenocortical Cells In Situ of Mice

    PubMed Central

    Chomphoo, Surang; Mothong, Wilaiwan; Sawatpanich, Tarinee; Kanla, Pipatphong; Sakagami, Hiroyuki; Kondo, Hisatake; Hipkaeo, Wiphawi

    2016-01-01

    EFA6 (exchange factor for ARF6) activates Arf6 (ADP ribosylation factor 6) by exchanging ADP to ATP, and the resulting activated form of Arf6 is involved in the membrane dynamics and actin re-organization of cells. The present study was attempted to localize EFA6 type D (EFA6D) in mouse adrenocortical cells in situ whose steroid hormone secretion is generally considered not to depend on the vesicle-involved regulatory mechanism. In immunoblotting, an immunoreactive band with the same size as brain EFA6D was detected in homogenates of adrenal cortical tissues almost free of adrenal capsules and medulla. In immuno-light microscopy, EFA6D-immunoreactivity was positive in adrenocortical cells and it was often distinct along the plasmalemma, especially along portions of the cell columns facing the interstitium. In immuno-electron microscopy, the gold-labeling was more dense in the peripheral intracellular domains than the central domain of the immunopositive cells. The labeling was deposited on the plasma membranes in a discontinuous pattern and in cytoplasmic domains rich in filaments. It was also associated with some, but not all, of pleiomorphic vesicles and coated pits/vesicles. No labeling was seen in association with lipid droplets or smooth endoplasmic reticulum. The present finding is in support of the importance of EFA6D for activation of Arf6 in adrenocortical cells. PMID:27462133

  6. Ultrastructural Localization of Endogenous Exchange Factor for ARF6 in Adrenocortical Cells In Situ of Mice.

    PubMed

    Chomphoo, Surang; Mothong, Wilaiwan; Sawatpanich, Tarinee; Kanla, Pipatphong; Sakagami, Hiroyuki; Kondo, Hisatake; Hipkaeo, Wiphawi

    2016-06-28

    EFA6 (exchange factor for ARF6) activates Arf6 (ADP ribosylation factor 6) by exchanging ADP to ATP, and the resulting activated form of Arf6 is involved in the membrane dynamics and actin re-organization of cells. The present study was attempted to localize EFA6 type D (EFA6D) in mouse adrenocortical cells in situ whose steroid hormone secretion is generally considered not to depend on the vesicle-involved regulatory mechanism. In immunoblotting, an immunoreactive band with the same size as brain EFA6D was detected in homogenates of adrenal cortical tissues almost free of adrenal capsules and medulla. In immuno-light microscopy, EFA6D-immunoreactivity was positive in adrenocortical cells and it was often distinct along the plasmalemma, especially along portions of the cell columns facing the interstitium. In immuno-electron microscopy, the gold-labeling was more dense in the peripheral intracellular domains than the central domain of the immunopositive cells. The labeling was deposited on the plasma membranes in a discontinuous pattern and in cytoplasmic domains rich in filaments. It was also associated with some, but not all, of pleiomorphic vesicles and coated pits/vesicles. No labeling was seen in association with lipid droplets or smooth endoplasmic reticulum. The present finding is in support of the importance of EFA6D for activation of Arf6 in adrenocortical cells. PMID:27462133

  7. Morphological changes in the pituitary-adrenocortical axis in natives of La Paz

    NASA Astrophysics Data System (ADS)

    Gosney, John; Heath, Donald; Williams, David; Rios-Dalenz, Jaime

    1991-03-01

    Increased activity of the hypothalamic-pituitary-adrenocortical axis is part of the response to the stress of initial exposure to hypoxia, but there is evidence to suggest that it persists after homeostatic stability has been regained and acclimatization achieved. The adrenal glands of five lifelong residents of La Paz, Bolivia, who had lived at altitudes in the range 3600 3800 m, were significantly larger than those in age-matched controls from sea level (15.3g vs 10.4g; P<0.001) and appeared hyperplastic. The pituitary glands of the highlanders were not significantly different in size from those of the controls (0.67 g vs 0.51 g), but contained larger populations of corticotrophs expressed in terms of the total cell population of their anterior lobes (25.6% vs 19.4%; P<0.001). In conjunction with other studies of this endocrine axis in man and animals exposed to a hypoxic environment, these data suggest that greater amounts of adrenocorticotrophic hormone (ACTH) are required to maintain normal adrenocortical function under such circumstances, probably as a result of hypoxic inhibition of adrenocortical sensitivity to stimulation. Physiological hyperplasia of the adrenal cortex may be common in people living at high altitude.

  8. Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia.

    PubMed

    Liu, Sisi; Saloustros, Emmanouil; Berthon, Annabel; Starost, Matthew F; Sahut-Barnola, Isabelle; Salpea, Paraskevi; Szarek, Eva; Faucz, Fabio R; Martinez, Antoine; Stratakis, Constantine A

    2016-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels. PMID:26438728

  9. Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia

    PubMed Central

    Liu, Sisi; Saloustros, Emmanouil; Berthon, Annabel; Starost, Matthew F.; Sahut-Barnola, Isabelle; Salpea, Paraskevi; Szarek, Eva; Faucz, Fabio R.; Martinez, Antoine; Stratakis, Constantine A.

    2015-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to adrenocorticotropin hormone (ACTH) - independent Cushing’s syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP–dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with Celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1,500 mg/kg Celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, Celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, Celecoxib caused histological changes that reversed, at least in part, BAH and this was associated with a reduction of corticosterone levels. PMID:26438728

  10. EFFECT OF BILATERAL OOPHORECTOMY ON ADRENOCORTICAL FUNCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS)

    PubMed Central

    Azziz, Ricardo; Chang, Wendy Y.; Stanczyk, Frank Z.; Woods, Keslie

    2012-01-01

    Objective To determine the impact of ovary-secreted products on adrenocortical function in women with PCOS by studying the adrenocortical response to acute adrenocorticotropic-stimulating hormone (ACTH) stimulation before and after bilateral oophorectomy. Design Prospective study. Setting Tertiary care medical center Participants Fourteen women with PCOS scheduled for bilateral oophorectomy for benign indications, on transdermal estradiol (E2) postoperatively. Interventions Physical exam, blood sampling before and after oophorectomy, measurement of hormone levels. Basal (Steroid0), maximum stimulated (Steroid60), and net increment (ΔSteroid) levels of androstenedione (A4), dehydroepiandrosterone (DHEA), and cortisol (F) before and after ACTH-1–24 stimulation were assessed. Main Outcome Measures Pre- and post-operative basal and ACTH(1–24)-stimulated hormonal levels. Results Total testosterone, free testosterone, and estrone levels decreased, and FSH levels increased significantly following oophorectomy. No significant differences in E2, DHEA sulfate (DHEAS) or sex hormone binding globulin levels were detected. Basal and ACTH-stimulated A4 levels decreased significantly following oophorectomy, and ΔA4 was significantly increased. No significant differences in DHEA0, DHEA60, or F0 levels were detected; F60 and ΔF levels tended to increase following oophorectomy, but the differencesdid not reach significance. Conclusions Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS. PMID:23122827

  11. Children with Cushing's syndrome: Primary Pigmented Nodular Adrenocortical Disease should always be suspected.

    PubMed

    da Silva, Renata Marques Gonçalves; Pinto, Emília; Goldman, Suzan M; Andreoni, Cássio; Vieira, Teresa C; Abucham, Julio

    2011-03-01

    Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of bilateral adrenocortical hyperplasia that is inherited in an autosomal dominant manner and leads to ACTH-independent Cushing's syndrome (CS). PPNAD may be isolated or associated with Carney Complex (CNC). For the diagnosis of PPNAD and CNC, in addition to the hormonal and imaging tests, searching for PRKAR1A mutations may be recommended. The aims of the present study are to discuss the clinical and molecular findings of two Brazilian patients with ACTH-independent CS due to PPNAD and to show the diagnostic challenge CS represents in childhood. Description of two patients with CS and the many sequential steps for the diagnosis of PPNAD is provided. Sequencing analysis of all coding exons of PRKAR1A in the blood, frozen adrenal nodules (patients 1 and 2) and testicular tumor (patient 1) is performed. After several clinical and laboratory drawbacks that misled the diagnostic investigation in both patients, the diagnosis of PPNAD was finally established and confirmed through pathology and molecular studies. In patient 1, sequencing of PRKAR1A gene revealed a novel heterozygous 10-bp deletion in exon 3, present in his blood, adrenal gland and testicular tumor. The etiologic diagnosis of endogenous CS in children is a challenge that requires expertise and a multidisciplinary collaboration for its prompt and correct management. Although rare, PPNAD should always be considered among the possible etiologies of CS, due to the high prevalence of this disease in this age group. PMID:20924687

  12. Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice

    PubMed Central

    Agrawal, Vijayendra; Maharjan, Sony; Kim, Kyeojin; Kim, Nam-Jung; Son, Jimin; Lee, Keunho; Choi, Hyun-Jung; Rho, Seung-Sik; Ahn, Sunjoo; Won, Moo-Ho; Ha, Sang-Jun; Koh, Gou Young; Kim, Young-Myeong; Suh, Young-Ger; Kwon, Young-Guen

    2014-01-01

    Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis. PMID:24811731

  13. Extramitochondrial OPA1 and adrenocortical function.

    PubMed

    Fülöp, László; Rajki, Anikó; Katona, Dávid; Szanda, Gergö; Spät, András

    2013-12-01

    We have previously described that silencing of the mitochondrial protein OPA1 enhances mitochondrial Ca(2+) signaling and aldosterone production in H295R adrenocortical cells. Since extramitochondrial OPA1 (emOPA1) was reported to facilitate cAMP-induced lipolysis, we hypothesized that emOPA1, via the enhanced hydrolysis of cholesterol esters, augments aldosterone production in H295R cells. A few OPA1 immunopositive spots were detected in ∼40% of the cells. In cell fractionation studies OPA1/COX IV (mitochondrial marker) ratio in the post-mitochondrial fractions was an order of magnitude higher than that in the mitochondrial fraction. The ratio of long to short OPA1 isoforms was lower in post-mitochondrial than in mitochondrial fractions. Knockdown of OPA1 failed to reduce db-cAMP-induced phosphorylation of hormone-sensitive lipase (HSL), Ca(2+) signaling and aldosterone secretion. In conclusion, OPA1 could be detected in the post-mitochondrial fractions, nevertheless, OPA1 did not interfere with the cAMP - PKA - HSL mediated activation of aldosterone secretion. PMID:23906536

  14. An unusual case of adrenocortical carcinoma with liver metastasis that occurred at 23 years after surgery.

    PubMed

    Bergeat, Damien; Rayar, Michel; Beuzit, Luc; Levi Sandri, Giovanni Battista; Dagher, Julien; Merdrignac, Aude; Tanguy, Laetitia; Boudjema, Karim; Sulpice, Laurent; Meunier, Bernard

    2016-06-01

    Adrenocortical carcinoma (ACC) is an uncommon and aggressive cancer occurring more frequently in women; local or distant recurrences occur in 80% of cases, typically within 1 year after curative resection. Liver is the preferred metastatic site. Herein, we report the case of a unique liver metastasis from ACC occurring 23 years after the curative prior tumor surgery. A 45-year-old woman was operated in 1991 for adrenocortical stage II without microvascular involvement or capsular infiltration. At that time, no adjuvant treatment was indicated. The initial surgery consisted on a left adrenalectomy with contemporaneous left nephrectomy and regional lymphadenectomy. Five years after surgery, the patient was considered cured. However, 23 years later, the patient presented an atypical right subcostal pain. A 4 cm liver ACC metastasis involving the segment 4 and initially diagnosed as a hemangioma was discovered. A curative resection of the segment 4 was performed. Final pathological examination confirmed the diagnosis of ACC metastasis with a complete R0 resection; no lymph node metastases were observed. This case is the latest metachronous ACC metastasis ever reported in literature. To date, the patient is alive with no signs of recurrence after a post-surgical follow-up of 13 months. PMID:27275470

  15. An unusual case of adrenocortical carcinoma with liver metastasis that occurred at 23 years after surgery

    PubMed Central

    Rayar, Michel; Beuzit, Luc; Levi Sandri, Giovanni Battista; Dagher, Julien; Merdrignac, Aude; Tanguy, Laetitia; Boudjema, Karim; Sulpice, Laurent; Meunier, Bernard

    2016-01-01

    Adrenocortical carcinoma (ACC) is an uncommon and aggressive cancer occurring more frequently in women; local or distant recurrences occur in 80% of cases, typically within 1 year after curative resection. Liver is the preferred metastatic site. Herein, we report the case of a unique liver metastasis from ACC occurring 23 years after the curative prior tumor surgery. A 45-year-old woman was operated in 1991 for adrenocortical stage II without microvascular involvement or capsular infiltration. At that time, no adjuvant treatment was indicated. The initial surgery consisted on a left adrenalectomy with contemporaneous left nephrectomy and regional lymphadenectomy. Five years after surgery, the patient was considered cured. However, 23 years later, the patient presented an atypical right subcostal pain. A 4 cm liver ACC metastasis involving the segment 4 and initially diagnosed as a hemangioma was discovered. A curative resection of the segment 4 was performed. Final pathological examination confirmed the diagnosis of ACC metastasis with a complete R0 resection; no lymph node metastases were observed. This case is the latest metachronous ACC metastasis ever reported in literature. To date, the patient is alive with no signs of recurrence after a post-surgical follow-up of 13 months.

  16. Pitfalls in the management of acute adrenocortical insufficiency: discussion paper.

    PubMed Central

    Waise, A; Young, R J

    1989-01-01

    In patients with acute adrenocortical insufficiency prompt recognition and treatment may be life-saving. Treatment should be initiated immediately before confirmation of the diagnosis. As shown by these case reports, junior staff on acute medical and surgical services, to whom these patients usually first present, may not appreciate that (a) hyponatraemia and hyperkalaemia, in the absence of renal failure, should immediately suggest the diagnosis of adrenal insufficiency and (b) treatment should precede confirmation of the diagnosis. Attempts to correct hyperkalaemia due to adrenocortical insufficiency with insulin and infusions of dextrose is inappropriate and potentially dangerous but seems to be a not unusual mistake. PMID:2614769

  17. Chronic effects of mercuric chloride ingestion on rat adrenocortical function

    SciTech Connect

    Agrawal, R.; Chansouria, J.P.N. )

    1989-09-01

    Mercurial contamination of environment has increased. Mercury accumulates in various organs and adversely affects their functions. Some of the most prominent toxic effects of inorganic mercury compounds include neurotoxicity, hepatotoxicity and nephrotoxicity. Besides this, mercury has also been reported to affect various endocrine glands like pituitary, thyroid, gonadal and adrenal glands. There have been no reports on the toxic effects of chronic oral administration of varying doses of mercuric chloride on adrenocortical function in albino rats. The present work was undertaken to study the adrenocortical response to chronic oral administration of mercuric chloride of varying dose and duration in albino rats.

  18. Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series

    PubMed Central

    Tageja, Nishant; Rosenberg, Avi; Mahalingam, Sowmya; Quezado, Martha; Velarde, Margarita; Edgerly, Maureen; Fojo, Tito

    2015-01-01

    Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. PMID:25412413

  19. Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

    PubMed Central

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-01-01

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

  20. Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors

    ClinicalTrials.gov

    2015-03-18

    Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Childhood Hepatoblastoma; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adrenocortical Carcinoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive; Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Retinoblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

  1. Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling

    PubMed Central

    Hayden, Ingrid

    2016-01-01

    Patients with heavily pretreated advanced cancer or with rare tumors are difficult to treat. Molecular profiling (MP) of tumors to identify biomarkers that predict potential outcomes with individual therapies is an emerging strategy to guide treatment decisions. Patients with rare tumors for which standard-of-care therapy was unavailable or more common tumors for which standard-of-care options had been exhausted underwent MP at a single Australian center. Data regarding treating physicians' choice of therapy, MP results and recommendations, and patient outcomes were collected. Seven patients had received prior standard first-line therapy (PST), 16 had rare tumors, and 31 had been heavily pretreated (HPT; ≥2 prior lines). Most treatments suggested by MP (541/594; 91.1%) were common chemotherapy drugs available in generic formulations. MP-guided therapy recommendations differed from physician's recommendations in 48 patients (88.9%). MP-guided therapy produced clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients with HPTs, rare tumors, and PSTs, respectively, and had a PFS ratio ≥1.3 in 22/37 evaluable patients (59.5%; 95% confidence interval 44–76%). The null hypothesis that ≤15% of these patients would have a PFS ratio ≥1.3 was rejected (one-sided p < 0.0001). In conclusion, using MP to guide therapy selection is feasible in clinical practice and may improve patient outcomes. PMID:27525268

  2. Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling.

    PubMed

    Dean, Andrew; Byrne, Aisling; Marinova, Mira; Hayden, Ingrid

    2016-01-01

    Patients with heavily pretreated advanced cancer or with rare tumors are difficult to treat. Molecular profiling (MP) of tumors to identify biomarkers that predict potential outcomes with individual therapies is an emerging strategy to guide treatment decisions. Patients with rare tumors for which standard-of-care therapy was unavailable or more common tumors for which standard-of-care options had been exhausted underwent MP at a single Australian center. Data regarding treating physicians' choice of therapy, MP results and recommendations, and patient outcomes were collected. Seven patients had received prior standard first-line therapy (PST), 16 had rare tumors, and 31 had been heavily pretreated (HPT; ≥2 prior lines). Most treatments suggested by MP (541/594; 91.1%) were common chemotherapy drugs available in generic formulations. MP-guided therapy recommendations differed from physician's recommendations in 48 patients (88.9%). MP-guided therapy produced clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients with HPTs, rare tumors, and PSTs, respectively, and had a PFS ratio ≥1.3 in 22/37 evaluable patients (59.5%; 95% confidence interval 44-76%). The null hypothesis that ≤15% of these patients would have a PFS ratio ≥1.3 was rejected (one-sided p < 0.0001). In conclusion, using MP to guide therapy selection is feasible in clinical practice and may improve patient outcomes. PMID:27525268

  3. [Functional results of partial nephrectomy for kidney tumors].

    PubMed

    Petrov, S B; Shpilenia, E S; Shkarupa, D D

    2009-01-01

    The aim of the investigation was to analyze functional results of organ-sparing operations using radioisotopic method in combination with the investigation of serum creatinine in 31 patients. The data obtained suggest that the functional results of organ-sparing operations for neoplasms of the kidney directly depend on the time of warm renal ischemia. Warm ischemia about 15 minutes long is able to result in an ultrastructural damage of the nephron and decreased filtration level by 20-30%. A sudden change of serum creatinine on the next day after operation can be taken as a long-term prognostic factor of the kidney function. If the suggested time of stopped renal blood flow is more than 10-15 minutes, local hypothermia is advisable to protect the kidney. PMID:19947426

  4. Nomograms to Predict Recurrence-Free and Overall Survival After Curative Resection of Adrenocortical Carcinoma

    PubMed Central

    Kim, Yuhree; Margonis, Georgios A.; Prescott, Jason D.; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Evans, Douglas B.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed I.; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Poultsides, George A.; Pawlik, Timothy M.

    2016-01-01

    IMPORTANCE Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor, and the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. OBJECTIVES To define clinicopathological variables associated with recurrence-free survival (RFS) and overall survival (OS) after curative surgical resection of ACC and to propose nomograms for individual risk prediction. DESIGN, SETTING, AND PARTICIPANTS Nomograms to predict RFS and OS after surgical resection of ACC were proposed using a multi-institutional cohort of patients who underwent curative-intent surgery for ACC at 13 major institutions in the United States between March 17, 1994, and December 22, 2014. The dates of our study analysis were April 15, 2015, to May 12, 2015. MAIN OUTCOMES AND MEASURES The discriminative ability and calibration of the nomograms to predict RFS and OS were tested using C statistics, calibration plots, and Kaplan-Meier curves. RESULTS In total, 148 patients who underwent surgery for ACC were included in the study. The median patient age was 53 years, and 65.5% (97 of 148) of the patients were female. One-third of the patients (35.1% [52 of 148]) had a functional tumor, and the median tumor size was 11.2 cm. Most patients (77.7% [115 of 148]) underwent R0 resection, and 8.8% (13 of 148) of the patients had N1 disease. Using backward stepwise selection of clinically important variables with the Akaike information criterion, the following variables were incorporated in the prediction of RFS: tumor size of at least 12 cm (hazard ratio [HR], 3.00; 95% CI, 1.63–5.70; P < .001), positive nodal status (HR, 4.78; 95% CI, 1.47–15.50; P = .01), stage III/IV (HR, 1.80; 95% CI, 0.95–3.39; P = .07), cortisol-secreting tumor (HR, 2.38; 95% CI, 1.27–4.48; P = .01), and capsular invasion (HR, 1.96; 95% CI, 1.02–3.74; P = .04). Factors selected as predicting OS were tumor size of at least 12 cm (HR, 1.78; 95% CI, 1.00–3.17; P = .05), positive

  5. Adrenocortical response to open-field test in rats with anterodorsal thalami nuclei lesion.

    PubMed

    Suárez, M; Perassi, N; Dal Zotto, S

    1996-01-01

    The influence of limbic anterodorsal thalami nuclei (ADTN) on adrenocortical activity and on emotional reactivity were investigated in male and female rats. The emotional reactivity was evaluated by means of the open-field test and the corticoadrenal function by means of plasma and adrenal corticosterone concentration. The results demonstrate that ADTN lesion does not affect the behavioural patterns in the open-field test on the 29th and 30th day after lesion nor adrenal response when animals are exposed to a novel situation. PMID:8724884

  6. Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratio as Predictors of Disease Specific Survival After Resection of Adrenocortical Carcinoma

    PubMed Central

    BAGANTE, FABIO; TRAN, THUY B.; POSTLEWAIT, LAUREN M.; MAITHEL, SHISHIR K.; WANG, TRACY S.; EVANS, DOUGLAS B.; HATZARAS, IOANNIS; SHENOY, RIVFKA; PHAY, JOHN E.; KEPLINGER, KARA; FIELDS, RYAN C.; JIN, LINDA X.; WEBER, SHARON M.; SALEM, AHMED; SICKLICK, JASON K.; GAD, SHADY; YOPP, ADAM C.; MANSOUR, JOHN C.; DUH, QUAN-YANG; SEISER, NATALIE; SOLORZANO, CARMEN C.; KIERNAN, COLLEEN M.; VOTANOPOULOS, KONSTANTINOS I.; LEVINE, EDWARD A.; POULTSIDES, GEORGE A.; PAWLIK, TIMOTHY M.

    2016-01-01

    Background The systemic inflammatory response may be associated with tumor progression. We sought to analyze the impact of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on recurrence-free survival (RFS) and disease-specific survival (DSS) among patients who underwent surgery for adrenocortical carcinoma (ACC). Methods Patients undergoing surgery for ACC were identified from a multi-center database. Cut-off values of 5 and 190 were defined as elevated NLR and PLR, respectively, and long-term outcome was assessed. Results Among 84 patients with ACC, 29 (34.%) had NLR >5 while 32 (40.5%) had PLR >190. NLR and PLR were associated with larger tumors (NLR >5: ≤ 5 cm, 0% vs. >5 cm, 39.7%; PLR >190: ≤ 5cm, 0% vs. >5 cm, 45.7%), as well as need to resect of other organs (NLR >5: other organ resected 48.8% vs. not resected 20.9%; PLR >190: other organ resected 25.0% vs. not resected 56.4%)(all P <0.05). Five-year RFS was associated with an elevated NLR (NLR ≤ 5, 14.2% vs. NLR>5, 10.5%) and PLR (PLR ≤190: 19.4% vs. PLR >190: 5.2%) (both P <0.05). On multivariate survival analyses, PLR remained a predictor of RFS (HR 1.72), while NLR was associated with both DSS (HR 2.21) and RFS (HR 1.99) (both P <0.05). Conclusions Immune markers such as NLR and PLR may be useful to stratify patients with regards to prognosis following surgery for ACC. PMID:26234285

  7. Ghrelin and obestatin inhibit enucleation-induced adrenocortical proliferation in the rat.

    PubMed

    Rucinski, Marcin; Trejter, Marcin; Ziolkowska, Agnieszka; Tyczewska, Marianna; Malendowicz, Ludwik K

    2010-05-01

    Studies involving the role of ghrelin (GHREL) in regulating the proliferative activity of various cell types have obtained variable results depending primarily on the experimental model applied. It was recently reported that neither GHREL nor obestatin (OBS) affected the proliferative activity of cultured rat adrenocortical cells. In view of the conflicting results, we investigated the effects of GHREL and OBS on the proliferative activity of rat adrenocortical cells in a model of bilateral enucleation-induced adrenocortical regeneration in the rat. Rats were sacrificed 5 or 8 days after surgery. Twenty-four hours before being sacrificed, the appropriate groups were infused with 3 nmol GHREL or OBS/100 g. The mitotic index was assessed using the stachmokinetic method with vincristine. In comparison with intact rats, expression levels of ppGHREL, BAX, JUN-B and JUN-C genes were notably higher in regenerating adrenals, and neither GHREL nor OBS infusion affected these levels. Expression levels of the GHS-R, GPR39v2 and FOS genes were affected neither by adrenal enucleation nor GHREL or OBS infusion. Expression of only two studied genes, GPR39v1 and EGR1, was regulated by OBS. In the regenerating adrenal glands, GPR39v1 and EGR1 mRNA levels were higher than the levels in intact animals. GHREL infusion had no effect while OBS infusion notably stimulated GPR39v1 mRNA levels in the regenerating adrenal gland and evoked an opposite effect on EGR1 mRNA. OBS administration resulted in a potent decrease in the mitotic index of the studied cells, an effect found at both days 5 and 8 of the experiment. GHREL exerted a similar effect only at day 5 of adrenocortical regeneration. Neither GHREL nor OBS had an effect on blood aldosterone concentrations. GHREL infusion lowered plasma corticosterone concentration at day 5 but not 8 of the experiment, while OBS administration was ineffective. Thus, this study is the first to demonstrate that, in vivo, both GHREL and OBS inhibit the

  8. Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children

    PubMed Central

    Kroenke, Candyce H; Epel, Elissa; Adler, Nancy; Bush, Nicole R.; Obradović, Jelena; Lin, Jue; Blackburn, Elizabeth; Stamperdahl, Juliet Lise; Boyce, W. Thomas

    2011-01-01

    Objective To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children. Methods The study sample comprised 78 five- and six-year-old children from a longitudinal cohort study of kindergarten social hierarchies, biological responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by realtime PCR, as the telomere-to-single copy gene (T/S) ratio. Parents provided demographic information; parents and teachers reported children’s internalizing and externalizing behavior problems. Components of children’s autonomic (heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP)) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relations between reactivity, internalizing and externalizing behavior, and BTL, adjusted for age, race, and gender. Results Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated. Internalizing behaviors were also inversely related to BTL (standardized β=−0.33, p=0.004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP) and high parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (N=12) had significantly shorter BTL (0.80 vs. 1.00, χ2=7.6, p=0.006), compared with other children. Conclusions Autonomic and adrenocortical reactivity in combination were associated with shorter buccal cell telomere length in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biological aging. PMID:21873585

  9. The PI3K/Akt Pathway in Tumors of Endocrine Tissues

    PubMed Central

    Robbins, Helen Louise; Hague, Angela

    2016-01-01

    The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a key driver in carcinogenesis. Defects in this pathway in human cancer syndromes such as Cowden’s disease and Multiple Endocrine Neoplasia result in tumors of endocrine tissues, highlighting its importance in these cancer types. This review explores the growing evidence from multiple animal and in vitro models and from analysis of human tumors for the involvement of this pathway in the following: thyroid carcinoma subtypes, parathyroid carcinoma, pituitary tumors, adrenocortical carcinoma, phaeochromocytoma, neuroblastoma, and gastroenteropancreatic neuroendocrine tumors. While data are not always consistent, immunohistochemistry performed on human tumor tissue has been used alongside other techniques to demonstrate Akt overactivation. We review active Akt as a potential prognostic marker and the PI3K pathway as a therapeutic target in endocrine neoplasia. PMID:26793165

  10. Characterizing adrenocortical activity in zoo-housed southern three-banded armadillos (Tolypeutes matacus).

    PubMed

    Howell-Stephens, Jennifer A; Brown, Joel S; Bernier, David; Mulkerin, Diane; Santymire, Rachel M

    2012-08-01

    Improving the husbandry in the southern three-banded armadillo (Tolypeutes matacus) through gaining knowledge of its stress physiology is imperative to maintaining a healthy, zoo-housed population. Our objectives were to: 1) validate the use of fecal hormone analysis for monitoring adrenocortical activity using both an adrenocorticotropic hormone (ACTH) challenge and biological events; and 2) characterize longitudinal adrenocortical activity in male and female southern three-banded armadillos. An ACTH injection was given intra-muscularly to one male (4IU/kg; 5.6IU total) and one female (5.5IU/kg; 8IU total) southern three-banded armadillo. Fecal samples were collected 1 day pre- and continued 5 days post-ACTH to capture the physiological response measured by elevated fecal glucocorticoid metabolites (FGM) to validate these techniques. Additionally, natural and routine events, including pairing individuals for breeding and veterinary procedures/handling, were used to biologically validate these techniques. To characterize adrenocortical activity, fecal samples (∼3025 total; n=275/animal/yr) were collected from 11 (5 males; 6 females) southern three-banded armadillos 5-7 times a week for 1 year at Lincoln Park Zoo (Chicago, IL). A cortisol enzyme immunoassay was used for FGM analysis. The ACTH challenge in the male resulted in a twofold increase of FGM (1123.2±36.2 ng/g dry feces) above baseline (675.7±10.0 ng/g dry feces) at approximately 54-94h post- injection. The female exhibited a twofold increase (1635.4 ng/g dry feces) over baseline FGMs (608.5±12.3 ng/g dry feces) approximately 30h post-injection. Reproductive behaviors and veterinary procedures resulted in elevated FGM concentrations from all individuals except for one male. The longitudinal characterization demonstrated that sex and season did not influence (P<0.05) FGM concentrations. Individuals were highly variable with mean FGM concentration of 2010.1±862.4 ng/g dry feces (range, 816.3-7889.1 ng

  11. Properties and requirements for production of a macrophage product which suppresses steroid production by adrenocortical cells.

    PubMed Central

    Mathison, J C; La Forest, A C; Ulevitch, R J

    1984-01-01

    Lipopolysaccharide-treated murine peritoneal exudate macrophages (PEM) release a factor or factors into the supernatant that suppress adrenocorticotropic hormone-induced steroidogenesis in explanted rabbit adrenocortical cells (J. C. Mathison et al., J. Immunol. 130:2757-2762, 1983). To determine the requirements for suppression, PEM supernatants (30 microliters) were added to explanted rabbit adrenocortical cells in a final volume of 120 microliters with 10 mU of adrenocorticotropic hormone per ml, and after 18 h at 37 degrees C, steroid concentrations were measured by a fluorometric assay. Supernatant from proteose peptone-elicited C3HeB/FeJ PEM (5 X 10(6) PEM per 3.5-cm well, 10 micrograms of Salmonella minnesota Re595 LPS per ml, 18 h) suppressed steroid production ca. 50%, and kinetic studies demonstrated that the appearance of suppressive activity in the supernatant was gradual over 4 to 18 h. Release of suppressive activity was not associated with decreased viability of the PEM (assessed by fluorescein diacetate staining and measurement of lactic dehydrogenase in the supernatant). Suppression was not observed when the PEM supernatant was diluted 10-fold before addition to the adrenocortical cells, whereas supernatant concentrated 20-fold (prepared with a 10,000-molecular-weight-cutoff filter) produced 75 to 80% suppression. The suppressive activity was stable at pH 4, pH 11, or 70 degrees C for 30 min but was inactivated at 100 degrees C (10 min). Suppressive activity was also induced in C3HeB/FeJ PEM by O111:B4 lipopolysaccharide or heat-killed Listeria monocytogenes. In contrast, PEM from C3H/HeJ mice did not produce detectable suppressive activity in response to Re595 lipopolysaccharide or heat-killed L. monocytogenes. Thus, these results provide additional support for the inducible, selective release of a macrophage product that could affect the host response to lipopolysaccharide by regulation of the adrenocortical response to adrenocorticotropic

  12. Cortisol-secreting adrenocortical tumours in dogs and their relevance for human medicine.

    PubMed

    Galac, Sara

    2016-02-01

    Spontaneous cortisol-secreting adrenocortical tumours in pet dogs are an attractive animal model for their human counterparts. Adrenal morphology and function are similar in dogs and humans, and adrenocortical tumours have comparable clinical and pathological characteristics. Their relatively high incidence in pet dogs represents a potential source of adrenocortical tumour tissue to facilitate research. The molecular characteristics of canine cortisol-secreting adrenocortical tumours suggest that they will be useful for the study of angiogenesis, the cAMP/protein kinase A pathway, and the role of Steroidogenic Factor-1 in adrenal tumourigenesis. Pet dogs with spontaneous cortisol-secreting adrenocortical tumours may also be useful in clinical testing of new drugs and in investigating the molecular background of adrenocortical tumours. PMID:26123587

  13. Expression of the spexin gene in the rat adrenal gland and evidences suggesting that spexin inhibits adrenocortical cell proliferation.

    PubMed

    Rucinski, Marcin; Porzionato, Andrea; Ziolkowska, Agnieszka; Szyszka, Marta; Macchi, Veronica; De Caro, Raffaele; Malendowicz, Ludwik K

    2010-04-01

    Spexin (SPX, also called NPQ) is a recently identified, highly conserved peptide which is processed and secreted. We analysed the SPX gene and its protein product in the rat adrenal gland to ascertain whether SPX is involved in the regulation of corticosteroid secretion of and growth of adrenocortical cells. In adult rat adrenal glands the highest levels of SPX mRNA were present in the glomerulosa (ZG) and fasciculate/reticularis (ZF/R) zones. High SPX gene expression levels were found in freshly isolated adult rat ZG and ZF/R cells. In cultured adrenocortical cells the levels of SPX mRNA were lower than in freshly isolated cells. SPX mRNA expression levels were found to be 2-3 times higher during days 90-540 of postnatal development than found during days 2-45. Prolonged ACTH administration lowered and dexamethasone increased adrenal SPX mRNA levels in vivo. Adrenal enucleation produced a significant linear increase in SPX mRNA levels, with the highest value occurring at day 8 after surgery, with control values taken on day 30 after enucleation. Immunohistochemistry revealed SPX-like immunoreactivity in the entire cortex of the adult male rat and in enucleation-induced regenerating cortex. A concentration of 10-6M SPX peptide stimulated basal aldosterone secretion by freshly isolated ZG. In prolonged exposure of adrenocortical cell primary cultures to SPX (10-6M) resulted in a small increase in corticosterone secretion and a notable decrease in BrdU incorporation. The results suggest the direct involvement of SPX in the regulation of adrenocortical cell proliferation; however, the mechanism of action remains unknown. PMID:20045034

  14. Environmental enrichment affects adrenocortical stress responses in the endangered black-footed ferret.

    PubMed

    Poessel, Sharon A; Biggins, Dean E; Santymire, Rachel M; Livieri, Travis M; Crooks, Kevin R; Angeloni, Lisa

    2011-07-01

    Potential stressors of wildlife living in captivity, such as artificial living conditions and frequent human contact, may lead to a higher occurrence of disease and reduced reproductive function. One successful method used by wildlife managers to improve general well-being is the provision of environmental enrichment, which is the practice of providing animals under managed care with environmental stimuli. The black-footed ferret (Mustela nigripes) is a highly-endangered carnivore species that was rescued from extinction by removal of the last remaining individuals from the wild to begin an ex situ breeding program. Our goal was to examine the effect of environmental enrichment on adrenocortical activity in ferrets by monitoring fecal glucocorticoid metabolites (FGM). Results demonstrated that enrichment lowered FGM in juvenile male ferrets, while increasing it in adult females; enrichment had no effect on FGM in juvenile females and adult males. These results correspond with our findings that juvenile males interacted more with the enrichment items than did adult females. However, we did not detect an impact of FGM on the incidence of disease or on the ability of ferrets to become reproductive during the following breeding season. We conclude that an environmental enrichment program could benefit captive juvenile male ferrets by reducing adrenocortical activity. PMID:21549121

  15. Environmental enrichment affects adrenocortical stress responses in the endangered black-footed ferret

    USGS Publications Warehouse

    Poessel, S.A.; Biggins, D.E.; Santymire, R.M.; Livieri, T.M.; Crooks, K.R.; Angeloni, L.

    2011-01-01

    Potential stressors of wildlife living in captivity, such as artificial living conditions and frequent human contact, may lead to a higher occurrence of disease and reduced reproductive function. One successful method used by wildlife managers to improve general well-being is the provision of environmental enrichment, which is the practice of providing animals under managed care with environmental stimuli. The black-footed ferret (Mustela nigripes) is a highly-endangered carnivore species that was rescued from extinction by removal of the last remaining individuals from the wild to begin an ex situ breeding program. Our goal was to examine the effect of environmental enrichment on adrenocortical activity in ferrets by monitoring fecal glucocorticoid metabolites (FGM). Results demonstrated that enrichment lowered FGM in juvenile male ferrets, while increasing it in adult females; enrichment had no effect on FGM in juvenile females and adult males. These results correspond with our findings that juvenile males interacted more with the enrichment items than did adult females. However, we did not detect an impact of FGM on the incidence of disease or on the ability of ferrets to become reproductive during the following breeding season. We conclude that an environmental enrichment program could benefit captive juvenile male ferrets by reducing adrenocortical activity. ?? 2011 Elsevier Inc.

  16. Combined transcriptome studies identify AFF3 as a mediator of the oncogenic effects of β-catenin in adrenocortical carcinoma

    PubMed Central

    Lefèvre, L; Omeiri, H; Drougat, L; Hantel, C; Giraud, M; Val, P; Rodriguez, S; Perlemoine, K; Blugeon, C; Beuschlein, F; de Reyniès, A; Rizk-Rabin, M; Bertherat, J; Ragazzon, B

    2015-01-01

    Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/β-catenin signaling pathway. However, the adrenal-specific targets of oncogenic β-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous β-catenin activating mutation was done to identify the Wnt/β-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of β-catenin in ACC. The Wnt response element site located at nucleotide position −1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/β-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing. PMID:26214578

  17. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study.

    PubMed

    Du, Yeting; Ter-Minassian, Monica; Brais, Lauren; Brooks, Nichole; Waldron, Amanda; Chan, Jennifer A; Lin, Xihong; Kraft, Peter; Christiani, David C; Kulke, Matthew H

    2016-08-01

    The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. PMID:27492634

  18. Comparison of the Effects of PRKAR1A and PRKAR2B Depletion on Signaling Pathways, Cell Growth, and Cell Cycle Control of Adrenocortical Cells

    PubMed Central

    Basso, F.; Rocchetti, F.; Rodriguez, S.; Nesterova, M.; Cormier, F.; Stratakis, C.; Ragazzon, B.; Bertherat, J.; Rizk-Rabin, M.

    2016-01-01

    The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation in the abundance of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-κB pathway. Nonetheless, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression. PMID:25268545

  19. Comparison of the effects of PRKAR1A and PRKAR2B depletion on signaling pathways, cell growth, and cell cycle control of adrenocortical cells.

    PubMed

    Basso, F; Rocchetti, F; Rodriguez, S; Nesterova, M; Cormier, F; Stratakis, C A; Ragazzon, B; Bertherat, J; Rizk-Rabin, M

    2014-11-01

    The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-κB pathway. However, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression. PMID:25268545

  20. Incidence and Risk Factors Associated with Readmission After Surgical Treatment for Adrenocortical Carcinoma

    PubMed Central

    Valero-Elizondo, Javier; Kim, Yuhree; Prescott, Jason D.; Margonis, Georgios A.; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Glenn, Jason A.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Poultsides, George A.

    2016-01-01

    Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Given the lack of data on readmission after resection of ACC, the objective of the current study was to define the incidence of readmission, as well as identify risk factors associated with readmission among patients with ACC who underwent surgical resection. Methods Two hundred nine patients who underwent resection of ACC between January 1993 and December 2014 at 1 of 13 major centers in the USA were identified. Demographic and clinicopathological data were collected and analyzed relative to readmission. Results Median patient age was 52 years, and 62 % of the patients were female. Median tumor size was 12 cm, and the majority of patients had an American Society of Anesthesiologists (ASA) class of 3–4 (n=85, 56 %). The overall incidence of readmission within 90 days from surgery was 18 % (n=38). Factors associated with readmission included high ASA class (odds ratio (OR), 4.88 (95 % confidence interval (CI), 1.75–13.61); P=0.002), metastatic disease on presentation (OR, 2.98 (95 % CI, 1.37–6.46); P=0.006), EBL (>700 mL: OR, 2.75 (95 % CI, 1.16–6.51); P=0.02), complication (OR, 1.91 (95 % CI, 1.20–3.05); P=0.007), and prolonged length of stay (LOS; ≥9 days: OR, 4.12 (95 % CI, 1.88–9.01); P<0.001). On multivariate logistic regression, a high ASA class (OR, 4.01 (95 % CI, 1.44–11.17); P=0.008) and metastatic disease on presentation (OR, 3.44 (95 % CI, 1.34–8.84); P=0.01) remained independently associated with higher odds of readmission. Conclusion Readmission following surgery for ACC was common as one in five patients experienced a readmission. Patients with a high ASA class and metastatic disease on presentation were over four and three times more likely to be readmitted after surgical treatment for ACC, respectively. PMID:26286367

  1. Curative Resection of Adrenocortical Carcinoma: Rates and Patterns of Postoperative Recurrence

    PubMed Central

    Amini, Neda; Margonis, Georgios Antonios; Kim, Yuhree; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Evans, Douglas B.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Poultsides, George A.; Pawlik, Timothy M.

    2016-01-01

    Background Adrenocortical carcinoma (ACC) is a rare malignancy. The aim of this study was to determine the incidence and patterns of recurrence after curative-intent surgery for ACC. Methods Patients who underwent curative-intent resection for ACC between 1993 and 2014 were identified from 13 academic institutions participating in the United States ACC study group. Patients with metastasis or an R2 margin were excluded. Patterns and rates of recurrence were determined and classified as locoregional and distant recurrence. Results A total of 180 patients with a median age of 52 years (interquartile range 43–61) were identified. Most patients underwent open surgery (n = 111, 64.5 %) and had an R0 resection margin (n = 117, 75.0 %). At last followup, 116 patients (64.4 %) had experienced recurrence (locoregional only, n = 41, 36.3 %; distant only, n = 51, 45.1 %; locoregional and distant, n = 21, 18.6 %). Median time to recurrence was 18.8 months. Several factors were associated with locoregional recurrence, including left-sided ACC location (odds ratio [OR] 2.71, 95 % confidence interval [CI] 1.06–6.89) and T3/T4 disease (reference T1/T2, OR 3.04, 95 % CI 1.19–7.80) (both p < 0.05). Distant recurrence was associated with larger tumor size (OR 1.11, 95 % CI 1.01–1.24) and T3/T4 disease (reference T1/T2, OR 5.23, 95 % CI 1.70–16.10) (both p < 0.05). Patients with combined locoregional and distant recurrence had worse survival (3- and 5-year survival: 39.5, 19.7 %) versus patients with distant-only (3- and 5-year survival 55.1, 43.3 %) or locoregional-only recurrence (3- and 5-year survival 81.4, 64.1 %) (p = 0.01). Conclusions Nearly two-thirds of patients experienced disease recurrence after resection of ACC. Although a subset of patients experienced recurrence with locoregional disease only, many patients experienced recurrence with distant disease as a component of recurrence and had a poor prognosis. PMID:26282907

  2. Adrenocortical Cells with Stem/Progenitor Cell Properties: Recent Advances

    PubMed Central

    Kim, Alex; Hammer, Gary D.

    2007-01-01

    The existence and location of undifferentiated cells with the capability of maintaining the homeostasis of the adrenal cortex have long been sought. These cells are thought to remain mostly quiescent with a potential to commit to self-renewal processes or terminal differentiation to homeostatically repopulate the organ. In addition, in response to physiologic stress, the undifferentiated cells undergo rapid proliferation to accommodate organismic need. Sufficient adrenocortical proliferative capacity lasting the lifespan of the host has been demonstrated through cell transplantation and enucleation experiments. Labeling experiments with tritium, BrdU, or trypan blue, as well as transgenic assays support the clonogenic identity and location of these undefined cells within the gland periphery. We define undifferentiated adrenocortical cells as cells devoid of steroidogenic gene expression, and differentiated cells as cells with steroidogenic capacity. In this review, we discuss historic developmental studies together with recent molecular examinations that aim to characterize such populations of cells. PMID:17240045

  3. A Large Family with Carney Complex Caused by the S147G PRKAR1A Mutation Shows a Unique Spectrum of Disease Including Adrenocortical Cancer

    PubMed Central

    Anselmo, João; Medeiros, Sandra; Carneiro, Victor; Greene, Elizabeth; Levy, Isaac; Nesterova, Maria; Lyssikatos, Charalampos; Horvath, Anelia; Carney, J. Aidan

    2012-01-01

    Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. Objective: We studied the genotype-phenotype correlation in CNC. Design and Setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro. Conclusions: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD

  4. Quantitative CT for volumetric analysis of medical images: initial results for liver tumors

    NASA Astrophysics Data System (ADS)

    Behnaz, Alexander S.; Snider, James; Chibuzor, Eneh; Esposito, Giuseppe; Wilson, Emmanuel; Yaniv, Ziv; Cohen, Emil; Cleary, Kevin

    2010-03-01

    Quantitative CT for volumetric analysis of medical images is increasingly being proposed for monitoring patient response during chemotherapy trials. An integrated MATLAB GUI has been developed for an oncology trial at Georgetown University Hospital. This GUI allows for the calculation and visualization of the volume of a lesion. The GUI provides an estimate of the volume of the tumor using a semi-automatic segmentation technique. This software package features a fixed parameter adaptive filter from the ITK toolkit and a tumor segmentation algorithm to reduce inter-user variability and to facilitate rapid volume measurements. The system also displays a 3D rendering of the segmented tumor, allowing the end user to have not only a quantitative measure of the tumor volume, but a qualitative view as well. As an initial validation test, several clinical cases were hand-segmented, and then compared against the results from the tool, showing good agreement.

  5. Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm.

    PubMed

    Corrales, J J; Robles-Lázaro, C; Sánchez-Marcos, A I; González-Sánchez, M C; Antúnez-Plaza, P; Miralles, J M

    2016-01-01

    Adrenocortical oncocytic neoplasms (oncocytomas) are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol) and androgens (androstenedione and DHEAS), a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing's syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline) according to the Lin-Weiss-Bisceglia criteria. PMID:27413559

  6. Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm

    PubMed Central

    Corrales, J. J.; Robles-Lázaro, C.; Sánchez-Marcos, A. I.; González-Sánchez, M. C.; Antúnez-Plaza, P.; Miralles, J. M.

    2016-01-01

    Adrenocortical oncocytic neoplasms (oncocytomas) are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol) and androgens (androstenedione and DHEAS), a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing's syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline) according to the Lin-Weiss-Bisceglia criteria. PMID:27413559

  7. TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation

    PubMed Central

    Atretkhany, Kamar-Sulu N.; Nosenko, Maxim A.; Gogoleva, Violetta S.; Zvartsev, Ruslan V.; Qin, Zhihai; Nedospasov, Sergei A.; Drutskaya, Marina S.

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo. PMID:27148266

  8. TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation.

    PubMed

    Atretkhany, Kamar-Sulu N; Nosenko, Maxim A; Gogoleva, Violetta S; Zvartsev, Ruslan V; Qin, Zhihai; Nedospasov, Sergei A; Drutskaya, Marina S

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo. PMID:27148266

  9. Endoscopic Ultrasonography-Guided Ethanol Ablation for Small Pancreatic Neuroendocrine Tumors: Results of a Pilot Study

    PubMed Central

    Choi, Jun-Ho; Oh, Dongwook; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2015-01-01

    Background/Aims Endoscopic ultrasonography (EUS)-guided ethanol ablation is gaining popularity for the treatment of focal pancreatic lesions. The aim of this study was to evaluate the safety, feasibility, and treatment response after EUS-guided ethanol injection for small pancreatic neuroendocrine tumors (p-NETs). Methods This was a retrospective analysis of a prospectively collected database including 11 consecutive patients with p-NETs who underwent EUS-guided ethanol injection. Results EUS-guided ethanol injection was successfully performed in 11 patients with 14 tumors. The final diagnosis was based on histology and clinical signs as follows: 10 non-functioning neuroendocrine tumors and four insulinomas. During follow-up (median, 370 days; range, 152 to 730 days), 10 patients underwent clinical follow-up after treatment, and one patient was excluded because of loss to follow-up. A single treatment session with an injection of 0.5 to 3.8 mL of ethanol resulted in complete responses (CRs) at the 3-month radiologic imaging for seven of 13 tumors (response rate, 53.8%). Multiple treatment sessions performed in three tumors with residual viable enhancing tissue increased the number of tumors with CRs to eight of 13 (response rate, 61.5%). Mild pancreatitis occurred in three of 11 patients. Conclusions EUS-guided ethanol injection appears to be a safe, feasible, and potentially effective method for treating small p-NETs in patients who are poor surgical candidates. PMID:25844345

  10. Adrenocortical function of Arctic-breeding glaucous gulls in relation to persistent organic pollutants.

    PubMed

    Verboven, Nanette; Verreault, Jonathan; Letcher, Robert J; Gabrielsen, Geir W; Evans, Neil P

    2010-03-01

    Unpredictable changes in the environment stimulate the avian hypothalamo-pituitary-adrenal axis to produce corticosterone, which induces behavioural and metabolic changes that enhance survival in the face of adverse environmental conditions. In addition to profound environmental perturbations, such as severe weather conditions and unpredictable food shortages, many Arctic-breeding birds are also confronted with chronic exposure to persistent organic pollutants (POPs), some of which are known to disrupt endocrine processes. This study investigated the adrenocortical function of a top predator in the Arctic marine environment, the glaucous gull (Larus hyperboreus). High concentrations of organochlorines, brominated flame retardants and metabolically-derived products in blood plasma of incubating glaucous gulls were associated with high baseline corticosterone concentrations in both sexes and a reduced stress response in males. Contaminant-related changes in corticosterone concentration occurred over and above differences in body condition and seasonal variation. Chronically high corticosterone concentrations and/or a compromised adrenocortical response to stress can have negative effects on the health of an individual. The results of the present study suggest that exposure to POPs may increase the vulnerability of glaucous gulls to environmental stressors and thus could potentially compromise their ability to adapt to the rapidly changing environmental conditions associated with climate change that are currently seen in the Arctic. PMID:19932109

  11. Evaluation of the results of surgery treatment in patients with benign lung tumors

    PubMed Central

    Bagheri, Reza; Haghi, Seyed Ziaollah; Dalouee, Marziyeh Nouri; Nasiri, Zakiyeh; Rajabnejad, Ata’ollah

    2015-01-01

    Background: Lung tumors are among the common tumors and can be benign or malignant. Benign lung tumors are less common compared to the malignant types. Recognition of the clinical symptoms, types of tumors, paraclinical findings, and treatment approaches can bring better therapeutic results. The present study aims to evaluate the characteristics, diagnosis methods, and therapeutic approaches of different benign lung tumors. Materials and Methods: In this retrospective study, 32 patients with a diagnosis of benign lung tumor, who had been referred to the Mashhad University of Medical Sciences between 1981 and 2009, were studied. Some of the studied variables were symptoms, the pulmonary location involved, surgery technique, pathology findings, recurrence, and surgery complications. Data were analyzed by SPSS package version 16. Results: The average age of the patients was 51.69 ± 20.5 years. Prevalence of benign lung tumors was equal in both genders. The most common symptom was cough (31.2%); right lung involvement was more common (71.9%), and the most common sampling technique was transbronchial lung biopsy (TBLB) (62.5%); 53.1% of the patients were operated on by thoracotomy and the wedge resection technique. In 78.1% of the patients, no complications occurred after surgery. There was no recurrence. Most operations were performed in one month after the start of the symptoms (68.8%). Conclusions: Benign lung tumors are commonly diagnosed by routine radiography because most of them are asymptomatic. The most common finding in radiography is the presence of mass in the lungs. Transbronchial lung biopsy is a valuable technique to be used for diagnosis. We chose thoracotomy and wedge resection for the treatment of patients. We recommend this approach as a useful method. PMID:25624593

  12. Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

    SciTech Connect

    Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M. )

    1991-02-01

    The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.

  13. Current results from treatment of bladder tumors with total cystectomy at roswell park memorial institute.

    PubMed

    Wajsman, Z; Merrin, C; Moore, R; Murphy, G P

    1975-06-01

    Results of our recent cystectomy series revealed good survival for patients with superficial bladder tumors. The morbidity rate was low, 8.6 per cent. Our series showed a statistically significant postoperative morbidity rate in a high risk patient group, then justifying preoperative selection of patients as condidates for this major operation. However, we believe that despite relatively good results in reducing the morbitidy and mortality rates and improvement in survival, the over-all results in treatment of bladder tumors with operation alone are still unsatisfactory and there is an urgent need to develop and to investigate new and combined modalities of treatment. PMID:807747

  14. Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Else, Tobias; Griffith, Kent A.; Ben-Josef, Edgar; Williams, Andrew; Miller, Barbra S.; Worden, Francis; Jolly, Shruti

    2015-06-01

    Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. Methods and Materials: We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. Results: From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. Conclusions: Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed.

  15. Adrenocorticotrophic hormone stimulates phosphotyrosine phosphatase SHP2 in bovine adrenocortical cells: phosphorylation and activation by cAMP-dependent protein kinase.

    PubMed Central

    Rocchi, S; Gaillard, I; van Obberghen, E; Chambaz, E M; Vilgrain, I

    2000-01-01

    During activation of adrenocortical cells by adrenocorticotrophic hormone (ACTH), tyrosine dephosphorylation of paxillin is stimulated and this correlates with protrusion of filopodial structures and a decreased number of focal adhesions. These effects are inhibited by Na(3)VO(4), a phosphotyrosine phosphatase inhibitor [Vilgrain, Chinn, Gaillard, Chambaz and Feige (1998) Biochem. J. 332, 533-540]. However, the tyrosine phosphatases involved in these processes remain to be identified. In this study, we provide evidence that the Src homology domain (SH)2-containing phosphotyrosine phosphatase (SHP)2, but not SHP1, is expressed in adrenocortical cells and is phosphorylated upon ACTH challenge. ACTH (10(-8) M) treatment of (32)P-labelled adrenocortical cells resulted in an increase in phosphorylated SHP2. By probing SHP2-containing immunoprecipitates with an antibody to phosphoserine we found that SHP2 was phosphorylated on serine in ACTH-treated cells in a dose- and time-dependent manner. Furthermore, using an in vitro kinase assay, we showed that SHP2 was a target for cAMP-dependent protein kinase (PKA). Serine was identified as the only target amino acid phosphorylated in SHP2. Phosphorylation of SHP2 by PKA resulted in a dramatic stimulation of phosphatase activity measured either with insulin receptor substrate-1 or with the synthetic peptide [(32)P]poly(Glu/Tyr) as substrate. In an in-gel assay of SHP2-containing immunoprecipitates, phosphorylated in vitro by PKA or isolated from adrenocortical cells treated with 10 nM ACTH, a pronounced activation of SHP2 activity was shown. These observations clearly support the idea that a PKA-mediated signal transduction pathway contributes to SHP2 regulation in adrenocortical cells and point to SHP2 as a possible mediator of the effects of ACTH. PMID:11085942

  16. Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors

    PubMed Central

    Nielsen, Helene Myrtue; How-Kit, Alexandre; Guerin, Carole; Castinetti, Frederic; Vollan, Hans Kristian Moen; De Micco, Catherine; Daunay, Antoine; Taieb, David; Van Loo, Peter; Besse, Celine; Kristensen, Vessela N; Hansen, Lise Lotte; Barlier, Anne; Sebag, Frederic; Tost, Jörg

    2015-01-01

    Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof. PMID:26400872

  17. Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors.

    PubMed

    Nielsen, Helene Myrtue; How-Kit, Alexandre; Guerin, Carole; Castinetti, Frederic; Vollan, Hans Kristian Moen; De Micco, Catherine; Daunay, Antoine; Taieb, David; Van Loo, Peter; Besse, Celine; Kristensen, Vessela N; Hansen, Lise Lotte; Barlier, Anne; Sebag, Frederic; Tost, Jörg

    2015-12-01

    Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof. PMID:26400872

  18. Combined Use of Etomidate and Dexmedetomidine Produces an Additive Effect in Inhibiting the Secretion of Human Adrenocortical Hormones.

    PubMed

    Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

    2015-01-01

    BACKGROUND The direct effects of etomidate were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of human of animals. Dexmedetomidine (DEX) is an anesthetic agent that may interfere with cortisol secretion via an unknown mechanism, such as involving inhibition of 11b-hydroxylase and the cholesterol side-chain cleavage enzyme system. The aim of this study was to determine whether dexmedetomidine (DEX) has a similar inhibitory effect on adrenocortical function, and whether combined use of etomidate (ETO) and DEX could produce a synergistic action in inhibiting the secretion of human adrenocortical hormones. MATERIAL AND METHODS Human adrenocortical cells were exposed to different concentrations of ETO and DEX. The dose-effect model between the ETO concentration and the mean secretion of cortisone (CORT) and aldosterone (ALDO) per hour was estimated. RESULTS Hill's equation well-described the dose-effect correlation between the ETO concentration and the amount of ALDO and CORT secretion. When the DEX concentration was introduced into the model by using E0 (basal secretion) as the covariate, the goodness of fit of the ETO-CORT dose-effect model was improved significantly and the objective function value was reduced by 4.55 points (P<0.05). The parameters of the final ETO-ALDO pharmacodynamics model were EC50=9.74, Emax=1.20, E0=1.33, and γ=18.5; the parameters of the final ETO-CORT pharmacodynamics model were EC50=9.49, Emax=8.16, E0=8.57, and γ=37.0. In the presence of DEX, E0 was 8.57-0.0247×(CDEX-4.6), and the other parameters remained unchanged. All parameters but γ were natural logarithm conversion values. CONCLUSIONS Combined use of DEX and ETO reduced ETO's inhibitory E0 (basal secretion) of CORT from human adrenocortical cells in a dose-dependent manner, suggesting that combined use of ETO and DEX produced an additive effect in inhibiting the secretion of human adrenocortical hormones. PMID:26568275

  19. Combined Use of Etomidate and Dexmedetomidine Produces an Additive Effect in Inhibiting the Secretion of Human Adrenocortical Hormones

    PubMed Central

    Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

    2015-01-01

    Background The direct effects of etomidate were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of human of animals. Dexmedetomidine (DEX) is an anesthetic agent that may interfere with cortisol secretion via an unknown mechanism, such as involving inhibition of 11β-hydroxylase and the cholesterol side-chain cleavage enzyme system. The aim of this study was to determine whether dexmedetomidine (DEX) has a similar inhibitory effect on adrenocortical function, and whether combined use of etomidate (ETO) and DEX could produce a synergistic action in inhibiting the secretion of human adrenocortical hormones. Material/Methods Human adrenocortical cells were exposed to different concentrations of ETO and DEX. The dose-effect model between the ETO concentration and the mean secretion of cortisone (CORT) and aldosterone (ALDO) per hour was estimated. Results Hill’s equation well-described the dose-effect correlation between the ETO concentration and the amount of ALDO and CORT secretion. When the DEX concentration was introduced into the model by using E0 (basal secretion) as the covariate, the goodness of fit of the ETO-CORT dose-effect model was improved significantly and the objective function value was reduced by 4.55 points (P<0.05). The parameters of the final ETO-ALDO pharmacodynamics model were EC50=9.74, Emax=1.20, E0=1.33, and γ=18.5; the parameters of the final ETO-CORT pharmacodynamics model were EC50=9.49, Emax=8.16, E0=8.57, and γ=37.0. In the presence of DEX, E0 was 8.57–0.0247×(CDEX–4.6), and the other parameters remained unchanged. All parameters but γ were natural logarithm conversion values. Conclusions Combined use of DEX and ETO reduced ETO’s inhibitory E0 (basal secretion) of CORT from human adrenocortical cells in a dose-dependent manner, suggesting that combined use of ETO and DEX produced an additive effect in inhibiting the secretion of human adrenocortical hormones. PMID

  20. Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies.

    PubMed

    Kubota-Nakayama, Fumie; Nakamura, Yasuhiro; Konosu-Fukaya, Sachiko; Azmahani, Abdullah; Ise, Kazue; Yamazaki, Yuto; Kitawaki, Yuko; Felizola, Saulo J A; Ono, Yoshikiyo; Omata, Kei; Morimoto, Ryo; Iwama, Noriyuki; Satoh, Fumitoshi; Sasano, Hironobu

    2016-08-01

    Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 11β-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced-B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription. PMID:27085553

  1. Tumor

    MedlinePlus

    ... be removed because of their location or harmful effect on the surrounding normal brain tissue. If a tumor is cancer , possible treatments may include: Chemotherapy Radiation Surgery Targeted cancer therapy Biologic therapy Other treatment options

  2. Breast Carcinomatous Tumoral Emboli Can Result From Encircling Lymphovasculogenesis Rather Than Lymphovascular Invasion

    PubMed Central

    Mahooti, Sepi; Porter, Kyle; Alpaugh, Mary L.; Ye, Yin; Xiao, Yi; Jones, Susie; Tellez, Joseph D.; Barsky, Sanford H.

    2010-01-01

    The canonical view of the origin of tumor lymphovascular emboli is that they usually originate from lymphovascular invasion as part of a multistep metastatic process. Recent experimental evidence has suggested that metastasis can occur earlier than previously thought and we found evidence that tumor emboli formation can result from the short-circuiting step of encircling lymphovasculogenesis. Experimentally, we used a xenograft of human inflammatory breast cancer (MARY-X), a model that exhibited florid tumor emboli, to generate tumoral spheroids in vitro. In observational studies, we chose human breast carcinoma cases where there appeared to be a possible transition of in situ carcinoma to lymphovascular emboli without intervening stromal invasion. These cases were studied by morphometry as well as IHC with tumor proliferation (Ki-67) and adhesion (E-cadherin) markers, myoepithelial (p63), as well as endothelial (podoplanin [D2-40], CD31, VEGFR-3, Prox-1) markers. Unlabelled spheroids coinjected with either GFP or RFP-human myoepithelial cells or murine embryonal fibroblasts (MEFs) gave rise to tumors which exhibited GFP/RFP immunoreactivity within the cells lining the emboli-containing lymphovascular channels. In vitro studies demonstrated that the tumoral spheroids induced endothelial differentiation of cocultured myoepithelial cells and MEFs, measured by real time PCR and immunofluorescence. In humans, the in situ clusters exhibited similar proliferation, E-cadherin immunoreactivity and size as the tumor emboli (p =.5), suggesting the possibility that the latter originated from the former. The in situ clusters exhibited a loss (50%-100%) of p63 myoepithelial immunoreactivity but not E-cadherin epithelial immunoreactivity. The tumor emboli were mainly present within lymphatic channels whose dual p63/CD31, p63/D2-40 and p63/VEGFR-3 and overall weak patterns of D2-40/CD31/VEGFR-3 immunoreactivities suggested that they represented immature and newly created

  3. Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

    SciTech Connect

    Kim, Yoo-Shin; Lee, Tae Hoon; O'Neill, Brian E.

    2015-08-14

    Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

  4. Steroidogenic Acute Regulatory Protein Overexpression Correlates with Protein Kinase A Activation in Adrenocortical Adenoma.

    PubMed

    Zhou, Weiwei; Wu, Luming; Xie, Jing; Su, Tingwei; Jiang, Lei; Jiang, Yiran; Cao, Yanan; Liu, Jianmin; Ning, Guang; Wang, Weiqing

    2016-01-01

    The association of pathological features of cortisol-producing adrenocortical adenomas (ACAs) with somatic driver mutations and their molecular classification remain unclear. In this study, we explored the association between steroidogenic acute regulatory protein (StAR) expression and the driver mutations activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling to identify the pathological markers of ACAs. Immunohistochemical staining for StAR and mutations in the protein kinase cAMP-activated catalytic subunit alpha (PRKACA), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) and guanine nucleotide binding protein, alpha stimulating (GNAS) genes were examined in 97 ACAs. The association of StAR expression with the clinical and mutational features of the ACAs was analyzed. ACAs with mutations in PRKACA, GNAS, and PRKAR1A showed strong immunopositive staining for StAR. The concordance between high StAR expression and mutations activating cAMP/PKA signaling in the ACAs was 99.0%. ACAs with high expression of StAR had significantly smaller tumor volume (P < 0.001) and higher urinary cortisol per tumor volume (P = 0.032) than those with low expression of StAR. Our findings suggest that immunohistochemical staining for StAR is a reliable pathological approach for the diagnosis and classification of ACAs with cAMP/PKA signaling-activating mutations. PMID:27606678

  5. Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells.

    PubMed

    Kopp, Florian; Hermawan, Adam; Oak, Prajakta Shirish; Ulaganathan, Vijay Kumar; Herrmann, Annika; Elnikhely, Nefertiti; Thakur, Chitra; Xiao, Zhiguang; Knyazev, Pjotr; Ataseven, Beyhan; Savai, Rajkumar; Wagner, Ernst; Roidl, Andreas

    2014-12-01

    Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)-specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition. PMID:25500079

  6. Methylprednisolone Pulse Treatment of Graves' Ophthalmopathy Is Not Associated with Secondary Adrenocortical Insufficiency

    PubMed Central

    Jespersen, Sofie; Nygaard, Birte; Kristensen, Lars Østergaard

    2015-01-01

    Objective Graves' ophthalmopathy (GO) is an inflammatory disease in the orbital region. The first-line medical treatment is glucocorticoids. An important potential side effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal (HPA) axis with impairment of endogenous cortisol production, implicating symptoms of adrenocortical insufficiency, especially in the period after cessation of therapy with possible risks in cases of intercurrent illness. The aim of this study was to evaluate HPA axis function before and after methylprednisolone pulse treatment of GO. Study Design HPA axis function was evaluated by measurements of plasma ACTH and an ACTH stimulation test with plasma cortisol measurements at 0 and 30 min after an intravenous bolus of synthetic ACTH (Synacthen® 250 µg). This was done in 12 patients with GO before and at cessation of methylprednisolone pulse treatment (500 mg i.v. per week for 6 weeks followed by 250 mg i.v. per week for an additional 6 weeks). Results All patients included fulfilled the criteria of intact HPA axis function before and at cessation of methylprednisolone pulse treatment. Data are given as medians (with ranges). Before glucocorticoid treatment basal plasma cortisol was 290 nM (196-579) and 786 nM (612-1,050) after ACTH stimulation. At cessation of therapy the corresponding values were 309 nM (88-718) and 852 nM (524-1,011), respectively. Thus, all patients passed a 30-min stimulated plasma cortisol of 500 nM. Before treatment plasma ACTH was 4.2 pmol/l (4-16) and at cessation of therapy the corresponding value was 4.8 pmol/l (2-9; p = 0.27). Conclusion Transient suppression of the HPA axis with secondary adrenocortical insufficiency does not seem to be a common phenomenon after intravenous methylprednisolone pulse therapy for GO. Therefore, routine precautions are not necessary. However, our results do not exclude that transient secondary adrenocortical insufficiency might occur occasionally. PMID

  7. Silencing of Doublecortin-Like (DCL) Results in Decreased Mitochondrial Activity and Delayed Neuroblastoma Tumor Growth

    PubMed Central

    Verissimo, Carla S.; Elands, Rachel; Cheng, Sou; Saaltink, Dirk-Jan; ter Horst, Judith P.; Alme, Maria N.; Pont, Chantal; van de Water, Bob; Håvik, Bjarte; Fitzsimons, Carlos P.; Vreugdenhil, Erno

    2013-01-01

    Doublecortin-like (DCL) is a microtubule-binding protein crucial for neuroblastoma (NB) cell proliferation. We have investigated whether the anti-proliferative effect of DCL knockdown is linked to reduced mitochondrial activity. We found a delay in tumor development after DCL knockdown in vivo in doxycycline-inducible NB tumor xenografts. To understand the mechanisms underlying this tumor growth retardation we performed a series of in vitro experiments in NB cell lines. DCL colocalizes with mitochondria, interacts with the mitochondrial outer membrane protein OMP25/ SYNJ2BP and DCL knockdown results in decreased expression of genes involved in oxidative phosphorylation. Moreover, DCL knockdown decreases cytochrome c oxidase activity and ATP synthesis. We identified the C-terminal Serine/Proline-rich domain and the second microtubule-binding area as crucial DCL domains for the regulation of cytochrome c oxidase activity and ATP synthesis. Furthermore, DCL knockdown causes a significant reduction in the proliferation rate of NB cells under an energetic challenge induced by low glucose availability. Together with our previous studies, our results corroborate DCL as a key player in NB tumor growth in which DCL controls not only mitotic spindle formation and the stabilization of the microtubule cytoskeleton, but also regulates mitochondrial activity and energy availability, which makes DCL a promising molecular target for NB therapy. PMID:24086625

  8. Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

    PubMed Central

    Patil, Sanganagouda S; Nene, Abhay M

    2016-01-01

    Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

  9. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma

    PubMed Central

    Özata, Deniz M; Caramuta, Stefano; Velázquez-Fernández, David; Akçakaya, Pinar; Xie, Hong; Höög, Anders; Zedenius, Jan; Bäckdahl, Martin; Larsson, Catharina; Lui, Weng-Onn

    2011-01-01

    Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC. PMID:21859927

  10. Obstructive hydrocephalus as a result of giant cell tumor of the thoracic spine: A case report

    PubMed Central

    WEI, CHENG-YU; CHEN, SHUO-TSUNG; TAI, HSU-CHIH; WANG, WEN-BING; CHANG, CHI-CHU; WANG, YAO-CHIN; WEI, LI; KUNG, WOON-MAN

    2016-01-01

    Giant cell tumors (GCTs) are rare bone tumors that account for ~5% of all primary bone tumors. When GCTs occur in the spine, patients usually present with localized pain and neurological symptoms, such as radiating pain or hyperesthesia. In the current report, an unusual case of a GCT of the thoracic spine associated with hydrocephalus is described. A 48-year-old male presented with urinary retention, loss of sensation in the lower limbs and inability to walk. The patient eventually developed hydrocephalus combined with altered consciousness, indicated by an inability to follow simple commands. Magnetic resonance (MR) imaging demonstrated the presence of a soft tissue mass at the T2 level, and biopsy examination of the tissue confirmed that it was a GCT. The patient experienced a sudden loss of consciousness due to an acute episode of obstructive hydrocephalus. A ventriculoperitoneal shunting procedure was performed to treat the hydrocephalus, and the patient regained normal consciousness, although the paraplegia persisted. An MR examination performed 30 months following surgery demonstrated that the tumor size was stable, consistent with the slow growth that is characteristic of GCTs. Diagnosis of GCTs may be challenging, and relies on radiographic and histopathologic findings. Although rare, acute hydrocephalus as a result of GCTs should not be excluded from a differential diagnosis. PMID:26870164

  11. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples

    PubMed Central

    Gara, Sudheer Kumar; Wang, Yonghong; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Meltzer, Paul S.; Kebebew, Electron

    2015-01-01

    To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics. PMID:26446994

  12. Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas.

    PubMed

    Nolé, Paola; Duijndam, Britt; Stenman, Adam; Juhlin, C Christofer; Kozyra, Mikael; Larsson, Catharina; Ingelman-Sundberg, Magnus; Johansson, Inger

    2016-01-01

    Human cytochome P450 2W1 (CYP2W1) enzyme is expressed in fetal colon and in colon tumors. The level of expression is higher in colon metastases than in the parent tumors and the enzyme is a possible drug target for treatment of colorectal cancer, as demonstrated in mouse xenograft studies. A previous study published in this journal reported that CYP2W1 is highly expressed in normal and transformed adrenal tissue. However, adrenal expression of CYP2W1 protein was not seen in previous studies in our research group. To clarify this inconsistency, we have used qRT-PCR and Western blotting with CYP2W1-specific antibodies to probe a panel of 27 adrenocortical carcinomas and 35 normal adrenal cortex samples. CYP2W1 mRNA expression is seen in all samples. However, significant CYP2W1 protein expression was found in only one tumor sample (a testosterone-producing adrenocortical carcinoma) and not in any normal tissue. Differences in the specificity of the CYP2W1 antibodies used in the two studies may explain the apparent discrepancy. We conclude that normal adrenal tissue lacks P450 2W1 enzyme expression; also, adrenocortical carcinomas generally do not express the enzyme. This information thus underline the colon cancer specificity of CYP2W1 enzyme expression and has implications for the development of anti-colon cancer therapies based on CYP2W1 as a drug target, since 2W1-dependent bioactivation of prodrugs for CYP2W1 will not take place in normal adrenal tissue or other non-transformed tissues. PMID:27598485

  13. Adrenocortical hemorrhagic necrosis: the role of catecholamines and retrograde medullary-cell embolism

    SciTech Connect

    Szabo, S.; McComb, D.J.; Kovacs, K.; Huettner, I.

    1981-10-01

    We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

  14. PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit.

    PubMed

    Calebiro, Davide; Hannawacker, Annette; Lyga, Sandra; Bathon, Kerstin; Zabel, Ulrike; Ronchi, Cristina; Beuschlein, Felix; Reincke, Martin; Lorenz, Kristina; Allolio, Bruno; Kisker, Caroline; Fassnacht, Martin; Lohse, Martin J

    2014-01-01

    We recently identified a high prevalence of mutations affecting the catalytic (Cα) subunit of protein kinase A (PKA) in cortisol-secreting adrenocortical adenomas. The two identified mutations (Leu206Arg and Leu199_Cys200insTrp) are associated with increased PKA catalytic activity, but the underlying mechanisms are highly controversial. Here we utilize a combination of biochemical and optical assays, including fluorescence resonance energy transfer in living cells, to analyze the consequences of the two mutations with respect to the formation of the PKA holoenzyme and its regulation by cAMP. Our results indicate that neither mutant can form a stable PKA complex, due to the location of the mutations at the interface between the catalytic and the regulatory subunits. We conclude that the two mutations cause high basal catalytic activity and lack of regulation by cAMP through interference of complex formation between the regulatory and the catalytic subunits of PKA. PMID:25477193

  15. 5th International ACC Symposium: Future and Current Therapeutic Trials in Adrenocortical Carcinoma.

    PubMed

    Hoff, Ana O; Berruti, Alfredo

    2016-02-01

    Adrenocortical carcinoma (ACC) is a rare and complex disease associated with a high mortality rate. Despite intensive translational and clinical research, prognosis remains poor. Over the past decade, a significant effort has been made to develop multinational, collaborative studies to better understand the pathogenesis and clinical features of this rare disease in attempt to improve the therapeutic strategies and patient outcome. The results of both standard and newer treatments are discussed in this review as well as the recent discovery of pathways involved in ACC pathogenesis that provide the rationale to introduce new molecular target therapies. Finally, remaining issues regarding how to improve available therapies in adjuvant setting are raised and addressed. PMID:26728470

  16. [Possibilities for inhibiting tumor-induced angiogenesis: results with multi-target tyrosine kinase inhibitors].

    PubMed

    Török, Szilvia; Döme, Balázs

    2012-03-01

    Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges. PMID:22403757

  17. Results of fast neutron teletherapy for locally advanced head and neck tumors

    SciTech Connect

    Battermann, J.J.; Breur, K.

    1981-08-01

    An analysis is given of the results of fast neutron therapy for locally advanced tumors of the head and neck region. All patients were treated five times per week with a 14 MeV d + T neutron beam and received dosages of about 19 Gy/sub ntumors were treated in this pilot study, the survival time is rather short for most patients. Only 8 patients are alive at the time of writing. The results of treatment for inoperable malignancies of the major salivary glands are very promising, as initial complete regression was achieved in over 90% (12/13).

  18. Non-invasive assessment of adrenocortical function in captive Nile crocodiles (Crocodylus niloticus).

    PubMed

    Ganswindt, Stefanie B; Myburgh, Jan G; Cameron, Elissa Z; Ganswindt, Andre

    2014-11-01

    The occurrence of stress-inducing factors in captive crocodilians is a concern, since chronic stress can negatively affect animal health and reproduction, and hence production. Monitoring stress in wild crocodiles could also be beneficial for assessing the state of health in populations which are potentially threatened by environmental pollution. In both cases, a non-invasive approach to assess adrenocortical function as a measure of stress would be preferable, as animals are not disturbed during sample collection, and therefore sampling is feedback-free. So far, however, such a non-invasive method has not been established for any crocodilian species. As an initial step, we therefore examined the suitability of two enzyme-immunoassays, detecting faecal glucocorticoid metabolites (FGMs) with a 11β,21-diol-20-one and 5β-3α-ol-11-one structure, respectively, for monitoring stress-related physiological responses in captive Nile crocodiles (Crocodylus niloticus). An adrenocorticotropic hormone (ACTH) challenge was performed on 10 sub-adult crocodiles, resulting in an overall increase in serum corticosterone levels of 272% above the pre-injection levels 5h post-injection. Saline-treated control animals (n=8) showed an overall increase of 156% in serum corticosterone levels 5h post-administration. Faecal samples pre- and post-injection could be obtained from three of the six individually housed crocodiles, resulting in FGM concentrations 136-380% above pre-injection levels, always detected in the first sample collected post-treatment (7-15 days post-injection). FGM concentrations seem comparatively stable at ambient temperatures for up to 72 h post-defaecation. In conclusion, non-invasive hormone monitoring can be used for assessing adrenocortical function in captive Nile crocodiles based on FGM analysis. PMID:25066028

  19. Global gene expression response to telomerase in bovine adrenocortical cells

    SciTech Connect

    Perrault, Steven D.; Hornsby, Peter J.; Betts, Dean H. . E-mail: bettsd@uoguelph.ca

    2005-09-30

    The infinite proliferative capability of most immortalized cells is dependent upon the presence of the enzyme telomerase and its ability to maintain telomere length and structure. However, telomerase may be involved in a greater system than telomere length regulation, as recent evidence has shown it capable of increasing wound healing in vivo, and improving cellular proliferation rate and survival from apoptosis in vitro. Here, we describe the global gene expression response to ectopic telomerase expression in an in vitro bovine adrenocortical cell model. Telomerase-immortalized cells showed an increased ability for proliferation and survival in minimal essential medium above cells transgenic for GFP. cDNA microarray analyses revealed an altered cell state indicative of increased adrenocortical cell proliferation regulated by the IGF2 pathway and alterations in members of the TGF-B family. As well, we identified alterations in genes associated with development and wound healing that support a model that high telomerase expression induces a highly adaptable, progenitor-like state.

  20. Postnatal foraging demands alter adrenocortical activity and psychosocial development.

    PubMed

    Lyons, D M; Kim, S; Schatzberg, A F; Levine, S

    1998-05-01

    Mother squirrel monkeys stop carrying infants at earlier ages in high-demand (HD) conditions where food is difficult to find relative to low-demand (LD) conditions. To characterize these transitions in psychosocial development, from 10- to 21-weeks postpartum we collected measures of behavior, adrenocortical activity, and social transactions coded for initiator (mother or infant), goal (make-contact or break-contact), and outcome (success or failure). Make-contact attempts were most often initiated by HD infants, but mothers often opposed these attempts and less than 50% were successful. Break-contact attempts were most often initiated by LD infants, but mothers often opposed these attempts and fewer LD than HD infant break-contact attempts were successful. Plasma levels of cortisol were significantly higher in HD than LD mothers, but differences in adrenocortical activity were less consistent in their infants. HD and LD infants also spent similar amounts of time nursing on their mothers and feeding on solid foods. By rescheduling some transitions in development (carry-->self-transport), and not others (nursing-->self-feeding), mothers may have partially protected infants from the immediate impact of an otherwise stressful foraging task. PMID:9589217

  1. Intrarenal Adrenocortical Adenoma Treated by Robotic Partial Nephrectomy with Adrenalectomy

    PubMed Central

    Sulek, Jay; Smith, Steven C.; Hampton, Lance J.

    2016-01-01

    Abstract Background: We present an intrarenal adrenocortical adenoma discovered incidentally after robot-assisted partial nephrectomy and total adrenalectomy for a suspicious renal mass. Current literature describes the rare occurrence of an adrenocortical adenoma arising from a renal–adrenal fusion. This case represents an uncommon, benign pathology that should be considered in the differential diagnosis of an enhancing renal mass. Case Presentation: The patient is a 62-year-old female found to have an enhancing mass at the anterolateral aspect of the upper pole of the right kidney concerning for renal-cell carcinoma. CT imaging was performed to work up a cause for hyperparathyroidism. During robot-assisted partial nephrectomy, the lesion was found to be partially adherent to the lateral limb of the right adrenal gland. Microscopic evaluation with Melan-A staining showed the mass to be of adrenal origin with benign features and lack of capsulation, indicating an adrenal adenoma arising from intrarenal ectopic adrenal rests. Conclusion: An intrarenal adrenal adenoma arising from ectopic adrenal tissue is a unique pathology that represents a benign differential diagnosis in the evaluation of an enhancing renal mass. However, it cannot be differentiated from renal-cell carcinoma based on cross-sectional imaging alone and requires postoperative pathologic assessment to confirm the diagnosis. PMID:27579413

  2. Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome

    PubMed Central

    Ghayee, Hans K.; Rege, Juilee; Watumull, Lori M.; Nwariaku, Fiemu E.; Carrick, Kelley S.; Rainey, William E.; Miller, Walter L.

    2011-01-01

    Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Objective: To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. Setting: University clinic, hospital, and laboratories. Design: Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. Participant: A 29-yr-old man with incidentally discovered bilateral adrenal enlargement. Intervention: Bilateral adrenalectomy. Main Outcome Measures: Molecular studies compared with control samples. Results: Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b5 (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. Conclusion: This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women. PMID:21084398

  3. Effect of corticosteroid binding proteins on the steroidogenic activity of bovine adrenocortical cell suspensions.

    PubMed

    Basset, M; Rostaing-Metz, B; Chambaz, E M

    1982-07-01

    The possible role of steroid binding proteins in the hormonal secretion process of a steroidogenic tissue was examined using bovine adrenocortical cell suspensions, either under basal conditions or in the presence of half-maximally active concentration (1 x 10(-9) M) of synthetic adrenocorticotropic hormone (ACTH). Three types of plasma cortisol binding proteins were used, namely bovine serum albumine (BSA), purified transcortin (CBG) and purified anticortisol immunoglobulins (IgG). When added to the incubation medium, CBG (at 1 x 10(-10) to 2 x 10(-9) M cortisol binding sites) and anticortisol IgG (at 4.8 x 10(-10) to 3 x 10(-9) M cortisol binding sites) did not influence either the basal nor the ACTH-stimulated net cortisol production of the cell preparations. Whereas crystallized and delipidated BSA showed also no effect, crude commercial BSA preparation (Cohn fraction V) exhibited an ACTH-like cofactor effect which resulted in a marked increase in the net cortisol production by stimulated cells. These observations might be explained by the presence in crude BSA of lipoprotein-cholesterol complexes, possibly acting as an extracellular source of cholesterol available for corticosteroidogenesis. It may be concluded that specific high affinity cortisol binding systems present outside adrenocortical steroidogenic cells do not influence their secretory activity under short term in vitro condition. In addition, it can be stressed that use of ill defined protein preparations (e.g. crude BSA) may lead to artifactual observations in the study of the differentiated functions of isolated steroidogenic cells. PMID:6287106

  4. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.

    PubMed

    Pan, Zhi-qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying-Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B

    2014-08-25

    Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention. PMID:25038520

  5. Adrenocortical response to low-dose ACTH test in female patients with rheumatoid arthritis.

    PubMed

    Radikova, Zofia; Rovensky, Jozef; Vlcek, Miroslav; Penesova, Adela; Kerlik, Jana; Vigas, Milan; Imrich, Richard

    2008-12-01

    Alterations in adrenal steroid production have been suggested in females with rheumatoid arthritis (RA). The aim of the present study was to assess adrenocortical function in RA females. We examined 11 female RA patients (RA: age 30 +/- 2 years, BMI 21.0 +/- 0.7 kg/m(2)) and 10 matched healthy controls (C: age 31 +/- 1 years, BMI 21.6 +/- 0.6 kg/m(2)). Low-dose adrenocorticotropic hormone (ACTH) test (i.v. bolus of 1 microg synthetic ACTH) was performed at 10.00 h with blood sampling every 15 min for 90 min. Cortisol, 17-OH-progesterone (17OHP), androstenedione (ASD), and dehydroepiandrosterone (DHEA) were assayed in plasma. Baseline cortisol levels were higher in RA patients (RA: 385 +/- 38 versus C: 229 +/- 28 nmol/L, P= 0.007). In both study groups, ACTH administration increased all the four steroids measured (P < 0.001). Cortisol response to ACTH administration was diminished in RA patients when compared to controls (Delta(max): 284 +/- 24 in RA versus 424 +/- 31 nmol/L in C, P= 0.002). ACTH-induced maximal rise in plasma DHEA was significantly lower in RA patients when compared to controls (Delta(max): 2.59 +/- 0.68 in RA versus 5.57 +/- 1.25 ng/mL in C, P= 0.015). No significant between-groups differences were found in responses of ASD or 17OHP. The molar ratio of ASD:cortisol was significantly lower (P < 0.05) in RA patients at base line, but did not differ during ACTH test. After ACTH bolus, the cortisol:17OHP ratio decreased significantly in the RA group (P < 0.001), whereas there was no change in the control group. The present results show decreased secretion of cortisol and DHEA in RA patients in response to ACTH, suggesting a subtle HPA hypofunction at the adrenocortical level. PMID:19120158

  6. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells

    PubMed Central

    Pan, Zhi-qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying-Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B.

    2014-01-01

    Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24hr significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention. PMID:25038520

  7. Adrenocorticotropic hormone in serial cerebrospinal fluid in man - Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?

    PubMed

    Kellner, Michael; Wortmann, Viola; Salzwedel, Cornelie; Kober, Daniel; Petzoldt, Martin; Urbanowicz, Tatiana; Pulic, Mersija; Boelmans, Kai; Yassouridis, Alexander; Wiedemann, Klaus

    2016-05-30

    Acute regulation of adrenocorticotropic hormone (ACTH) in cerebrospinal fluid (CSF) by the hypothalamic-pituitary-adrenocortical system has not been investigated in man. In a pilot study in healthy male volunteers we measured ACTH every twenty minutes in serial CSF for three hours after an intravenous placebo, hydrocortisone (100mg) or insulin (2mg/kg) injection. No acute inhibitory or stimulatory effects of these interventions were discovered. Our results corroborate previous findings in rhesus monkeys. The regulation of CSF ACTH and its potential relevance for behavioral alterations in health and disease (e.g. major depression or anorexia nervosa) in humans need further study. PMID:27031591

  8. Diagnostic Utility of Orthopedia Homeobox (OTP) in Pulmonary Carcinoid Tumors.

    PubMed

    Nonaka, Daisuke; Papaxoinis, George; Mansoor, Wasat

    2016-06-01

    Recently, Orthopedia Homeobox (OTP) was described as a prognostic marker for pulmonary carcinoid tumors; however, little is known about the function and distribution pattern of this transcription factor in normal organs/tissues and in tumors. Consequently, OTP expression was investigated in a variety of tumors, with special interest in pulmonary and nonpulmonary neuroendocrine tumors (NETs) and high-grade neuroendocrine carcinomas. OTP immunohistochemical analysis was performed on a total of 162 pulmonary carcinoid tumors, 31 pulmonary neuroendocrine hyperplasias, 104 pulmonary high-grade neuroendocrine carcinomas (large cell neuroendocrine and small cell neuroendocrine), 102 nonpulmonary NETs (G1/G2 NETs, small cell and large cell neuroendocrine carcinomas, and Merkel cell carcinomas), 150 endocrine tumors (thyroid, parathyroid, adrenocortical, and pheochromocytomas/paragangliomas), 279 adenocarcinomas, and 88 squamous cell carcinomas of various organs, including those of the lungs and others. In addition, normal tissues from various organs were studied. OTP nuclear expression was seen in 80% of lung carcinoid tumors. Among other tumors, 4 small-cell carcinomas showed focal expression (2 pulmonary and 2 bladder), but all other tumors were completely negative. Overall, the sensitivity and specificity of OTP were 80.2% and 99.4%, respectively. All TTF1-positive lung carcinoid tumors were diffusely positive for OTP, but none of the OTP-negative carcinoid tumors was positive for TTF1. OTP expression was not seen in any normal tissues/organs. OTP was also negative in neuroendocrine cells of the normal bronchus/bronchiole. However, OTP was strongly expressed in neuroendocrine hyperplasia, including reactive and preneoplastic hyperplasia. Our results suggest that OTP may serve as a useful diagnostic marker for lung carcinoid tumors. PMID:26927888

  9. The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

    PubMed Central

    Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

    2015-01-01

    The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic

  10. Temperament moderates the influence of periadolescent social experience on behavior and adrenocortical activity in adult male rats

    PubMed Central

    Caruso, M.J.; McClintock, M.K.; Cavigelli, S.A.

    2014-01-01

    Adolescence is a period of significant behavioral and physiological maturation, particularly related to stress responses. Animal studies that have tested the influence of adolescent social experiences on stress-related behavioral and physiological development have led to complex results. We used a rodent model of neophobia to test the hypothesis that the influence of adolescent social experience on adult behavior and adrenocortical function is modulated by preadolescent temperament. Exploratory activity was assessed in 53 male Sprague-Dawley rats to classify temperament and then they were housed in one of three conditions during postnatal days (PND) 28-46: (1) with familiar kin, (2) with novel social partners, or (3) individually with no social partners. Effects on adult adrenocortical function were evaluated from fecal samples collected while rats were individually-housed and exposed to a 1-hour novel social challenge during PND 110-114. Adolescent-housing with novel or no social partners led to reduced adult glucocorticoid production compared to adolescent-housing with familiar littermates. Additionally, highly-exploratory pre-weanling rats that were housed with novel social partners during adolescence exhibited increased exploratory behavior and a more rapid return to basal glucocorticoid production in adulthood compared to those housed with familiar or no social partners during adolescence and compared to low-exploratory rats exposed to novel social partners. In sum, relatively short-term adolescent social experiences can cause transient changes in temperament and potentially longer-term changes in recovery of glucocorticoid production in response to adult social challenges. Furthermore, early temperament may modulate the influence of adolescent experiences on adult behavioral and adrenocortical function. PMID:25066485

  11. Implementation and experimental results of 4D tumor tracking using robotic couch

    SciTech Connect

    Buzurovic, I.; Yu, Y.; Werner-Wasik, M.; Biswas, T.; Anne, P. R.; Dicker, A. P.; Podder, T. K.

    2012-11-15

    Purpose: This study presents the implementation and experimental results of a novel technique for 4D tumor tracking using a commercially available and commonly used treatment couch and evaluates the tumor tracking accuracy in clinical settings. Methods: Commercially available couch is capable of positioning the patient accurately; however, currently there is no provision for compensating physiological movement using the treatment couch in real-time. In this paper, a real-time couch tracking control technique is presented together with experimental results in tumor motion compensation in four dimensions (superior-inferior, lateral, anterior-posterior, and time). To implement real-time couch motion for tracking, a novel control system for the treatment couch was developed. The primary functional requirements for this novel technique were: (a) the treatment couch should maintain all previous/normal features for patient setup and positioning, (b) the new control system should be used as a parallel system when tumor tracking would be deployed, and (c) tracking could be performed in a single direction and/or concurrently in all three directions of the couch motion (longitudinal, lateral, and vertical). To the authors' best knowledge, the implementation of such technique to a regular treatment couch for tumor tracking has not been reported so far. To evaluate the performance of the tracking couch, we investigated the mechanical characteristics of the system such as system positioning resolution, repeatability, accuracy, and tracking performance. Performance of the tracking system was evaluated using dosimetric test as an endpoint. To investigate the accuracy of real-time tracking in the clinical setting, the existing clinical treatment couch was replaced with our experimental couch and the linear accelerator was used to deliver 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) treatment plans with and without tracking. The results of

  12. Surveillance Strategies for Sarcoma: Results of a Survey of Members of the Musculoskeletal Tumor Society

    PubMed Central

    2016-01-01

    Background. Surveillance is crucial to oncology, yet there is scant evidence to guide strategies. Purpose. This survey identified sarcoma surveillance strategies for Musculoskeletal Tumor Society (MSTS) members and rationales behind them. Understanding current practice should facilitate studies to generate evidence-based surveillance protocols. Methods. Permission was granted by the Research and Executive Committee of the MSTS to survey members on surveillance strategies. First, the questionnaire requested demographic and clinical practice information. Second, the survey focused on clinicians' specific surveillance soft tissue and bone sarcoma protocols. Results. 20 percent of MSTS members completed the survey. The primary rationale for protocols was training continuation, followed by published guidelines, and finally personal interpretation of the literature. 95% of the respondents believe that additional studies regarding appropriate surveillance protocols are needed. 87% reported patient concerns regarding radiation exposure from surveillance imaging. For soft tissue and bone sarcoma local recurrence, responders identified surgical margin, histologic grade, and tumor size as the most important factors. For metastases, important risk factors identified included histologic grade, tumor size, and histologic type. Protocols demonstrated wide variation. Conclusion. This survey demonstrates that surveillance strategies utilized by MSTS members are not evidence-based, providing rationale for multi-institutional studies. It also confirms the public health issue of excessive radiation exposure. PMID:27478404

  13. Results of d+T fast neutron irradiation on advanced tumors of bladder and rectum

    SciTech Connect

    Battermann, J.J.

    1982-12-01

    From November, 1975 to November, 1981, around 400 patients were irradiated with 14 MeV d+T fast neutrons at the Antoni van Leeuwenhoek Hospital in Amsterdam. Special interest was focused on inoperable tumors of bladder and rectum. During the pilot phase of the study 47 patients were treated, mostly via two parallel opposed ports with dosages that ranged from 18 to more than 22 Gy. Although persistent local control was achieved in 23 patients (48%), 14 patients (29%) died of severe complications. By the introduction of a six field technique, the fatal complication rate could be reduced significantly. Since May 1978 patients were randomized in a three arm trial, using two dose levels on the neutron site. The preliminary results of a group of 91 patients show a similar survival in the three treatment arms with a somewhat better local control rate for high dose neutrons. An attempt was made to estimate RBE values for tumor control and normal tissue reactions by comparing the data for neutron irradiation with the data obtained with photons on a similar group of patients. From the values derived it must be concluded that the gain for neutron irradiation on these tumors in the pelvis will be negligible.

  14. Results of d+T fast neutron irradiation on advanced tumors of bladder and rectum

    SciTech Connect

    Battermann, J.J.

    1982-12-01

    From November, 1975 to November, 1981, around 400 patients were irradiated with 14 MeV d+T fast neutrons at the Antoni van Leeuwenhoek Hospital in Amsterdam. Special interest was focused on inoperable tumors of bladder and rectum. During the pilot phase of the study 47 patients were treated, mostly via two parallel opposed ports with dosages that ranged from 18 to more than 22 Gy. Although persistent local control was achieved in 23 patients (48%), 14 patients (29%) died of severe complications. By the introduction of a six field technique, the fatal complication rate could be reduced significantly. Since May 1978 patients were randomized in a three arm trial, using two dose levels on the neutron site. The preliminary results of a group of 91 patients show a similar survival in the three treatment arms with a somewhat better local control rate for high dose neutrons. An attempt was made to estimate RBE values for tumor control and normal tissue reaction by comparing the data for neutron irradiation with the data obtained with photons on a similar group of patients. From the values derived it must be concluded that the gain for neutron irradiation on these tumors in the pelvis will be negligible.

  15. Evaluation of Clinical Results and Complications of Structural Allograft Reconstruction after Bone Tumor Surgery

    PubMed Central

    Gharedaghi, Mohammad; Peivandi, Mohammad Taghi; Mazloomi, Mehdi; Shoorin, Hasan Rahimi; Hasani, Mohammad; Seyf, Parham; Khazaee, Fatemeh

    2016-01-01

    Background: Massive bone allograft is an option in cases of limb preservation and reconstruction after massive benign and malignant bone tumor resection. The purpose of this study was to analyze the outcome of these procedures at Imam Reza Hospital, Mashhad University of Medical Sciences. Methods: In this study, 113 cases have been presented. Eleven cases were excluded (patients has a traumatic defect or they passed away before the completion of the study’s two-year follow up period). Each patient completed a questionnaire, went through a physical examination and, if indicated, X-ray information was collected. The patients were divided into three groups: chemotherapy, chemotherapy plus radiation therapy, and no-adjuvant-therapy. Results: Fifty-four cases were male and the mean age was 24.5±5.39. The number of cases and indications for surgery were: 33 cases of aggressive benign tumors or low grade malignant bone tumors (large bone defects) including 16 germ cell tumors, eight aneurysmal bone cysts, five low grade osteosarcomas, and four chondrosarcomas. Another 69 cases were high-grade malignant bone tumors including 42 osteosarcomas, 21 Ewing’s sarcoma, and six other high grade osteosarcomas. Patients were divided into three groups: the first group received no adjuvant therapy, the second group received chemotherapy, and the third group received chemotherapy plus radiotherapy. The location of tumors were as follows: eight cases in the pelvic bone, 12 in the proximal femur, 18 in the femoral shaft, 36 in the distal femur, 12 in the proximal tibia, and 16 in the humeral bone. The 12 cases of proximal femoral defects were reconstructed by allograft composite prosthesis, 18 diaphyseal defects with intercalary allograft, and 36 distal femoral defects were reconstructed using osteoarticular allograft. The rate of deep infection was 7:8% (eight patients) and in this regard, we found a significant difference among the three groups, such that most cases of infection

  16. How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues?

    PubMed

    Almeida, Madson Q; Stratakis, Constantine A

    2011-04-10

    The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP signaling pathway. A small number of both massive macronodular adrenocortical disease and cortisol-producing adenomas harbor somatic GNAS mutations. Micronodular adrenocortical hyperplasias are either pigmented (the classic form being that of primary pigmented nodular adrenocortical disease) or non-pigmented; micronodular adrenocortical hyperplasias can be seen in the context of other conditions or isolated; for example, primary pigmented nodular adrenocortical disease usually occurs in the context of Carney complex, but isolated primary pigmented nodular adrenocortical disease has also been described. Both Carney complex and isolated primary pigmented nodular adrenocortical disease are caused by germline PRKAR1A mutations; somatic mutations of this gene that regulates cAMP-dependent protein kinase are also found in cortisol-producing adenomas, and abnormalities of PKA are present in most cases of massive macronodular adrenocortical disease. Micronodular adrenocortical hyperplasias and some cortisol-producing adenomas are associated with phosphodiesterase 11A and 8B defects, coded, respectively, by the PDE11A and PDE8B genes. Mouse models of Prkar1a deficiency also show that increased cAMP signaling leads to tumors in adrenal cortex and other tissues. In this review, we summarize all recent data from ours and other laboratories, supporting the view that Wnt-signaling acts as an important mediator of tumorigenicity induced by abnormal PRKAR1A function and aberrant cAMP signaling. PMID:21111774

  17. A Case of Oncocytic Adrenocortical Neoplasm of Borderline (Uncertain) Malignant Potential.

    PubMed

    Shenouda, Mina; Brown, Linda G; Denning, Krista L; Pacioles, Toni

    2016-01-01

    Oncocytic neoplasms are tumors composed predominantly or exclusively of oncocytes (large polygonal cells with granular eosinophilic cytoplasm due to abnormal mitochondrial accumulation). These tumors are frequently reported in the thyroid, kidneys, and salivary glands. However, they are distinctly rare in the adrenal cortex. Oncocytic adrenocortical neoplasms (OAN) are classified regarding their biological behavior by their histological features according to the Lin-Weiss-Bisceglia system (LWB). Here, we report a case of OAN of borderline or uncertain malignant potential (BMP) with subsequently identified papillary thyroid carcinoma (PTC). A 34-year-old female with a nine-month history of fatigue presented with chest pain. A right adrenal mass was incidentally found while ruling out pulmonary embolism. A CT-guided adrenal biopsy, although not routinely indicated, was performed and interpreted as malignant with no definitive origin. Hormonal workup was unremarkable. PET-scan showed hypermetabolic adrenal mass with peak standardized uptake value of 15, suspicious of malignancy. A hypermetabolic thyroid nodule was also identified, but there was no evidence of metastatic disease. The patient underwent adrenalectomy, and the initial pathology report was interpreted as atypical pink cell tumor. A second pathology report from another laboratory favored OAN based on the morphology and immunohistochemical staining. While the histologic criteria of malignancy were not met, the large tumor size makes it compatible with BMP according to LWB criteria. A follow-up thyroid ultrasound revealed a complex thyroid nodule. A total thyroidectomy was performed, and pathology was consistent with PTC. Of interest, PTC frequently shows an increase in mitochondrial content, which is characteristic of oncocytic tumors. This case illustrates that OAN, although rare, should be considered in the differential diagnosis of adrenal masses. When OAN is identified, it should be classified

  18. A Case of Oncocytic Adrenocortical Neoplasm of Borderline (Uncertain) Malignant Potential

    PubMed Central

    Brown, Linda G; Denning, Krista L; Pacioles, Toni

    2016-01-01

    Oncocytic neoplasms are tumors composed predominantly or exclusively of oncocytes (large polygonal cells with granular eosinophilic cytoplasm due to abnormal mitochondrial accumulation). These tumors are frequently reported in the thyroid, kidneys, and salivary glands. However, they are distinctly rare in the adrenal cortex. Oncocytic adrenocortical neoplasms (OAN) are classified regarding their biological behavior by their histological features according to the Lin-Weiss-Bisceglia system (LWB). Here, we report a case of OAN of borderline or uncertain malignant potential (BMP) with subsequently identified papillary thyroid carcinoma (PTC). A 34-year-old female with a nine-month history of fatigue presented with chest pain. A right adrenal mass was incidentally found while ruling out pulmonary embolism. A CT-guided adrenal biopsy, although not routinely indicated, was performed and interpreted as malignant with no definitive origin. Hormonal workup was unremarkable. PET-scan showed hypermetabolic adrenal mass with peak standardized uptake value of 15, suspicious of malignancy. A hypermetabolic thyroid nodule was also identified, but there was no evidence of metastatic disease. The patient underwent adrenalectomy, and the initial pathology report was interpreted as atypical pink cell tumor. A second pathology report from another laboratory favored OAN based on the morphology and immunohistochemical staining. While the histologic criteria of malignancy were not met, the large tumor size makes it compatible with BMP according to LWB criteria. A follow-up thyroid ultrasound revealed a complex thyroid nodule. A total thyroidectomy was performed, and pathology was consistent with PTC. Of interest, PTC frequently shows an increase in mitochondrial content, which is characteristic of oncocytic tumors. This case illustrates that OAN, although rare, should be considered in the differential diagnosis of adrenal masses. When OAN is identified, it should be classified

  19. Treatment of Giant Fibroadenoma in Young Women: Results after Tumor Excision without Reconstructive Surgery

    PubMed Central

    Hille-Betz, U.; Klapdor, R.; Henseler, H.; Soergel, P.; Länger, F.

    2015-01-01

    Introduction: Giant fibroadenoma (GFA) of the breast is defined as fibroadenoma larger than 5 cm, usually presenting unilaterally and manifesting as breast asymmetry or deformity of the breast. Material and Methods: A retrospective database search was done of all patients with giant fibroadenoma who underwent surgery for GFA in the breast center of Hanover Medical School between 2007 and 2014; all patients with GFA were followed up. Data were analyzed with regard to tumor and patient characteristics and esthetic outcome. Results: A total of 13 patients with symptomatic GFA underwent surgery between 2007 and 2014. Mean patient age was 21.2 years (range 14–31 years). In 8 of 13 patients the tumor had resulted in breast deformity and/or breast asymmetry. Average size of the mass was 10.2 cm (range 8.5–12 cm) and average weight was 203.6 g (range 151.2–323.5 g). Initial clinical suspicion of GFA was confirmed by ultrasound examination. Preoperative core biopsy revealed fibroadenoma in 8/13 cases, cellular fibroepithelial lesions with a differential diagnosis of benign phyllodes tumor in 3 cases and unspecific histological findings in the remaining 2 cases. Conclusion: Excision was done using an inframammary or periareolar approach without reconstructive plasty. The cosmetic results were good, as were the outcomes on follow-up. We therefore favor this surgical technique to treat giant fibroadenoma of similar size to those described above. PMID:26500369

  20. [Importance of proliferative potential (as the ratio of a proliferative cells number and duration of mitosis) in diagnoses of malignant degree and prognosis of adrenocortical cancer].

    PubMed

    Raĭkhlin, N T; Bukaeva, I A; Filimoniuk, A V; Smirnova, E A; Probatova, N A; Pavlovskaia, A I; Shabanov, M A; Ponomareva, M V

    2011-01-01

    The aim of research has been the estimation of a proliferative potential as simultaneous detection of a proliferative cells number (Ki-67 index) and duration of mitosis (nucleolar argyrophilic protein expression--B23/nucleophosmin and C23/nucleolin) at patients with adrenocortical cancer. In according to lifetime of patients after operation 2 groups had been sorted out. The first one included patients surviving 56.12 months, the second one--9.25 months. We've found out that different aspects of tumor diagnosis as well distinction of benignant or malignant tumor growth, a malignant degree of tumors, a prognostic criteria of illness, survival of patients etc. must be characterized by total research both a proliferative cells fraction (Ki-67 index) and a rate of mitosis (expressions of B23/nucleophosmin and C23/nucleolin). PMID:22288173

  1. Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma.

    PubMed

    Zheng, Siyuan; Cherniack, Andrew D; Dewal, Ninad; Moffitt, Richard A; Danilova, Ludmila; Murray, Bradley A; Lerario, Antonio M; Else, Tobias; Knijnenburg, Theo A; Ciriello, Giovanni; Kim, Seungchan; Assie, Guillaume; Morozova, Olena; Akbani, Rehan; Shih, Juliann; Hoadley, Katherine A; Choueiri, Toni K; Waldmann, Jens; Mete, Ozgur; Robertson, A Gordon; Wu, Hsin-Ta; Raphael, Benjamin J; Shao, Lina; Meyerson, Matthew; Demeure, Michael J; Beuschlein, Felix; Gill, Anthony J; Sidhu, Stan B; Almeida, Madson Q; Fragoso, Maria C B V; Cope, Leslie M; Kebebew, Electron; Habra, Mouhammed A; Whitsett, Timothy G; Bussey, Kimberly J; Rainey, William E; Asa, Sylvia L; Bertherat, Jérôme; Fassnacht, Martin; Wheeler, David A; Hammer, Gary D; Giordano, Thomas J; Verhaak, Roel G W

    2016-05-01

    We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers. PMID:27165744

  2. An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis.

    PubMed

    Imrich, Richard; Vlcek, Miroslav; Aldag, Jean C; Kerlik, Jana; Radikova, Zofia; Rovensky, Jozef; Vigas, Milan; Masi, Alfonse T

    2010-04-01

    The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients' illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin-stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent. PMID:20398019

  3. Virilizing adrenocortical carcinoma advancing to central precocious puberty after surgery.

    PubMed

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-05-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery. PMID:26019766

  4. Heating stents with radio frequency energy to prevent tumor ingrowth: modeling and experimental results

    NASA Astrophysics Data System (ADS)

    Ryan, Thomas P.; Lawes, Kate; Goldberg, S. Nahum

    1998-04-01

    Stents are often inserted into internal orifices to treat blockage due to tumor ingrowth. Stents are favored due to their minimally invasive nature, possible avoidance of a surgical procedure, and their ability to palliate surgically non-resectable disease. Because of rapid tumor growth however, a treatment means to prevent overgrowth through the stent and resultant blockage is required. To further this goal, experiments were performed in which a stent was placed in tissue and heated with radiofrequency (RF) energy to coagulate a cylinder of tissue, thereby eradicating viable tissue in the proximity of the stent. Temperatures were measured at the central stent surface and edges over time during a 5 - 10 minute heating in phantom and in fresh tissue. In addition, a finite element model was used to simulate the electric field and temperature distribution. Blood flow was also introduced in the model by evaluating RF application to stents to determine effectiveness of the energy applications. Changing perfusion and tissue electrical conductivity as a function of temperature was applied as the tissue was heated to 100 degree(s)C. Results from the electric field model will be shown as well as the thermal distribution over time from the simulations. Lastly, results from the damage integral will be discussed.

  5. Adrenocortical function in cane toads from different environments.

    PubMed

    Hernández, Sandra E; Sernia, Conrad; Bradley, Adrian J

    2016-05-01

    The adrenocortical function of cane toads (Rhinella marina) exposed to different experimental procedures, as well as captured from different environments, was assessed by challenging the hypothalamic-pituitary-adrenal (HPA) axis. It was found that restriction stress as well as cannulation increased plasma corticosterone (B) levels for up to 12h. A single dose of dexamethasone (DEX 2mg/kg) significantly reduced B levels demonstrating its potential for use in the evaluation of the HPA axis in amphibia. We also demonstrate that 0.05 IU/g BW (im) of synthetic adrenocorticotropic hormone (ACTH) significantly increased plasma B levels in cane toads. Changes in size area of the cortical cells were positively associated with total levels of B after ACTH administration. We also found differences in adrenal activity between populations. This was assessed by a DEX-ACTH test. The animals captured from the field and maintained in captivity for one year at the animal house (AH) present the highest levels of total and free B after ACTH administration. We also found that animals from the front line of dispersion in Western Australia (WA) present the weakest adrenal response to a DEX-ACTH test. The animals categorized as long established in Queensland Australia (QL), and native in Mexico (MX), do not shown a marked difference in the HPA activity. Finally we found that in response to ACTH administration, females reach significantly higher levels of plasma B than males. For the first time the adrenocortical response in cane toads exposed to different experimental procedures, as well as from different populations was assessed systematically. PMID:26877241

  6. Preliminary oncological results of endosopic laser surgery in advanced head and neck tumors

    NASA Astrophysics Data System (ADS)

    Baker-Schreyer, Antonio; Sadick, Haneen; Juncker, Cathrine; Bergler, Wolfgang; Hoermann, Karl

    1998-01-01

    Lasersurgery has established itself in the treatment of minor tumors (T1 - T2) of the upper aerodigestive tract. However, advanced carcinomas of the head and neck (T3 - T4) are generally treated with conventional surgical procedures which include pharyngolaryngectomy. The purpose of this study was to evaluate the oncological outcome of endoscopic lasersurgery in advanced head and neck tumors and to compare the results with conventional surgical procedures. Between January 1994 to December 1996, 86 patients with advanced squamous cell carcinomas of the larynx and hypopharynx underwent endoscopic lasersurgery instead of pharyngolaryngectomy as a curative measure. Besides the recurrence and survival rate, the necessity of tracheostomy, postoperative complications and the mean duration of hospitalization were documented. The results showed that the recurrence and survival rate were similar or even better after conventional pharyngolaryngectomy, whereas the patients' postoperative rehabilitation was better after lasersurgery. In this contribution the indication for lasersurgical intervention or pharyngolaryngectomy in advanced carcinomas of the head and neck is discussed.

  7. Genetic p53 deficiency partially rescues the adrenocortical dysplasia (acd) phenotype at the expense of increased tumorigenesis

    PubMed Central

    Else, Tobias; Trovato, Alessia; Kim, Alex C.; Wu, Yipin; Ferguson, David O.; Kuick, Rork D.; Lucas, Peter C.; Hammer, Gary D.

    2009-01-01

    Summary Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis. In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd. Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy. Survival to weaning age is significantly increased in Acdacd/acd p53−/− mice. On the contrary p53−/− and p53+/− mice with the Acdacd/acd genotype show a decreased tumor free survival compared to Acd+/+ mice. Tumors from Acdacd/acd p53+/− mice show a striking switch from the classical spectrum of p53−/− mice towards carcinomas. The acd mouse model provides further support for an in vivo role of telomere deprotection in tumorigenesis. Significance Critically shortened dysfunctional telomeres of the Terc−/− mice have been shown to impact tissue development and maintenance and lead to the occurrence of a pro-cancer genome. The present study examines the contribution of telomere shortening vs. telomere deprotection to the development of genetic instability and cancer. By studying the acd mouse, we show that telomere deprotection without significant telomere shortening is sufficient to induce tumor formation in the context of p53 absence. It also raises the possibility that telomere deprotection contributes to the high prevalence of carcinomas in humans. PMID:19477426

  8. ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs.

    PubMed

    LaPensee, Christopher R; Mann, Jacqueline E; Rainey, William E; Crudo, Valentina; Hunt, Stephen W; Hammer, Gary D

    2016-05-01

    ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis. PMID:26986192

  9. Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

    PubMed Central

    Unger, Wendy WJ; Mayer, Christian T; Engels, Steef; Hesse, Christina; Perdicchio, Maurizio; Puttur, Franz; Streng-Ouwehand, Ingeborg; Litjens, Manja; Kalay, Hakan; Berod, Luciana; Sparwasser, Tim; van Kooyk, Yvette

    2014-01-01

    Therapeutic vaccinations against cancer are still largely ineffective. Major caveats are inefficient delivery of tumor antigens to dendritic cells (DCs) and excessive immune suppression by Foxp3+ regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3+ Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8+ T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity. PMID:26405564

  10. Reciprocal influences among adrenocortical activation, psychosocial processes, and the behavioral adjustment of clinic-referred children.

    PubMed

    Granger, D A; Weisz, J R; McCracken, J T; Ikeda, S C; Douglas, P

    1996-12-01

    The reciprocal effects among cognitive-behavioral, environmental, and biological influences on clinic-referred children's (N = 64; 34 boys; M age 12.71 years) short-term psychological and psychiatric adjustment were studied. At clinic intake and 6 months later, standardized measures of adjustment and control-related beliefs were assessed. Before and after conflict-oriented parent-child interaction tasks the children's saliva was sampled. Adrenocortical responses (i.e., increases in salivary cortisol) to the social conflict task predicted children's internalizing problem behaviors and anxiety disorders at follow-up. Consistently high adrenocortical reactivity at intake and follow-up was associated with deflated social competence over the 6-month period. Also, specific patterns of discontinuity in children's internalizing behavior problems predicted individual differences in their subsequent adrenocortical responsiveness. Specifically, rising behavior problem levels across time predicted higher and declining behavior problem levels predicted lower adrenocortical reactivity at follow-up. Findings are among the first to suggest links among internalizing behavior problems, adrenocortical responsiveness to social challenge, and clinic-referred children's short-term cognitive-behavioral and emotional adjustment. PMID:9071780

  11. Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma.

    PubMed

    Duregon, Eleonora; Molinaro, Luca; Volante, Marco; Ventura, Laura; Righi, Luisella; Bolla, Stefania; Terzolo, Massimo; Sapino, Anna; Papotti, Mauro G

    2014-09-01

    Mitotic count on hematoxylin and eosin slides is a fundamental morphological criterion in the diagnosis and grading of adrenocortical carcinoma in any scoring system employed. Moreover, it is the unique term strongly associated with patient's prognosis. Phospho-histone H3 is a mitosis-specific antibody, which was already proven to facilitate mitotic count in melanoma and other tumors. Therefore, a study was designed to assess the diagnostic and prognostic role of phospho-histone H3 in 52 adrenocortical carcinomas, comparing manual and computerized count to standard manual hematoxylin- and eosin-based method and Ki-67 index. Manual hematoxylin and eosin and phospho-histone H3 mitotic counts were highly correlated (r=0.9077, P<0.0001), better than computer-assisted phospho-histone H3 evaluations, and had an excellent inter-observer reproducibility at Bland-Altman analysis. Three of 15 cases having <5 mitotic figures per 50 high-power fields by standard count on hematoxylin and eosin gained the mitotic figure point of Weiss Score after a manual count on phospho-histone H3 slides. Traditional mitotic count confirmed to be a strong predictor of overall survival (P=0.0043), better than phospho-histone H3-based evaluation (P=0.051), but not as strong as the Ki-67 index (P<0.0001). The latter further segregated adrenocortical carcinomas into three prognostic groups, stratifying cases by low (<20%), intermediate (20-50%), and high (>50%) Ki-67 values. We conclude that (a) phospho-histone H3 staining is a useful diagnostic complementary tool to standard hematoxylin and eosin mitotic count, enabling optimal mitotic figure evaluation (including atypical mitotic figures) even in adrenocortical carcinomas with a low mitotic index and with a very high reproducibility; (b) Ki-67 proved to be the best prognostic indicator of overall survival, being superior to the mitotic index, irrespective of the method (standard on hematoxylin and eosin or phospho-histone H3-based) used to count

  12. Regulation of the adrenocortical stem cell niche: implications for disease

    PubMed Central

    Walczak, Elisabeth M.; Hammer, Gary D.

    2015-01-01

    Stem cells are endowed with the potential for self-renewal and multipotency. Pluripotent embryonic stem cells have an early role in the formation of the three germ layers (ectoderm, mesoderm and endoderm), whereas adult tissue stem cells and progenitor cells are critical mediators of organ homeostasis. The adrenal cortex is an exceptionally dynamic endocrine organ that is homeostatically maintained by paracrine and endocrine signals throughout postnatal life. In the past decade, much has been learned about the stem and progenitor cells of the adrenal cortex and the multiple roles that these cell populations have in normal development and homeostasis of the adrenal gland and in adrenal diseases. In this Review, we discuss the evidence for the presence of adrenocortical stem cells, as well as the various signalling molecules and transcriptional networks that are critical for the embryological establishment and postnatal maintenance of this vital population of cells. The implications of these pathways and cells in the pathophysiology of disease are also addressed. PMID:25287283

  13. Temperature and adrenocortical responses in rhesus monkeys exposed to microwaves

    SciTech Connect

    Lotz, W.G.; Podgorski, R.P.

    1982-12-01

    To determine if the endocrine response to microwave exposure was similar in a primate to that reported for other animals, rectal temperature and plasma levels of cortisol, thyroxine (T4), and growth hormone (GH) were measured in rhesus monkeys exposed to 1.29-GHz microwave radiation. Exposures were carried out under far-field conditions with the monkey restrained in a chair. Incident power densities of 0, 20, 28, and 38 mW/sq cm were used, with corresponding specific absorption rates of 0, 2.1, 3.0, and 4.1 W/kg. Blood samples were taken hourly via an indwelling jugular venous catheter over a 24-h period before, during, and after an 8-h exposure. Rectal temperature increased an average of 0.5, 0.7, and 1.7 C for the three intensities used. No changes in T4 or GH were observed. Cortisol levels were increased during exposure to 38 mW/sq cm. It was concluded that the temperature and adrenocortical responses to microwave exposure of the rhesus monkey are similar to the corresponding responses of other animals.

  14. Network analysis reveals potential markers for pediatric adrenocortical carcinoma

    PubMed Central

    Kulshrestha, Anurag; Suman, Shikha; Ranjan, Rakesh

    2016-01-01

    Pediatric adrenocortical carcinoma (ACC) is a rare malignancy with a poor outcome. Molecular mechanisms of pediatric ACC oncogenesis and advancement are not well understood. Accurate and timely diagnosis of the disease requires identification of new markers for pediatric ACC. Differentially expressed genes (DEGs) were identified from the gene expression profile of pediatric ACC and obtained from Gene Expression Omnibus. Gene Ontology functional and pathway enrichment analysis was implemented to recognize the functions of DEGs. A protein–protein interaction (PPI) and gene–gene functional interaction (GGI) network of DEGs was constructed. Hub gene detection and enrichment analysis of functional modules were performed. Furthermore, a gene regulatory network incorporating DEGs–microRNAs–transcription factors was constructed and analyzed. A total of 431 DEGs including 228 upregulated and 203 downregulated DEGs were screened. These genes were largely involved in cell cycle, steroid biosynthesis, and p53 signaling pathways. Upregulated genes, CDK1, CCNB1, CDC20, and BUB1B, were identified as the common hubs of PPI and GGI networks. All the four common hub genes were also part of modules of the PPI network. Moreover, all the four genes were also present in the largest module of GGI network. A gene regulatory network consisting of 82 microRNAs and 100 transcription factors was also constructed. CDK1, CCNB1, CDC20, and BUB1B may serve as potential biomarker of pediatric ACC and as potential targets for therapeutic approach, although experimental studies are required to authenticate our findings. PMID:27555782

  15. Complications of Microwave Ablation for Liver Tumors: Results of a Multicenter Study

    SciTech Connect

    Livraghi, Tito; Meloni, Franca; Solbiati, Luigi; Zanus, Giorgio; Collaboration: For the Collaborative Italian Group using AMICA system

    2012-08-15

    Purpose: New technologies for microwave ablation (MWA) have been conceived, designed to achieve larger areas of necrosis compared with radiofrequency ablation (RFA). The purpose of this study was to report complications by using this technique in patients with focal liver cancer. Methods: Members of 14 Italian centers used a 2.45-GMHz generator delivering energy through a cooled miniature-choke MW antenna and a standardized protocol for follow-up. They completed a questionnaire regarding number and type of deaths, major and minor complications and side effects, and likelihood of their relationship to the procedure. Enrollment included 736 patients with 1.037 lesions: 522 had hepatocellular carcinoma with cirrhosis, 187 had metastases predominantly from colorectal cancer, and 27 had cholangiocellular carcinoma. Tumor size ranged from 0.5 to 10 cm. In 13 centers, the approach used was percutaneous, in 4 videolaparoscopic, and in 3 laparotomic. Results: No deaths were reported. Major complications occurred in 22 cases (2.9%), and minor complications in 54 patients (7.3%). Complications of MWA do not differ from those RFA, both being based on the heat damage. Conclusion: Results of this multicenter study confirmed those of single-center experiences, indicating that MWA is a safe procedure, with no mortality and a low rate of major complications. The low rate of complications was probably due to precautions adopted, knowing in advance possible risk conditions, on the basis of prior RFA experience.

  16. Gastrointestinal stromal tumors of the duodenum: Surgical management and survival results

    PubMed Central

    Liang, Xiao; Yu, Hong; Zhu, Lin-Hua; Wang, Xian-Fa; Cai, Xiu-Jun

    2013-01-01

    AIM: To provide long-term survival results of operable duodenal gastrointestinal stromal tumors (DGISTs) in a tertiary center in China. METHODS: In this retrospective study, the pathological data of 28 patients with DGISTs who had been treated surgically at the Second Department of General Surgery, Sir Run Run Shaw Hospital (SRRSH) from June 1998 to December 2006 were reviewed. All pathological slides were examined by a single pathologist to confirm the diagnosis. In patients whose diagnosis was not confirmed by immunohistochemistry at the time of resection, representative paraffin blocks were reassembled, and sections were studied using antibodies against CD117 (c-kit), CD34, smooth muscle actin (SMA), vimentin, S-100, actin (HHF35), and desmin. Operative procedures were classified as wedge resection (WR, local resection with pure closure, without duodenal transection or anastomosis), segmental resection [SR, duodenal transection with Roux-Y or Billroth II gastrojejunostomy (G-J), end-to-end duodenoduodenostomy (D-D), end-to-end or end-to-side duodenojejunostomy (D-J)], and pancreaticoduodenectomy (PD, Whipple operation with pancreatojejunostomy). R0 resection was pursued in all cases, and at least R1 resection was achieved. Regional lymphadenectomy was not performed. Clinical manifestations, surgery, medical treatment and follow-up data were retrospectively analyzed. Related studies in the literature were reviewed. RESULTS: There were 12 males and 16 females patients, with a median age of 53 years (20-76 years). Their major complaints were “gastrointestinal bleeding” (57.2%) and “nonspecific discomfort” (32.1%). About 14.3%, 60.7%, 17.9%, and 7.1% of the tumors originated in the first to fourth portion, respectively, with a median size of 5.8 cm (1.6-20 cm). Treatment was by WR in 5 cases (17.9%), SR in 13 cases (46.4%), and by PD in 10 cases (35.7%). The morbidity and mortality rates were 35.7% and 3.6%, respectively. The median post-operative stay was

  17. Beauty product-related exposures and childhood brain tumors in seven countries: results from the SEARCH International Brain Tumor Study.

    PubMed

    Efird, J T; Holly, E A; Cordier, S; Mueller, B A; Lubin, F; Filippini, G; Peris-Bonet, R; McCredie, M; Arslan, A; Bracci, P; Preston-Martin, S

    2005-04-01

    Data from 1218 cases of childhood brain tumors (CBT) diagnosed between 1976 and 1994 and 2223 matched controls from the general population were included in an analysis of maternal beauty product exposure and beauty-related employment in 9 centers in 7 countries. A 50% increased odds ratio (OR) [95% confidence interval (CI) = 1.0-2.1] for CBT was observed among children of mothers who were exposed via personal use of and/or possible ambient contact with beauty products during the 5 years preceding the index child's birth compared with children of mothers never exposed to beauty products during this time period. Overall maternal personal use of hair-coloring agents in the month before or during the pregnancy of the index child's birth was not associated with CBT (OR = 1.0, CI = 0.83-1.3) or with astroglial (OR = 1.1, CI = 0.85-1.4), PNET (OR = 1.0, CI = 0.71-1.5) and other glial subtypes (OR = 1.0, CI = 0.62-1.0). Similarly, no statistically increased ORs or discernable pattern of risk estimates were observed for period of use or for number of applications per year for maternal personal use of hair-coloring agents overall or by histologic type. Among children born on or after 1980, increased ORs for CBT were associated with maternal non-work-related exposure to any beauty products (OR = 2.6, CI = 1.2-5.9), hair-dyes (OR = 11, CI = 1.2-90), and hair sprays (OR = 3.4, CI = 1.0-11). No overall increased OR for CBT was observed among children of mothers employed in beauty-related jobs during the 5 years preceding the index child's birth compared with those who reported no beauty-related employment. In general, other specific beauty product-related exposures were not associated with increased ORs for CBT. Data from our study provide little evidence of an increased risk for CBT with mothers' exposures to beauty products. PMID:15925993

  18. Interparental Aggression and Adolescent Adjustment: The Role of Emotional Insecurity and Adrenocortical Activity

    PubMed Central

    Bergman, Kathleen N.; Cummings, E. Mark; Davies, Patrick T.

    2013-01-01

    Adolescents exposed to interparental aggression are at increased risk for developing adjustment problems. The present study explored intervening variables in these pathways in a community sample that included 266 adolescents between 12 and 16 years old (M = 13.82; 52.5% boys, 47.5% girls). A moderated mediation model examined the moderating role of adrenocortical reactivity on the meditational capacity of their emotional insecurity in this context. Information from multiple reporters and adolescents’ adrenocortical response to conflict were obtained during laboratory sessions attended by mothers, fathers and their adolescent child. A direct relationship was found between marital aggression and adolescents’ internalizing behavior problems. Adolescents’ emotional insecurity mediated the relationship between marital aggression and adolescents’ depression and anxiety. Adrenocortical reactivity moderated the pathway between emotional insecurity and adolescent adjustment. The implications for further understanding the psychological and physiological effects of adolescents’ exposure to interparental aggression and violence are discussed. PMID:25360061

  19. Laser capture microdissection–reduced representation bisulfite sequencing (LCM-RRBS) maps changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse

    PubMed Central

    Schillebeeckx, Maximiliaan; Schrade, Anja; Löbs, Ann-Kathrin; Pihlajoki, Marjut; Wilson, David B.; Mitra, Robi D.

    2013-01-01

    DNA methylation is a mechanism for long-term transcriptional regulation and is required for normal cellular differentiation. Failure to properly establish or maintain DNA methylation patterns leads to cell dysfunction and diseases such as cancer. Identifying DNA methylation signatures in complex tissues can be challenging owing to inaccurate cell enrichment methods and low DNA yields. We have developed a technique called laser capture microdissection-reduced representation bisulfite sequencing (LCM-RRBS) for the multiplexed interrogation of the DNA methylation status of cytosine–guanine dinucleotide islands and promoters. LCM-RRBS accurately and reproducibly profiles genome-wide methylation of DNA extracted from microdissected fresh frozen or formalin-fixed paraffin-embedded tissue samples. To demonstrate the utility of LCM-RRBS, we characterized changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. Compared with adjacent normal tissue, the adrenocortical tumors showed reproducible gains and losses of DNA methylation at genes involved in cell differentiation and organ development. LCM-RRBS is a rapid, cost-effective, and sensitive technique for analyzing DNA methylation in heterogeneous tissues and will facilitate the investigation of DNA methylation in cancer and organ development. PMID:23589626

  20. Lost in Translation: Ambiguity in Nerve Sheath Tumor Nomenclature and Its Resultant Treatment Effect

    PubMed Central

    Bernthal, Nicholas M.; Jones, Kevin B.; Monument, Michael J.; Liu, Ting; Viskochil, David; Randall, R. Lor

    2013-01-01

    There is much ambiguity surrounding the diagnosis of nerve sheath tumors, including atypical neurofibroma and low-grade MPNST, and yet, the distinction between these entities designates either benign or malignant behavior and thus carries presumed profound prognostic importance that often guides treatment. This study reviews the diagnostic criteria used to designate atypical neurofibroma from low-grade MPNSTs and reviews existing literature the natural history of each of these tumors to see if the distinction is, in fact, of importance. PMID:24216989

  1. Tumor induction following intraoperative radiotherapy: Late results of the National Cancer Institute canine trials

    SciTech Connect

    Barnes, M.; Duray, P.; DeLuca, A.; Anderson, W.; Sindelar, W.; Kinsella, T. )

    1990-09-01

    Intraoperative radiotherapy has been employed in human cancer research for over a decade. Since 1979, trials to assess the acute and late toxicity of IORT have been carried out at the National Cancer Institute in an adult dog model in an attempt to establish dose tolerance guidelines for a variety of organs. Of the 170 animals entered on 12 studies with a minimum follow-up of 2 years, 148 dogs received IORT; 22 control animals received only surgery. Animals were sacrificed at designated intervals following IORT, usually at 1, 6, 12, 24, and 60 month intervals. 102 of 148 irradiated dogs were sacrificed less than 24 months; 46 dogs were followed greater than or equal to 24 months after IORT. To date, 34 of the 46 animals have been sacrificed; the 12 remaining animals are to be followed to 5 years. These 12 animals have minimum follow-up of 30 months. In the irradiated group followed for greater than or equal to 24 months, 10 tumors have arisen in 9 animals. One animal developed an incidental spontaneous breast carcinoma outside the IORT port, discovered only at scheduled post-mortem exam. The remaining nine tumors arose within IORT ports. Two tumors were benign neural tumors--a neuroma and a neurofibroma. One animal had a collision tumor comprised of grade I chondrosarcoma adjacent to grade III osteosarcoma arising in lumbar vertebrae. Two other grade III osteosarcomas, one grade III fibrosarcoma, and one grade III malignant fibrous histiocytoma arose in retroperitoneal/paravertebral sites. An embryonal rhabdomyosarcoma (sarcoma botryoides) arose within the irradiated urinary bladder of one animal. No sham irradiated controls nor IORT animals sacrificed less than 24 months have developed any spontaneous or radiation-induced tumors. The time range of diagnoses of tumors was 24-58 months. The IORT dose range associated with tumor development was 20-35 Gy.

  2. Adrenocortical effects of oral estrogens and soy isoflavones in female monkeys.

    PubMed

    Wood, Charles E; Cline, J Mark; Anthony, Mary S; Register, Thomas C; Kaplan, Jay R

    2004-05-01

    The goal of this study was to evaluate the long-term adrenocortical effects of premenopausal oral contraceptives (OC) and postmenopausal conjugated equine estrogens (CEE) and soy isoflavones in a female cynomolgus monkey model. Half of the animals received a triphasic OC for a period of 26 months, after which all monkeys were ovariectomized and randomized to one of three diet groups for 36 months: 1). isoflavone-depleted soy protein (control) (n = 54); 2). soy protein with isoflavones (129 mg/d equivalent) (SPI+) (n = 56); or 3). isoflavone-depleted soy protein with CEE (0.625 mg/d equivalent) (n = 59). In the premenopausal phase, OC treatment resulted in significantly higher cortisol (F) and lower dehydroepiandrosterone sulfate, androstenedione, and testosterone relative to intact controls. In the postmenopausal phase, CEE treatment resulted in significantly higher basal F and lower dehydroepiandrosterone sulfate, androstenedione, and testosterone when compared with control and SPI+ diets. Serum F and androgens in the SPI+ group did not differ significantly from the control group. The SPI+ group had significantly lower adrenal weight than either control or CEE groups, and this effect was localized primarily to the zona fasciculata region of the adrenal cortex. These findings suggest that long-term estrogen treatment may contribute to an androgen-deficient and hypercortisolemic state. PMID:15126559

  3. Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors.

    PubMed

    Baird, Jason R; Friedman, David; Cottam, Benjamin; Dubensky, Thomas W; Kanne, David B; Bambina, Shelly; Bahjat, Keith; Crittenden, Marka R; Gough, Michael J

    2016-01-01

    Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiotherapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiotherapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T-cell-independent and TNFα-dependent hemorrhagic necrosis at early times, followed by later CD8 T-cell-dependent control of residual disease. Clinically, STING was found to be expressed extensively in human pancreatic tumor and stromal cells. Our findings suggest that this novel STING ligand could offer a potent adjuvant for leveraging radiotherapeutic management of pancreatic cancer. PMID:26567136

  4. French brain tumor database: 5-year histological results on 25 756 cases.

    PubMed

    Rigau, Valérie; Zouaoui, Sonia; Mathieu-Daudé, Hélène; Darlix, Amélie; Maran, Aurélie; Trétarre, Brigitte; Bessaoud, Faiza; Bauchet, Fabienne; Attaoua, Redha; Fabbro-Peray, Pascale; Fabbro, Michel; Kerr, Christine; Taillandier, Luc; Duffau, Hugues; Figarella-Branger, Dominique; Costes, Valérie; Bauchet, Luc

    2011-11-01

    This work aimed to prospectively record all primary central nervous system tumor (PCNST) cases in France, for which histological diagnosis is available. The objectives were to (i) create a national registry and a network to perform epidemiological studies; (ii) implement clinical and basic research protocols; and (iii) harmonize the health care of patients affected by PCNST. For 5 years, 25 756 cases of newly diagnosed and histologically confirmed PCNST have been recorded. Histological diagnoses included glioma (48.9%), all other neuroepithelial tumors (5%), meningioma (28.8%), nerve sheath tumors (8.4%), lymphoma (3.2%) and others (5.7%). Cryopreservation was reported for 6018 PCNST specimens. Tumor resections (R) were performed in 78% cases, while biopsies accounted for 22%. Median age (MA), sex, percentage R and number of cryopreserved tumors were detailed for each histology; for example, out of 6053 glioblastomas (MA 63 years, male 59.4%, R 62%, 1611 were cryopreserved), and out of 37 atypical teratoid/rhabdoid tumors (MA 2 years, male 56.8%, R 94%, 17 were cryopreserved). This database or databank dedicated to PCNST cases contains detailed data on clinical, histological and other characteristics, such as the inclusion of data on cryopreserved specimens that are not available in other European registries. Therefore, this is a valuable resource that can be used for planning future epidemiological and clinical research. PMID:21554472

  5. END STAGE RENAL DISEASE IN PATIENTS WITH WILMS TUMOR: RESULTS FROM THE NATIONAL WILMS TUMOR STUDY GROUP AND THE U.S. RENAL DATA SYSTEM

    PubMed Central

    Breslow, Norman E.; Grigoriev, Yevgeny A.; Peterson, Susan M.; Collins, Allan J.; Ritchey, Michael L.; Green, Daniel M.

    2006-01-01

    Purpose: To accurately assess the full spectrum of end stage renal disease (ESRD) in Wilms tumor survivors by combining the unique resources of the National Wilms Tumor Study Group (NWTSG) and the U.S. Renal Data System (USRDS), and to confirm preliminary reports of an increased incidence of ESRD in those with the Wilms tumor-aniridia (WAGR) syndrome. Material and Methods: ESRD was ascertained for 5,910 patients enrolled on NWTSG studies during 1969-1994 both by record linkage to USRDS and by direct follow-up. Cumulative ESRD incidence was estimated accounting for inter-current mortality. Results: Ten of 115 cases of ESRD (9%) were ascertained by NWTSG alone, 13 (11%) by USRDS alone and 92 (80%) by both. Cumulative incidence of ESRD at 20 years from diagnosis of unilateral Wilms tumor (WT) was 74% for 17 patients with Deny-Drash syndrome (DDS), 36% for 37 patients with WAGR syndrome, 7% for 125 male patients with hypospadias or cryptorchism (GU anomalies) and 0.6% for 5,347 patients with none of these conditions. The incidence for bilateral Wilms tumor was 50% for DDS (n=6), 90% for WAGR (n=10), 25% for GU anomaly (n=25) and 12% for other patients (n=409). ESRD for patients with WAGR syndrome or GU anomalies tended to occur relatively late, often during or after adolescence. Conclusions: The risk of ESRD is remarkably low for the majority of WT patients. Those with WAGR syndrome or associated GU anomalies, however, are at higher risk and should be screened indefinitely to facilitate prospective management of impaired renal function. PMID:16217371

  6. Neutron-capture therapy of human cancer: in vivo results on tumor localization of boron-10-labeled antibodies to carcinoembryonic antigen in the gw-39 tumor model system

    SciTech Connect

    Goldenberg, D.M.; Sharkey, R.M.; Primus, F.J.; Mizusawa, E.; Hawthorne, M.F.

    1984-01-01

    Antibody against carcinoembryonic antigen (CEA) was conjugated with p-(1,2-dicarba-closo-(1-/sup 3/H)dodecaboran(12)-2-yl)benzenediazonium ion by an azo-coupling reaction, resulting in 30 boron atoms per IgG molecule with no loss of antibody protein. Antibody immunoreactivity was not appreciably affected by this conjugation and was stable after incubation in vitro in hamster plasma for 24 hr. The efficacy of the boron-conjugated anti-CEA IgG for localizing selectively in CEA-containing human colonic carcinomas propagated in the hind leg musculature of hamsters was evaluated by labeling the antibodies with /sup 131/I and determining distribution of the radioactivity in vivo. The results show that the boron-conjugated antibodies retain selective localization in the tumors, thus indicating their suitability for transporting boron-10 to tumors for use in neutron-capture therapy of cancer. 17 references, 3 tables, 2 figures.

  7. The cAMP pathway and the control of adrenocortical development and growth

    PubMed Central

    de Joussineau, Cyrille; Sahut-Barnola, Isabelle; Levy, Isaac; Saloustros, Emmanouil; Val, Pierre; Stratakis, Constantine A.; Martinez, Antoine

    2013-01-01

    In the last 10 years, extensive studies showed that the cAMP pathway is deregulated in patients suffering from adrenocortical tumours, and particularly in primary pigmented nodular adrenocortical disease (PPNAD). Here we describe how evidence arising from the analysis of patients’ data, mouse models and in vitro experiments, have shed light on the cAMP pathway as a central player in adrenal physiopathology. We also show how novel data generated from mouse models may point to new targets for potential therapies. PMID:22019902

  8. Localized Hypoxia Results in Spatially Heterogeneous Metabolic Signatures in Breast Tumor Models1

    PubMed Central

    Jiang, Lu; Greenwood, Tiffany R; Artemov, Dmitri; Raman, Venu; Winnard, Paul T; Heeren, Ron MA; Bhujwalla, Zaver M; Glunde, Kristine

    2012-01-01

    Tumor hypoxia triggers signaling cascades that significantly affect biologic outcomes such as resistance to radiotherapy and chemotherapy in breast cancer. Hypoxic regions in solid tumor are spatially heterogeneous. Therefore, delineating the origin and extent of hypoxia in tumors is critical. In this study, we have investigated the effect of hypoxia on different metabolic pathways, such as lipid and choline metabolism, in a human breast cancer model. Human MDA-MB-231 breast cancer cells and tumors, which were genetically engineered to express red fluorescent tdTomato protein under hypoxic conditions, were used to investigate hypoxia. Our data were obtained with a novel three-dimensional multimodal molecular imaging platform that combines magnetic resonance (MR) imaging, MR spectroscopic imaging (MRSI), and optical imaging of hypoxia and necrosis. A higher concentration of noninvasively detected total choline-containing metabolites (tCho) and lipid CH3 localized in the tdTomato-fluorescing hypoxic regions indicated that hypoxia can upregulate tCho and lipid CH3 levels in this breast tumor model. The increase in tCho under hypoxia was primarily due to elevated phosphocholine levels as shown by in vitro MR spectroscopy. Elevated lipid CH3 levels detected under hypoxia were caused by an increase in mobile MR-detectable lipid droplets, as demonstrated by Nile Red staining. Our findings demonstrate that noninvasive MRSI can help delineate hypoxic regions in solid tumors by means of detecting the metabolic outcome of tumor hypoxia, which is characterized by elevated tCho and lipid CH3. PMID:22952426

  9. Transurethral En Bloc Resection of Bladder Tumor Using an Endoscopic Submucosal Dissection Technique: Preliminary Results in an Animal Model

    PubMed Central

    Morizane, Shuichi; Sejima, Takehiro; Iwamoto, Hideto; Masago, Toshihiko; Honda, Masashi; Ikebuchi, Yuichiro; Matsumoto, Kazuya; Ueki, Masaru; Takenaka, Atsushi

    2016-01-01

    Background Transurethral resection of bladder tumor (TURBT) technique has been considered the routine method for removing most bladder tumors for decades. In contrast, endoscopic submucosal dissection (ESD) is the gold-standard treatment for gastrointestinal superficial tumors. We investigated the effectiveness and applicability of a new technique for en bloc bladder tumor resection using ESD procedure. Methods Four Landrace Large White Duroc female pigs were anesthetized with isoflurane prior endoscopic resection using a large-caliber prototype fiber bronchoscope. After local infiltration of the submucosa with sodium hyaluronate using an injector needle, a section of the target area (1.0–2.0 cm diameter circular area) was cut with the Dual Knife. Results In total, seven target sections were resected from the pigs. The median size of the resected sections was 1.8 cm (range 1.0–2.5 cm) and the median time taken to perform the resection of one section was 20 min (range 4–35 min). These target sections were completely resected en bloc. Although the small bladder perforations occurred on two occasions, no other short-term complications such as uncontrollable bleeding were observed. Conclusion This procedure is a slightly difficult in the pigs with thin bladder walls. However, this procedure with the slim flexible cystoscope may allow us to be able to remove bladder tumors using only light sedation, especially for cases when small tumor recurrence is observed during routine cystoscopy for the patients with non-muscle invasive bladder cancer. PMID:27493485

  10. Blunted Opiate Modulation of Hypothalamic-Pituitary-Adrenocortical Activity in Men and Women Who Smoke

    PubMed Central

    al’Absi, Mustafa; Wittmers, Lorentz E.; Hatsukami, Dorothy; Westra, Ruth

    2016-01-01

    Objective To examine the extent to which nicotine dependence alters endogenous opioid regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis functions. Endogenous opiates play an important role in regulating mood, pain, and drug reward. They also regulate the HPA functions. Previous work has demonstrated an abnormal HPA response to psychological stress among dependent smokers. Methods Smokers and nonsmokers (total n = 48 participants) completed two sessions during which a placebo or 50 mg of naltrexone was administered, using a double-blind design. Blood and saliva samples, cardiovascular and mood measures were obtained during a resting absorption period, after exposure to two noxious stimuli, and during an extended recovery period. Thermal pain threshold and tolerance were assessed in both sessions. Participants also rated pain during a 90-second cold pressor test. Results Opioid blockade increased adrenocorticotropin, plasma cortisol, and salivary cortisol levels; these increases were enhanced by exposure to the noxious stimuli. These responses were blunted in smokers relative to nonsmokers. Smokers tended to report less pain than nonsmokers, and women reported more pain during both pain procedures, although sex differences in pain were significant only among nonsmokers. Conclusions We conclude that nicotine dependence is associated with attenuated opioid modulation of the HPA. This dysregulation may play a role in the previously observed blunted responses to stress among dependent smokers. PMID:18799426

  11. Role of ALADIN in Human Adrenocortical Cells for Oxidative Stress Response and Steroidogenesis

    PubMed Central

    Jühlen, Ramona; Idkowiak, Jan; Taylor, Angela E.; Kind, Barbara; Arlt, Wiebke; Huebner, Angela; Koehler, Katrin

    2015-01-01

    Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN. We investigated the role of ALADIN in the human adrenocortical cell line NCI-H295R1 by either over-expression or down-regulation of ALADIN. Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, we show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. We conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome. PMID:25867024

  12. Adrenocortical suppression in workers employed in manufacturing synthetic glucocorticosteroids: solutions to a problem.

    PubMed Central

    Newton, R W; Browning, M C; Nicholson, P C; Mowat, D A

    1982-01-01

    Earlier studies showed gross adrenocortical suppression in three workers employed in manufacturing synthetic glucocorticoids. A further nine had either recognisable abnormalities of their responses to tetracosactrin or evidence of chronic skin contact with glucocorticoids. By 1978 the mean morning cortisol concentration of 20 workers employed in active steroid processes was 235 nmol/1 +/- 28.6 (8.5 microgram/ml +/- 1.04), which was significantly lower than the value of 428 nmol/l +/- 37.7 (15.5 microgram/ml +/- 1.40) obtained in a control group of 19 men (p less than 0.005). The mean morning cortisol of workers employed in processing steroids believed to be physiologically inactive, 306 nmol/l +/- 22.4 (11.1 microgram/ml +/- 0.81), was also significantly lower than this control group (0.01 greater than p greater than 0.005). Improvement of protection for workers together with operational and plant changes resulted in a significant rise in the mean morning cortisol values of workers until, in 1979, men employed in all steroid processes had concentrations that did not differ from those of a control group. PMID:6461351

  13. Adrenocortical function during prolonged treatment with clobetasone butyrate in children with chronic atopic dermatitis and elevated IgE levels.

    PubMed

    Boner, A L; Richelli, C; De Stefano, G; Antolini, I; Aprili, F; Mengoni, M

    1985-01-01

    Twelve children with chronic atopic dermatitis and elevated IgE levels (age range: 2-13 years; mean age = 8.2 +/- 3.5 years) were selected for the study and treated with clobetasone butyrate (0.05% cream) thrice daily during the first week, then twice daily for three weeks. Adrenocortical function was evaluated at the beginning and the end of treatment period. The results show that there was no statistically significant change in adrenal function during the study period (tetracosactrin test). The results of the immunological studies, namely total IgE using the paper disc radioimmunoassay technique, specific IgE using the radioallergosorbent test and immunoglobulin levels are given. PMID:4018942

  14. Photodynamic therapy (PDT) of malignant tumors by photosensitzer photosens: results of 45 clinical cases

    NASA Astrophysics Data System (ADS)

    Sokolov, Victor V.; Chissov, Valery I.; Yakubovskaya, Raisa I.; Aristarkhova, E. I.; Filonenko, E. V.; Belous, T. A.; Vorozhtsov, Georgy N.; Zharkova, Natalia N.; Smirnov, V. V.; Zhitkova, Margarita B.

    1996-01-01

    Photosensitizer Photosens is a mixture of sulphonated Al-phthalocyanines with a different number of substituents per phthalocyanine molecule. In the beginning of 1994, this photosensitizer was approved for clinical trials. Since that time till May 1995, 45 patients with 120 tumors were treated by PDT-Photosens. The main tumor localizations were lung (5/6), head and neck (4/4), esophagus (8/8), stomach (2/2), vulva (2/2), bladder (1/1), breast cancer (3/3), skin (basalioma, melanoma, sarcoma Kaposi, mts breast cancer) (20 patients/94 tumors). The lesions were photoirradiated 48-72 h after intravenous injection of Photosens in doses from 0.5 to 2.0 mg/kg b.w. (1.0 mg/kg b.w., on average). PDT was performed by laser power density from 20 to 1400 mW/sq cm (300 mW/sq.cm, on average), energy density varying from 15 to 200 J/sq cm (100 J/sq.cm, on average). The therapeutical effect of PDT was evaluated histologically, endoscopically, roentgenologically and sonographically 3 - 4 weeks after the treatment. Complete regression of tumors was reached in 56%, significant remission was reached in 34%, and partial remission was observed in 10% of cases. The follow-up of patients with complete tumor regression was to 15 months.

  15. Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors

    PubMed Central

    Biehl, Michael; Taylor, Angela E.; Hahner, Stefanie; Libé, Rossella; Hughes, Beverly A.; Schneider, Petra; Smith, David J.; Stiekema, Han; Krone, Nils; Porfiri, Emilio; Opocher, Giuseppe; Bertherat, Jerôme; Mantero, Franco; Allolio, Bruno; Terzolo, Massimo; Nightingale, Peter; Shackleton, Cedric H. L.; Bertagna, Xavier; Fassnacht, Martin; Stewart, Paul M.

    2011-01-01

    Context: Adrenal tumors have a prevalence of around 2% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2–11% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19–84 yr) and 45 ACC patients (20–80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26–201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas. PMID:21917861

  16. A clinical and immunological study of adrenocortical insufficiency (Addison's disease)

    PubMed Central

    Irvine, W. J.; Stewart, A. G.; Scarth, Laura

    1967-01-01

    Fifty-one patients with adrenocortical insufficiency were subdivided into three groups according to the nature of their adrenal disease; twelve patients with idiopathic, twenty-three patients with probable idiopathic and sixteen patients with tuberculous adrenal insufficiency. The importance of objective confirmation of a clinical diagnosis of adrenal insufficiency is stressed and the difficulties of classification of many patients with adult onset adrenal insufficiency are discussed. Idiopathic and probable idiopathic adrenal insufficiency had a sex ratio that was predominantly female (2·5:1) with a mean age of onset of 33 years. Antibodies to adrenal cortex were detected by the methods of immunofluorescence and complement fixation. They were detected in the serum of 80% (20:25) of the females with idiopathic or probable idiopathic adrenal insufficiency and in only 10% (1:10) of the males. The titre of the adrenal antibody was low (≤32) as tested either by immunofluorescence or complement fixation. The serum of only one patient with tuberculous adrenal insufficiency reacted with adrenal tissue in the complement fixation test but the immunofluorescence method showed that this serum reacted with the vascular endothelium and not the secretory cells. No correlation was observed between the duration of the clinical illness and the presence, or absence, or titre of the adrenal antibody. Adrenal antibody was not detected in the sera of fifty-one control subjects matched for age and sex. Four of sixty-nine patients with lymphadenoid goitre, one out of ninety-three patients with diabetes mellitus and none of 230 patients with thyrotoxicosis, primary hypothyroidism or pernicious anaemia had antibody in the serum specific for adrenocortical secretory cells. There is a clinical and immunological overlap between idiopathic adrenal insufficiency and other diseases associated with autoimmune phenomena— thyroid disease, atrophic gastritis and hypoparathyroidism. It is

  17. Infant Brain Tumors: Incidence, Survival, and the Role of Radiation Based on Surveillance, Epidemiology, and End Results (SEER) Data

    SciTech Connect

    Bishop, Andrew J.; McDonald, Mark W.; Chang, Andrew L.; Esiashvili, Natia

    2012-01-01

    Purpose: To evaluate the incidence of infant brain tumors and survival outcomes by disease and treatment variables. Methods and Materials: The Surveillance, Epidemiology, and End Results (SEER) Program November 2008 submission database provided age-adjusted incidence rates and individual case information for primary brain tumors diagnosed between 1973 and 2006 in infants less than 12 months of age. Results: Between 1973 and 1986, the incidence of infant brain tumors increased from 16 to 40 cases per million (CPM), and from 1986 to 2006, the annual incidence rate averaged 35 CPM. Leading histologies by annual incidence in CPM were gliomas (13.8), medulloblastoma and primitive neuroectodermal tumors (6.6), and ependymomas (3.6). The annual incidence was higher in whites than in blacks (35.0 vs. 21.3 CPM). Infants with low-grade gliomas had the highest observed survival, and those with atypical teratoid rhabdoid tumors (ATRTs) or primary rhabdoid tumors of the brain had the lowest. Between 1979 and 1993, the annual rate of cases treated with radiation within the first 4 months from diagnosis declined from 20.5 CPM to <2 CPM. For infants with medulloblastoma, desmoplastic histology and treatment with both surgery and upfront radiation were associated with improved survival, but on multivariate regression, only combined surgery and radiation remained associated with improved survival, with a hazard ratio for death of 0.17 compared with surgery alone (p = 0.005). For ATRTs, those treated with surgery and upfront radiation had a 12-month survival of 100% compared with 24.4% for those treated with surgery alone (p = 0.016). For ependymomas survival was higher in patients treated in more recent decades (p = 0.001). Conclusion: The incidence of infant brain tumors has been stable since 1986. Survival outcomes varied markedly by histology. For infants with medulloblastoma and ATRTs, improved survival was observed in patients treated with both surgery and early radiation

  18. Primary malignant bone tumors and solitary metastases of the thoracolumbar spine: results by management with total en bloc spondylectomy

    PubMed Central

    Melcher, Ingo; Khodadadyan-Klostermann, Cyrus; Tohtz, Stefan; Smolny, Mirko; Stöckle, Ulrich; Haas, Norbert P.; Schaser, Klaus-Dieter

    2007-01-01

    Primary malignant spinal tumors and solitary vertebral metastases of selected tumor entities in the thoracolumbar spine are indications for total en bloc spondylectomy (TES). This study aimed to describe our oncological and surgical management and to analyze the treatment results by management with TES for extra- and intracompartmental solitary spinal metastases and primary malignant vertebral bone tumors. In 15 patients (3 malignant bone tumors and 12 solitary metastases), tumors were distributed in the thoracic (n = 8) and lumbar (n = 7) spine. Tumors were classified as intra- (n = 8) and extracompartmental (n = 7). All patients underwent TES via a laterally extended posterior approach followed by dorsoventral reconstruction. Function and quality of life were assessed by Oswestry disability index (ODI) and SF-36 score. At follow-up (100%; mean: 33 ± 22 months), 11 patients had no evidence of disease. Two patients were alive with the disease and two were dead of the disease (no primary bone tumors). Histology revealed negative margins (R0) in all patients with wide (n = 11) and marginal (n = 4) resections. Two patients developed pulmonal metastases of which they died at 4 and 16 months of survival. No local recurrence was observed. Major complications did not occur. TES resulted in an acceptable outcome in the quality of life and function. TES is a demanding procedure reaching wide to marginal resections in a curative approach. In conjunction with multimodal therapies, local recurrences can effectively be prevented while control of distant disease needs to be improved. Proper selection of adequate patients combined with careful surgical planning are prerequisites for low complication rates, acceptable function and improved overall prognosis. PMID:17252218

  19. Adrenocortical cancer (ACC) - literature overview and own experience.

    PubMed

    Dworakowska, Dorota; Drabarek, Agata; Wenzel, Ingrid; Babińska, Anna; Świątkowska-Stodulska, Renata; Sworczak, Krzysztof

    2014-01-01

    Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers. PMID:25554619

  20. Regulation of the hypothalamic-pituitary-adrenocortical stress response

    PubMed Central

    Herman, James P.; McKlveen, Jessica M.; Ghosal, Sriparna; Kopp, Brittany; Wulsin, Aynara; Makinson, Ryan; Scheimann, Jessie; Myers, Brent

    2016-01-01

    The hypothalamo-pituitary-adrenocortical (HPA axis) is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem), promote trans-synaptic inhibition by limbic structures (e.g, hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic and brainstem circuits. Importantly, an individual’s response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex and age. The context in which stressors occur will determine whether an individual’s acute or chronic stress responses are adaptive or maladaptive (pathological). PMID:27065163

  1. Boronated porphyrins in NCT: Results with a new potent tumor localizer

    SciTech Connect

    Kahl, S.B.; Koo, M.S.; Laster, B.H.; Fairchild, R.G.

    1988-01-01

    Several chemical methods are available for the solubilization of boronated porphyrins. We have previously reported the tumor localization of nido carboranyl porphyrins in which the icosahedral carborane cages have been opened to give B/sub 9/C/sub 2/ anions. One of these species has shown tumor boron levels of nearly 50 ..mu..g B/g when delivered by week-long subcutaneous infusions. We report here recent in vivo experiments with a new, highly water-soluble porphyrin based on the hematoporphyrin-type of compound in which aqueous solubility is achieved using the two propionic acid side chains of the ''natural'' porphyrin frame. 7 refs.

  2. Expression of anti-VEGF antibody together with anti-EGFR or anti-FAP enhances tumor regression as a result of vaccinia virotherapy

    PubMed Central

    Huang, Ting; Wang, Huiqiang; Chen, Nanhai G; Frentzen, Alexa; Minev, Boris; Szalay, Aladar A

    2015-01-01

    The tumor microenvironment plays an important role in tumor growth and progression. Here we demonstrate that vaccinia virus-mediated, constitutively expressed intratumoral antibodies against vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and fibroblast activation protein (FAP) significantly improved tumor regression and oncolytic virotherapy through suppression of angiogenesis, cell proliferation, and stromagenesis in virus-colonized tumors. In contrast to the tumor growth inhibition by the three tumor growth-inhibiting antibodies individually, when two of the three antibodies were expressed simultaneously by single vaccinia virus strains tumor regression was further enhanced. These findings strongly indicate that interference with the two tumor growth-stimulating mechanisms did in fact result in enhanced therapeutic efficacy in tumor xenograft models and may lead to an effective therapy in patients with cancer. PMID:27119102

  3. Does famotidine enhance tumor infiltrating lymphocytes in breast cancer? Results of a randomized prospective pilot study.

    PubMed

    Parshad, Rajinder; Kapoor, Sorabh; Gupta, Siddhartha Datta; Kumar, Arvind; Chattopadhyaya, Tushar K

    2002-01-01

    Thirty patients with breast cancer were prospectively randomized into case and control groups receiving 40 mg famotidine preoperatively for 10-14 days and routine premedication, respectively. Surgical specimens were evaluated objectively for tumor infiltrating lymphocytes in the center and in the periphery of the tumor along with evaluation of metastatic lymph nodes for reactive changes. Ten famotidine-treated cases (67%) showed significant lymphocytic infiltration in the center compared to 4 controls (27%) (p = 0.03). Eleven cases (77%) had significant lymphocytic infiltration in the periphery (p = 0.03) compared to 5 controls (33%). Considering both sites, lymphocytic response was significant in 9 (60%) cases as opposed to only 3 (20%) controls (p = 0.03). This response did not correlate with the stage, grade of tumor or menopausal status of patients in either group. Seventy-eight percent (78%) of the cases showed significant reactive changes in the metastatic lymph nodes as compared to 22% in controls (p < 0.01). This study suggests that famotidine enhances tumor infiltrating lymphocytes in breast cancer and might have potential as an immunomodulator. A larger confirmatory study is suggested. PMID:12234028

  4. T-Cell Tumor Elimination as a Result of T-Cell Receptor-Mediated Activation

    NASA Astrophysics Data System (ADS)

    Ashwell, Jonathan D.; Longo, Dan L.; Bridges, Sandra H.

    1987-07-01

    It has recently been shown that activation of murine T-cell hybridomas with antigen inhibits their growth in vitro. The ``suicide'' of these neoplastic T cells upon stimulation with antigen suggested the possibility that activation via the antigen-specific receptor could also inhibit the growth of neoplastic T cells in vivo. To test this, mice were subcutaneously inoculated with antigen-specific T-cell hybridomas and then treated intraperitoneally with antigen. Administration of the appropriate antigen immediately after inoculation with the T-cell hybridoma abrogated tumor formation; antigen administered after tumors had become established decreased the tumor burden and, in a substantial fraction of animals, led to long-term survival. The efficacy of antigen therapy was due to both a direct inhibitory effect on tumor growth and the induction of host immunity. These studies demonstrate the utility of cellular activation as a means of inhibiting neoplastic T-cell growth in vivo and provide a rationale for studying the use of less selective reagents that can mimic the activating properties of antigen, such as monoclonal antibodies, in the treatment of T-cell neoplasms of unknown antigen specificity.

  5. Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects

    PubMed Central

    Dolinsek, Tanja; Sersa, Gregor; Prosen, Lara; Bosnjak, Masa; Stimac, Monika; Razborsek, Urska; Cemazar, Maja

    2015-01-01

    Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. PMID:26712792

  6. Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects.

    PubMed

    Dolinsek, Tanja; Sersa, Gregor; Prosen, Lara; Bosnjak, Masa; Stimac, Monika; Razborsek, Urska; Cemazar, Maja

    2015-01-01

    Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. PMID:26712792

  7. Validation of a Fecal Glucocorticoid Assay to Assess Adrenocortical Activity in Meerkats Using Physiological and Biological Stimuli

    PubMed Central

    Heistermann, Michael; Santema, Peter; Dantzer, Ben; Mausbach, Jelena; Ganswindt, Andre; Manser, Marta B.

    2016-01-01

    In mammals, glucocorticoid (i.e. GC) levels have been associated with specific life-history stages and transitions, reproductive strategies, and a plethora of behaviors. Assessment of adrenocortical activity via measurement of glucocorticoid metabolites in feces (FGCM) has greatly facilitated data collection from wild animals, due to its non-invasive nature, and thus has become an established tool in behavioral ecology and conservation biology. The aim of our study was to validate a fecal glucocorticoid assay for assessing adrenocortical activity in meerkats (Suricata suricatta), by comparing the suitability of three GC enzyme immunoassays (corticosterone, 11β-hydroxyetiocholanolone and 11oxo-etiocholanolone) in detecting FGCM increases in adult males and females following a pharmacological challenge with adrenocorticotropic hormone (ACTH) and biological stimuli. In addition, we investigated the time course characterizing FGCM excretion, the effect of age, sex and time of day on FGCM levels and assessed the potential effects of soil contamination (sand) on FGCM patterns. Our results show that the group specific 11β-hydroxyetiocholanolone assay was most sensitive to FGCM alterations, detecting significant and most distinctive elevations in FGCM levels around 25 h after ACTH administration. We found no age and sex differences in basal FGCM or on peak response levels to ACTH, but a marked diurnal pattern, with FGCM levels being substantially higher in the morning than later during the day. Soil contamination did not significantly affect FGCM patterns. Our results emphasize the importance of conducting assay validations to characterize species-specific endocrine excretion patterns, a crucial step to all animal endocrinology studies using a non-invasive approach. PMID:27077741

  8. Validation of a Fecal Glucocorticoid Assay to Assess Adrenocortical Activity in Meerkats Using Physiological and Biological Stimuli.

    PubMed

    Braga Goncalves, Ines; Heistermann, Michael; Santema, Peter; Dantzer, Ben; Mausbach, Jelena; Ganswindt, Andre; Manser, Marta B

    2016-01-01

    In mammals, glucocorticoid (i.e. GC) levels have been associated with specific life-history stages and transitions, reproductive strategies, and a plethora of behaviors. Assessment of adrenocortical activity via measurement of glucocorticoid metabolites in feces (FGCM) has greatly facilitated data collection from wild animals, due to its non-invasive nature, and thus has become an established tool in behavioral ecology and conservation biology. The aim of our study was to validate a fecal glucocorticoid assay for assessing adrenocortical activity in meerkats (Suricata suricatta), by comparing the suitability of three GC enzyme immunoassays (corticosterone, 11β-hydroxyetiocholanolone and 11oxo-etiocholanolone) in detecting FGCM increases in adult males and females following a pharmacological challenge with adrenocorticotropic hormone (ACTH) and biological stimuli. In addition, we investigated the time course characterizing FGCM excretion, the effect of age, sex and time of day on FGCM levels and assessed the potential effects of soil contamination (sand) on FGCM patterns. Our results show that the group specific 11β-hydroxyetiocholanolone assay was most sensitive to FGCM alterations, detecting significant and most distinctive elevations in FGCM levels around 25 h after ACTH administration. We found no age and sex differences in basal FGCM or on peak response levels to ACTH, but a marked diurnal pattern, with FGCM levels being substantially higher in the morning than later during the day. Soil contamination did not significantly affect FGCM patterns. Our results emphasize the importance of conducting assay validations to characterize species-specific endocrine excretion patterns, a crucial step to all animal endocrinology studies using a non-invasive approach. PMID:27077741

  9. The Role of Radiotherapy in the Treatment of Primary or Recurrent Desmoid Tumors and Long-Term Results

    PubMed Central

    Ergen, Şefika Arzu; Tiken, Elif Eda; Öksüz, Didem Çolpan; Dinçbaş, Fazilet Öner; Dervişoğlu, Sergülen; Mandel, Nil Molinas; Hız, Murat; Koca, Sedat

    2016-01-01

    Background: Desmoid tumors are uncommon and benign mesenchymal neoplasms. The optimal treatment of patients with desmoid tumors is still controversial. Surgery is the primary treatment for locally invasive or recurrent desmoid tumors. Also, radiotherapy is a treatment option for patients at high risk for local failure such as those with positive margins or recurrent and unresectable tumors. Aims: To report our institutional experience and long-term results of patients with desmoid tumors who received radiotherapy. Study Design: Retrospective cross-sectional study. Methods: Between 1980 and 2009, 20 patients who received radiotherapy (RT) in our institution were analyzed. The majority of patients (80%) were referred with a recurrent tumor after previous surgery. Thirteen patients underwent marginal resection, 4 had wide local excision and 3 patients had only biopsy. Resection margin was positive in 15 (75%) patients. All patients received radiation therapy. The median prescribed dose was 60 Gy. Five patients received less than 54 Gy. Results: The median follow-up time was 77.5 months (28–283 months). Nine patients developed local recurrence after RT. Seven local failures (78%) were in field. Time to local recurrence ranged from 3–165 months (median 33 months). The 2–5 year local control (LC) rates were 80% and 69%, respectively. On univariate analysis, the 5 year local control rate was significantly better in the patients treated with ≥54 Gy than in patients who received <54 Gy (p=0.023). The most common acute side effect was grade 1–2 skin toxicity. As a late side effect of radiotherapy, soft tissue fibrosis was detected in 10 patients and lymphangitis was seen in 1 patient. One patient developed radiation-induced sarcoma. Conclusion: According to our results, radiotherapy is especially effective in recurrent disease and provides a high local control rate in the patients received more than 54 Gy. PMID:27308076

  10. Evening Activities as a Potential Confound in Research on the Adrenocortical System in Children

    ERIC Educational Resources Information Center

    Kertes, Darlene A.; Gunnar, Megan R.

    2004-01-01

    The relation among children's evening activities, behavioral characteristics, and activity of the hypothalamic-pituitary-adrenocortical axis was assessed in normally developing children ages 7 to 10 years. Salivary cortisol at bedtime was compared on evenings when children had structured activities outside of the home with unstructured evenings at…

  11. Emotional and Adrenocortical Regulation in Early Adolescence: Prediction by Attachment Security and Disorganization in Infancy

    ERIC Educational Resources Information Center

    Spangler, Gottfried; Zimmermann, Peter

    2014-01-01

    The aim of the present study was to examine differences in emotion expression and emotion regulation in emotion-eliciting situations in early adolescence from a bio-psycho-social perspective, specifically investigating the influence of early mother-infant attachment and attachment disorganization on behavioural and adrenocortical responses. The…

  12. Maternal-child adrenocortical attunement in early childhood: continuity and change.

    PubMed

    Hibel, Leah C; Granger, Douglas A; Blair, Clancy; Finegood, Eric D

    2015-01-01

    This study evaluated continuity and change in maternal-child hypothalamic-pituitary-adrenal axis attunement in early childhood. Participants were drawn from a prospective study of 1,292 mother-child dyads, which were racially diverse, predominantly low-income, and non-urban. Child focused stress tasks designed to elicit anger, fear, and frustration were administered during early infancy, later infancy, and toddlerhood. Mothers' and children's saliva samples (later assayed for cortisol) were collected before and after the tasks. The strength of mother-child adrenocortical attunement was conserved across infancy and toddlerhood. The magnitude of maternal-child adrenocortical attunement decreased in response to the child-focused stress tasks. Maternal sensitivity and the child's task-related emotional reactivity moderated adrenocortical attunement across the task, with greater maternal sensitivity during a free-play, and lower levels of child emotional reactivity during the stress tasks, stabilizing attunement from pre- to post-task levels. The findings advance our understanding of individual differences in the social regulation of adrenocortical activity in early childhood. PMID:25417896

  13. The Relations between Bullying Exposures in Middle Childhood, Anxiety, and Adrenocortical Activity

    ERIC Educational Resources Information Center

    Carney, JoLynn V.; Hazler, Richard J.; Oh, Insoo; Hibel, Leah C.; Granger, Douglas A.

    2010-01-01

    This exploratory study investigated how exposure to bullying at school in middle childhood is associated with student anxiety levels and adrenocortical activity at a time preceding lunch when anxiety about potential bullying would potentially be higher. Ninety-one sixth-grade students (55 female and 36 male) reported being exposed one or more…

  14. Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors

    PubMed Central

    Dima, Mariavittoria; Kang, Kristy S.; Dasrath, Florence; Liao, Xiao-Hui; Refetoff, Samuel; Montagna, Cristina; Di Cristofano, Antonio

    2011-01-01

    Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr−/− tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients. PMID:22190384

  15. Differential Effects of Etomidate and its Pyrrole Analogue Carboetomidate on the Adrenocortical and Cytokine Responses to Endotoxemia

    PubMed Central

    Pejo, Ervin; Feng, Yan; Chao, Wei; Cotten, Joseph F; Ge, Ri Le; Raines, Douglas E

    2011-01-01

    Objective We developed a novel pyrrole analogue of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate’s desirable anesthetic and hemodynamic properties but lacks its potent inhibitory affect on adrenocorticotropic hormone-stimulated steroid synthesis. The objective of this study was to test the hypothesis that in contrast to etomidate, carboetomidate neither suppresses the adrenocortical response to endotoxemia nor enhances the accompanying production of pro-inflammatory cytokines. Design Animal study Setting University research laboratory Subjects Male Sprague-Dawley rats Interventions For both single and multiple anesthetic dose studies, rats were injected with Escherichia coli lipopolysaccharide immediately followed by a hypnotic dose of etomidate, carboetomidate or vehicle alone (dimethyl sulfoxide) as a control. For single dose studies, no additional anesthetic (or vehicle) was administered. For multiple anesthetic dose studies, additional doses of anesthetic (or vehicle) were administered every 15 min for a total of eight anesthetic (or vehicle) doses. Measurements and Main Results Plasma adrenocorticotropic hormone, corticosterone, and cytokine concentrations were measured before lipopolysaccharide administration and intermittently throughout the 5 hour experiment. In single anesthetic dose studies, plasma adrenocorticotropic hormone and cytokine concentrations were not different at any time point among the etomidate, carboetomidate, and vehicle groups whereas plasma corticosterone concentrations were briefly (60–120 min) reduced in the etomidate group. In multiple anesthetic dose studies, plasma corticosterone concentrations were persistently lower and peak plasma IL-1β and IL-6 concentrations were higher in the etomidate group versus the carboetomidate and control groups. Peak plasma IL-10 concentrations were similarly elevated in the etomidate and carboetomidate groups versus the control group

  16. Assessment of adrenocortical activity by non-invasive measurement of faecal cortisol metabolites in dromedary camels (Camelus dromedarius).

    PubMed

    Sid-Ahmed, Omer-Elfaroug; Sanhouri, Ahmed; Elwaseela, Badr-Eldin; Fadllalah, Imad; Mohammed, Galal-Eldin Elazhari; Möstl, Erich

    2013-08-01

    The aim of this study was to determine whether glucocorticoid production could be monitored non-invasively in dromedary camels by measuring faecal cortisol metabolites (FCMs). Five Sudanese dromedaries, two males and three females, were injected with a synthetic adrenocorticotropic hormone (ACTH) analogue. Blood samples were collected pre- and post-ACTH injection. Faeces were sampled after spontaneous defecation for five consecutive days (2 days before and 3 days after ACTH injection). Baseline plasma cortisol values ranged from 0.6 to 10.8 ng/ml in males and from 1.1 to 16.6 ng/ml in females, while peak values after ACTH injection were 10.9-41.9 in males and 10-42.2 ng/ml in females. Peak blood cortisol values were reached between 1.5 and 2.0 h after ACTH injection. The concentration of FCMs increased after ACTH injection in the faeces of both sexes, although steroid levels peaked earlier in males [24 h; (286.7-2,559.7 ng/g faeces)] than in females [36-48 h; (1,182.6-5,169.1 ng/g faeces)], reflecting increases of 3.1-8.3- and 4.3-8-fold above baseline levels. To detect chromatographic patterns of immunoreactive FCMs, faecal samples with high FCM concentrations from both sexes were pooled and subjected to reverse phase high performance liquid chromatography (RP-HPLC). RP-HPLC analysis revealed sex differences in the polarity of FCMs, with females showing more polar FCMs than males. We concluded that stimulation of adrenocortical activity by ACTH injection resulted in a measurable increase in blood cortisol that was reliably paralleled by increases in FCM levels. Thus, measurement of FCMs is a powerful tool for monitoring the adrenocortical responses of dromedaries to stressors in field conditions. PMID:23430659

  17. Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II.

    PubMed Central

    Lebrethon, M C; Naville, D; Begeot, M; Saez, J M

    1994-01-01

    The regulation of ACTH receptor binding sites and mRNA by ACTH and angiotensin II (A-II) was studied using cultured human adrenal fasciculata reticularis cells (HAC). These cells expressed two major ACTH receptor transcripts of 1.8 and 3.4 kb and three minor ones of 4, 7, and 11 kb. ACTH increased the levels of all these transcripts in a time- and dose-dependent manner. At a maximal concentration of 10(-8) M, ACTH enhanced 21- and 4-fold the level of ACTH receptor mRNA and the number of receptors per cell, respectively. Pretreatment of HAC with A-II produced a dose-dependent enhancement of ACTH receptor mRNA that was associated with an increase of both ACTH receptor number and responsiveness to this hormone. The effects of A-II were completely blocked by an AT1 receptor subtype antagonist but not by an AT2 antagonist. The effects of ACTH together with A-II on ACTH receptor mRNA were greater than those induced by each hormone alone. These results show that ACTH receptor number and mRNA are positively regulated by the two main hormones (ACTH and A-II) which, in vivo, regulate adrenocortical functions. In addition, they also show that HAC are a target for A-II. Thus, regulation of ACTH receptors may be one mechanism by which ACTH and A-II regulate adrenocortical functions under both normal and pathological conditions. Images PMID:8163681

  18. Age-related variation in the adrenocortical response to stress in nestling white storks (Ciconia ciconia) supports the developmental hypothesis.

    PubMed

    Blas, Julio; Baos, Raquel; Bortolotti, Gary R; Marchant, Tracy A; Hiraldo, Fernando

    2006-09-01

    The post-natal development of the adrenocortical response to stress was investigated in European white storks. Sixty wild nestlings aged 24-59 days old were subjected to a standardized capture and restraint protocol, and the time-course pattern of the response to stress was assessed through determination of circulating corticosterone in blood samples collected at five fixed times during the 45-min period following capture. The time course of the response was best fit to a third-order function of handling time, and showed a strong effect of age. Although age did not affect baseline titers and all birds showed a positive post-capture increase in circulating corticosterone, age had a positive effect on the relative increase from baseline titer, the recorded time to reach maximum level, and the acute concentration after 10 min following capture and restraint. While young nestlings displayed very little response to capture, the response near fledging resembled the typical adrenocortical pattern widely reported in fully developed birds. Our results concur with those found in altricial and semi-altricial species, and suggest that non-precocial birds follow a similar mode of development of the hypothalamic-pituitary-adrenal (HPA) axis. The fact that HPA sensitivity to stress is functional suggests that young storks gradually develop emergency responses of adaptive value and are able to overcome acute perturbations in spite of their parental dependence, at least during the last two-thirds of post-natal development. According to the Developmental Hypothesis, such gradual changes would allow nestlings to respond to perturbations as a function of the specific behavioral and physiological abilities of their age. The potential sources of stress that nestlings have to face during development (i.e., weather conditions, dietary restrictions, and social competition) are discussed according to developmental changes in behavioral and physiological abilities. PMID:16624312

  19. Treatment results of stereotactic interstitial brachytherapy for primary and metastatic brain tumors

    SciTech Connect

    Lucas, G.L.; Luxton, G.; Cohen, D.; Petrovich, Z.; Langholz, B.; Apuzzo, M.L.; Sapozink, M.D. )

    1991-08-01

    A total of 41 stereotactic interstitial brain implants in 39 patients were performed for recurrence after teletherapy (recurrence implant), or as part of initial treatment in conjunction with teletherapy (primary implant). Implanted tumors consisted of malignant gliomas (33), other primary brain tumors (3), and single metastatic lesions (3). All patients were temporarily implanted with Ir-192 using a coaxial catheter afterloading system; two patients were implanted twice. Survival post-implant for glioblastoma multiforme (GBM), 13 patients, was 10 months whether implanted primarily or for recurrence. Mean time to recurrence, measured from initiation of teletherapy to implantation, was 10 months. Twenty patients with anaplastic astrocytoma (AA) had a median survival post-implant of 23 months for primary implants (7 patients) and 11 months for recurrence implants (13 patients). Mean time to recurrence, measured from initiation of teletherapy to implantation, was 19 months. Three patients (9%) of the evaluable group required reoperation for symptomatic mass effect, all with initial diagnosis of AA. Survival for this subgroup was 14, 22, and 32 months post-implantation. Using stereotactic techniques, interstitial brachytherapy of brain tumors was technically feasible with negligible acute morbidity and mortality, and appeared to offer limited prolongation of control for a subset of patients with recurrent malignant gliomas. The role of this modality in primary treatment for malignant gliomas needs to be further defined by prospectively randomized trials.

  20. Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells12

    PubMed Central

    Kopp, Florian; Hermawan, Adam; Oak, Prajakta Shirish; Ulaganathan, Vijay Kumar; Herrmann, Annika; Elnikhely, Nefertiti; Thakur, Chitra; Xiao, Zhiguang; Knyazev, Pjotr; Ataseven, Beyhan; Savai, Rajkumar; Wagner, Ernst; Roidl, Andreas

    2014-01-01

    Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition. PMID:25500079

  1. Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, anti-tumor effects

    PubMed Central

    Yoo, Ji Young; Hurwitz, Brian S; Bolyard, Chelsea; Yu, Jun-Ge; Zhang, Jianying; Selvendiran, Karuppaiyah; Rath, Kellie S; He, Shun; Bailey, Zachary; Eaves, David; Cripe, Timothy P; Parris, Deborah S.; Caligiuri, Michael A.; Yu, Jianhua; Old, Matthew; Kaur, Balveen

    2014-01-01

    Background Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy. Methods The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test. Results Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α (western blot analysis) and the UPR (induction of hsp40, 70 and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo. Conclusions The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients. PMID:24815720

  2. Different gap junction-propagated effects on cisplatin transfer result in opposite responses to cisplatin in normal cells versus tumor cells

    PubMed Central

    Zhang, Yuan; Tao, Liang; Fan, Lixia; Peng, Yuexia; Yang, Kefan; Zhao, Yifan; Song, Qi; Wang, Qin

    2015-01-01

    Previous work has shown that gap junction intercellular communication (GJIC) enhances cisplatin (Pt) toxicity in testicular tumor cells but decreases it in non-tumor testicular cells. In this study, these different GJIC-propagated effects were demonstrated in tumor versus non-tumor cells from other organ tissues (liver and lung). The downregulation of GJIC by several different manipulations (no cell contact, pharmacological inhibition, and siRNA suppression) decreased Pt toxicity in tumor cells but enhanced it in non-tumor cells. The in vivo results using xenograft tumor models were consistent with those from the above-mentioned cells. To better understand the mechanism(s) involved, we studied the effects of GJIC on Pt accumulation in tumor and non-tumor cells from the liver and lung. The intracellular Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreased in tumor cells when GJIC was downregulated. Further analysis indicated that the opposite effects of GJIC on Pt accumulation in normal versus tumor cells from the liver were due to its different effects on copper transporter1 and multidrug resistance-associated protein2, membrane transporters attributed to intracellular Pt transfer. Thus, GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer. PMID:26215139

  3. Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

    SciTech Connect

    Wharam, M.D.; Kaizer, H.; Leventhal, B.G.; Munoz, L.; Tutschka, P.J.; Santos, G.W.; Elfenbein, G.J.; Order, S.E.

    1980-02-01

    Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologous marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survived, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occurred in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.

  4. Oxaliplatin in Treating Young Patients With Recurrent Solid Tumors That Have Not Responded to Previous Treatment

    ClinicalTrials.gov

    2013-06-04

    Childhood Central Nervous System Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Hepatoblastoma; Childhood Hepatocellular Carcinoma; Childhood High-grade Cerebral Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Recurrent Adrenocortical Carcinoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Colon Cancer; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Nasopharyngeal Cancer; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Rectal Cancer; Recurrent Renal Cell Cancer

  5. Species-specific sensitivity to selenium-induced impairment of cortisol secretion in adrenocortical cells of rainbow trout (Oncorhynchus mykiss) and brook trout (Salvelinus fontinalis)

    SciTech Connect

    Miller, L.L. Hontela, A.

    2011-06-01

    Species differences in physiological and biochemical attributes exist even among closely related species and may underlie species-specific sensitivity to toxicants. Rainbow trout (RT) are more sensitive than brook trout (BT) to the teratogenic effects of selenium (Se), but it is not known whether all tissues exhibit this pattern of vulnerability. In this study, primary cultures of RT and BT adrenocortical cells were exposed to selenite (Na{sub 2}SO{sub 3}) and selenomethionine (Se-Met) to compare cell viability and ACTH-stimulated cortisol secretion in the two fish species. Cortisol, the primary stress hormone in fish, facilitates maintenance of homeostasis when fish are exposed to stressors, including toxicants. Cell viability was not affected by Se, but selenite impaired cortisol secretion, while Se-Met did not (RT and BT EC{sub 50} > 2000 mg/L). RT cells were more sensitive (EC{sub 50} = 8.7 mg/L) to selenite than BT cells (EC{sub 50} = 90.4 mg/L). To identify the targets where Se disrupts cortisol synthesis, selenite-impaired RT and BT cells were stimulated with ACTH, dbcAMP, OH-cholesterol, and pregnenolone. Selenite acted at different steps in the cortisol biosynthesis pathway in RT and BT cells, confirming a species-specific toxicity mechanism. To test the hypothesis that oxidative stress mediates Se-induced toxicity, selenite-impaired RT cells were exposed to NAC, BSO and antioxidants (DETCA, ATA, Vit A, and Vit E). Inhibition of SOD by DETCA enhanced selenite-induced cortisol impairment, indicating that oxidative stress plays a role in Se toxicity; however, modifying GSH content of the cells did not have an effect. The results of this study, with two closely related salmonids, provided additional evidence for species-specific differences in sensitivity to Se which should be considered when setting thresholds and water quality guidelines. - Research Highlights: > We investigated species-specific sensitivity to Se in trout adrenocortical cells. > Selenite

  6. Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.

    PubMed

    Fujisawa, Yasuko; Sakaguchi, Kimiyoshi; Ono, Hiroyuki; Yamaguchi, Rie; Kato, Fumiko; Kagami, Masayo; Fukami, Maki; Ogata, Tsutomu

    2016-05-01

    Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events. PMID:26940356

  7. Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis.

    PubMed

    Droste, Susanne K; Gesing, Angela; Ulbricht, Sabine; Müller, Marianne B; Linthorst, Astrid C E; Reul, Johannes M H M

    2003-07-01

    We studied the effects of long-term (i.e. 4 wk) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice. Voluntary exercise was provided by giving mice access to a running wheel, in which they indeed ran for about 4 km/d. Exercising mice showed similar body weights as control animals but presented less abdominal fat, lighter thymuses, and heavier adrenal glands. Exercise resulted in asymmetric structural changes in the adrenal glands. Whereas control mice had larger left than right adrenals, this condition was abolished in exercising animals, mainly because of enlargement of the right adrenal cortex. Tyrosine hydroxylase mRNA expression in the adrenal medullas of exercising mice was increased. In exercising mice, early-morning baseline plasma ACTH levels were decreased, whereas plasma corticosterone levels at the start of the dark phase were twice as high as those in control animals. To forced swimming and restraint stress, exercising mice responded with higher corticosterone levels than those of the control animals but with similar ACTH levels. However, if exposed to a novel environment, then exercising mice presented decreased ACTH responses. Interestingly, exercising mice showed a decreased corticosterone response to novelty only when the novel environment contained a functioning running wheel. Glucocorticoid receptor levels were unchanged, whereas mineralocorticoid receptor levels were decreased, in hippocampus of exercising animals. Corticotropin-releasing factor mRNA levels in the paraventricular nucleus were lower in exercising mice. Thus, voluntary exercise results in complex, adaptive changes at various levels within the HPA axis as well as in sympathoadrenomedullary and limbic/neocortical afferent control mechanisms. These changes seem to underlie the differential responsiveness of the HPA axis to physical vs. emotional challenges. PMID:12810557

  8. Evaluation of tumor angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma: Results of RTOG 9505

    SciTech Connect

    Foote, Robert L. . E-mail: foote.robert@mayo.edu; Weidner, Noel; Harris, Jonathan; Hammond, Elizabeth; Lewis, Jean E.; Vuong, Te; Ang, K. Kian; Fu, Karen K.

    2005-03-01

    Purpose: The objective of this study was to evaluate tumor angiogenesis as measured by microvessel density (MVD) as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy alone. Methods and materials: Eligible patients included those with NPC treated with radiotherapy. Paraffin blocks of the primary tumor had a hematoxylin and eosin-stained section prepared at the block face. One representative section for tumor was stained for factor VIII-related antigen using a standard immunoperoxidase staining technique. MVD was determined by light microscopy in areas of invasive tumor containing the highest numbers of capillaries and microvessels per area. Individual microvessel counts were made on a 200x field within the area of most intense tumor neovascularization. Results were expressed as the highest number of microvessels identified within any single 200x field. Using a breakpoint of MVD < 60 vs. {>=}60, the distributions between the two MVD groups were compared by the method of Gray. Overall survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. A multivariate Cox proportional hazard model was employed to examine the relationship between MVD and disease outcomes while adjusting for other concomitant variables. Results: One hundred sixty-six were eligible, of whom 123 had values determined for MVD. The MVD values ranged from 9 to 243 with a median of 70. In the multivariate analysis of overall survival, distant metastases, and local-regional failure, MVD did not significantly improve the model containing T stage, N stage, age, radiation dose, and World Health Organization class. Conclusions: We found no significant differences in overall survival, time to distant metastasis, or time to local-regional failure using a breakpoint of MVD < 60 vs. MVD {>=}60. The study was perhaps limited by the small size of the NPC samples.

  9. The treatment of Stage III nonseminomatous testicular tumors. Roswell Park Memorial Institute results (1970-1979).

    PubMed

    Pontes, J E; Wajsman, Z; Beckley, S; Williams, P; Murphy, G P

    1983-04-01

    A review of 92 patients with Stage III nonseminomatous tumors treated at Roswell Park Memorial Institute between 1970-1979 was undertaken to verify changes in concepts as related to multiple agent chemotherapy and cytoreductive surgery. Each patient had a minimal follow-up of 18 months. Fifty-three patients were seen before 1975. Eighteen had metastasis to the lungs only. These were treated with a variety of single chemotherapeutic agents and cytoreductive surgery. The survival of this group was 38%. Among 35 patients with lung and visceral involvement seen at the same time, only one patient is alive. Thirty-nine patients were seen after 1975 and treated with multi-drug chemotherapy and cytoreductive surgery. The current survival rate of 23 patients with lung metastasis only is 69%. Among 16 patients with lung and visceral involvement, the present survival rate is 31%. This report confirms the effectiveness of multi-drug therapy in conjunction with cytoreductive surgery in the treatment of disseminated testicular tumors. PMID:6186354

  10. Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma

    PubMed Central

    Else, Tobias; Everett, Jessica N.; Long, Jessica M.; Gruber, Stephen B.; Hammer, Gary D.

    2013-01-01

    Purpose: Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50–97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied. Patients and Methods: A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons. Results: Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45. Conclusions: Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers. PMID:23175693

  11. SU-E-J-94: Positioning Errors Resulting From Using Bony Anatomy Alignment for Treating SBRT Lung Tumor

    SciTech Connect

    Frame, C; Ding, G

    2014-06-01

    Purpose: To quantify patient setups errors based on bony anatomy registration rather than 3D tumor alignment for SBRT lung treatments. Method: A retrospective study was performed for patients treated with lung SBRT and imaged with kV cone beam computed tomography (kV-CBCT) image-guidance. Daily CBCT images were registered to treatment planning CTs based on bony anatomy alignment and then inter-fraction tumor movement was evaluated by comparing shift in the tumor center in the medial-lateral, anterior-posterior, and superior-inferior directions. The PTV V100% was evaluated for each patient based on the average daily tumor displacement to assess the impact of the positioning error on the target coverage when the registrations were based on bony anatomy. Of the 35 patients studied, 15 were free-breathing treatments, 10 used abdominal compression with a stereotactic body frame, and the remaining 10 were performed with BodyFIX vacuum bags. Results: For free-breathing treatments, the range of tumor displacement error is between 1–6 mm in the medial-lateral, 1–13 mm in the anterior-posterior, and 1–7 mm in the superior-inferior directions. These positioning errors lead to 6–22% underdose coverage for PTV - V100% . Patients treated with abdominal compression immobilization showed positional errors of 0–4mm mediallaterally, 0–3mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% underdose ranging between 6–17%. For patients immobilized with the vacuum bags, the positional errors were found to be 0–1 mm medial-laterally, 0–1mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% under dose ranging between 5–6% only. Conclusion: It is necessary to align the tumor target by using 3D image guidance to ensure adequate tumor coverage before performing SBRT lung treatments. The BodyFIX vacuum bag immobilization method has the least positioning errors among the three methods studied when bony anatomy is used for

  12. Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models.

    PubMed

    Jansen, Marc H A; Lagerweij, Tonny; Sewing, A Charlotte P; Vugts, Danielle J; van Vuurden, Dannis G; Molthoff, Carla F M; Caretti, Viola; Veringa, Susanna J E; Petersen, Naomi; Carcaboso, Angel M; Noske, David P; Vandertop, W Peter; Wesseling, Pieter; van Dongen, Guus A M S; Kaspers, Gertjan J L; Hulleman, Esther

    2016-09-01

    The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of (89)Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of (89)Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by (89)Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166-74. ©2016 AACR. PMID:27325687

  13. Comparison of the methods for measuring the Ki-67 labeling index in adrenocortical carcinoma: manual versus digital image analysis.

    PubMed

    Yamazaki, Yuto; Nakamura, Yasuhiro; Shibahara, Yukiko; Konosu-Fukaya, Sachiko; Sato, Naomi; Kubota-Nakayama, Fumie; Oki, Yutaka; Baba, Satoshi; Midorikawa, Sanae; Morimoto, Ryo; Satoh, Fumitoshi; Sasano, Hironobu

    2016-07-01

    Adrenocortical carcinoma (ACC) is a rare, highly malignant neoplasm harboring marked histologic heterogeneity. The Ki-67 labeling index (LI) is one of the most effective diagnostic and prognostic markers in ACC. However, its assessment has by no means been standardized. Therefore, in this study, we analyzed the Ki-67 LI in 18 ACC cases both by seven pathologists using microscopes (MA; manual analysis) and with digital image analysis (DIA) and also compared the Ki-67 LI obtained by selecting "hot spots" and formulating the "average" reading of the whole tumor specimen. In addition, we performed statistical analysis of the association between Ki-67 LI and the clinical and pathologic features of individual cases. The DIA was significantly correlated with MA in hot spots but not in the average fields. The Ki-67 LI in hot spots was significantly and consistently higher than that in average areas by both MA and DIA, indicating intratumoral heterogeneity. The Ki-67 LI was significantly correlated with the Weiss criteria (eosinophilic cytoplasm, nuclear atypia, atypical mitoses, and sinusoidal invasion) by any mode of evaluation. The clinical outcome was significantly better in the patients with a Ki-67 < 10% than in those with a Ki-67 > 10% by MA in hot spots. The Ki-67 LI in hot spots measured by MA best reflected the clinical and pathologic features of ACC. Employment of DIA to obtain the Ki-67 LI in ACC requires further improvement, including correction of its overestimation of the value by counting non-tumorous cells and nuclear segmentation in areas of high cell density. PMID:26980031

  14. Ultrasonic attenuation and backscatter coefficient estimates of rodent-tumor-mimicking structures: comparison of results among clinical scanners.

    PubMed

    Nam, Kibo; Rosado-Mendez, Ivan M; Wirtzfeld, Lauren A; Pawlicki, Alexander D; Kumar, Viksit; Madsen, Ernest L; Ghoshal, Goutam; Lavarello, Roberto J; Oelze, Michael L; Bigelow, Timothy A; Zagzebski, James A; O'Brien, William D; Hall, Timothy J

    2011-10-01

    In vivo estimations of the frequency-dependent acoustic attenuation (alpha) and backscatter (eta) coefficients using radiofrequency (rf) echoes acquired with clinical ultrasound systems must be independent of the data acquisition setup and the estimation procedures. In a recent in vivo assessment of these parameters in rodent mammary tumors, overall agreement was observed among alpha and eta estimates using data from four clinical imaging systems. In some cases, particularly in highly-attenuating heterogeneous tumors, multisystem variability was observed. This paper compares alpha and eta estimates of a well-characterized rodent-tumor-mimicking homogeneous phantom scanned using seven transducers with the same four clinical imaging systems: a Siemens Acuson S2000, an Ultrasonix RP, a Zonare Z.one and a VisualSonics Vevo2100. alpha and eta estimates of lesion-mimicking spheres in the phantom were independently assessed by three research groups, who analyzed their system's rf echo signals. Imaging-system-based estimates of alpha and eta of both lesion-mimicking spheres were comparable to through-transmission laboratory estimates and to predictions using Faran's theory, respectively. A few notable variations in results among the clinical systems were observed but the average and maximum percent difference between alpha estimates and laboratory-assessed values was 11% and 29%, respectively. Excluding a single outlier dataset, the average and maximum average difference between eta estimates for the clinical systems and values predicted from scattering theory was 16% and 33%, respectively. These results were an improvement over previous interlaboratory comparisons of attenuation and backscatter estimates. Although the standardization of our estimation methodologies can be further improved, this study validates our results from previous rodent breast-tumor model studies. PMID:22518954

  15. Early Significant Tumor Volume Reduction After Radiosurgery in Brain Metastases From Renal Cell Carcinoma Results in Long-Term Survival

    SciTech Connect

    Kim, Wook Ha; Kim, Dong Gyu; Han, Jung Ho; Paek, Sun Ha; Chung, Hyun-Tai; Park, Chul-Kee; Kim, Chae-Yong; Kim, Yong Hwy; Kim, Jin Wook; Jung, Hee-Won

    2012-04-01

    Purpose: To retrospectively evaluate survival of patients with brain metastasis from renal cell carcinoma (RCC) after radiosurgery. Patients and Methods: Between 1998 and 2010, 46 patients were treated with radiosurgery, and the total number of lesions was 99. The mean age was 58.9 years (range, 33-78 years). Twenty-six patients (56.5%) had a single brain metastasis. The mean tumor volume was 3.0 cm{sup 3} (range, 0.01-35.1 cm{sup 3}), and the mean marginal dose prescribed was 20.8 Gy (range, 12-25 Gy) at the 50% isodose line. A patient was classified into the good-response group when the sum of the volume of the brain metastases decreased to less than 75% of the original volume at a 1-month follow-up evaluation using MRI. Results: As of December 28, 2010, 39 patients (84.8%) had died, and 7 (15.2%) survived. The overall median survival time was 10.0 {+-} 0.4 months (95% confidence interval, 9.1-10.8). After treatment, local tumor control was achieved in 72 (84.7%) of the 85 tumors assessed using MRI after radiosurgery. The good-response group survived significantly longer than the poor-response group (median survival times of 18.0 and 9.0 months, respectively; p = 0.025). In a multivariate analysis, classification in the good-response group was the only independent prognostic factor for longer survival (p = 0.037; hazard ratio = 0.447; 95% confidence interval, 0.209-0.953). Conclusions: Radiosurgery seems to be an effective treatment modality for patients with brain metastases from RCC. The early significant tumor volume reduction observed after radiosurgery seems to result in long-term survival in RCC patients with brain metastases.

  16. Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.

    PubMed Central

    Hay, I D; Smail, P J; Forsyth, C C

    1981-01-01

    Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure. PMID:7197507

  17. Adrenocortical Stem and Progenitor Cells: Unifying Model of Two Proposed Origins

    PubMed Central

    Wood, Michelle A.; Hammer, Gary D.

    2010-01-01

    The origins of our understanding of the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland have arisen from studies on the role of Sf1 in steroidogenesis and adrenal development initiated 20 years ago in the laboratory of Dr. Keith Parker. Adrenocortical stem/progenitor cells have been predicted to be undifferentiated and quiescent cells that remain at the periphery of the cortex until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Identification of these stem/progenitor cells has only recently been explored. Recent efforts have examined signaling molecules, including Wnt, Shh, and Dax1, which may coordinate intricate lineage and signaling relationships between the adrenal capsule (stem cell niche) and underlying cortex (progenitor cell pool) to maintain organ homeostasis in the adrenal gland. PMID:21094677

  18. Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells.

    PubMed

    Yang, Tingting; Zhang, Hai-Liang; Liang, Qingnan; Shi, Yingtang; Mei, Yan-Ai; Barrett, Paula Q; Hu, Changlong

    2016-09-01

    Aldosterone, which plays a key role in maintaining water and electrolyte balance, is produced by zona glomerulosa cells of the adrenal cortex. Autonomous overproduction of aldosterone from zona glomerulosa cells causes primary hyperaldosteronism. Recent clinical studies have highlighted the pathological role of the KCNJ5 potassium channel in primary hyperaldosteronism. Our objective was to determine whether small-conductance Ca(2+)-activated potassium (SK) channels may also regulate aldosterone secretion in human adrenocortical cells. We found that apamin, the prototypic inhibitor of SK channels, decreased membrane voltage, raised intracellular Ca(2+) and dose dependently increased aldosterone secretion from human adrenocortical H295R cells. By contrast, 1-Ethyl-2-benzimidazolinone, an agonist of SK channels, antagonized apamin's action and decreased aldosterone secretion. Commensurate with an increase in aldosterone production, apamin increased mRNA expression of steroidogenic acute regulatory protein and aldosterone synthase that control the early and late rate-limiting steps in aldosterone biosynthesis, respectively. In addition, apamin increased angiotensin II-stimulated aldosterone secretion, whereas 1-Ethyl-2-benzimidazolinone suppressed both angiotensin II- and high K(+)-stimulated production of aldosterone in H295R cells. These findings were supported by apamin-modulation of basal and angiotensin II-stimulated aldosterone secretion from acutely prepared slices of human adrenals. We conclude that SK channel activity negatively regulates aldosterone secretion in human adrenocortical cells. Genetic association studies are necessary to determine whether mutations in SK channel subtype 2 genes may also drive aldosterone excess in primary hyperaldosteronism. PMID:27432863

  19. Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells.

    PubMed

    Ramanjaneya, Manjunath; Tan, Bee K; Rucinski, Marcin; Kawan, Mohamed; Hu, Jiamiao; Kaur, Jaspreet; Patel, Vanlata H; Malendowicz, Ludwik K; Komarowska, Hanna; Lehnert, Hendrik; Randeva, Harpal S

    2015-07-01

    NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 are expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts. PMID:25869615

  20. Neuromedin-U stimulates enucleation-induced adrenocortical regeneration in the rat.

    PubMed

    Trejter, Marcin; Neri, Giuliano; Rucinski, Marcin; Majchrzak, Mariola; Nussdorfer, Gastone G; Malendowicz, Ludwik K

    2008-06-01

    Neuromedin-U (NMU) is a brain-gut peptide, which has been previously found to stimulate hypothalamic-pituitary-adrenal axis in the rat. Enucleation-induced adrenal regeneration in rats with contralateral adrenalectomy is a well-established model of adrenal growth, that not only depends on the compensatory ACTH hypersecretion, but is also modulated by several regulatory peptides. Hence, we investigated whether NMU may be included in this group of bioactive molecules. Reverse transcription-polymerase chain reaction and immunocytochemistry showed that regenerating rat adrenocortical cells at days 5 and 8 after surgery express the NMU receptor NMUR1 as mRNA and protein. NMU8 administration to rats bearing regenerating adrenals markedly raised the plasma concentration of corticosterone and notably enhanced proliferative activity of adrenocortical cells. ACTH blood level was unchanged at day 5 and significantly decreased at day 8. The conclusion is drawn that NMU stimulates regeneration of rat adrenal cortex, via a mechanism independent of pituitary ACTH and involving the activation of NMUR1 located on adrenocortical cells. PMID:18506360

  1. Toying with fate: Redirecting the differentiation of adrenocortical progenitor cells into gonadal-like tissue

    PubMed Central

    Röhrig, Theresa; Pihlajoki, Marjut; Ziegler, Ricarda; Cochran, Rebecca S.; Schrade, Anja; Schillebeeckx, Maximiliaan; Mitra, Robi D.; Heikinheimo, Markku; Wilson, David B.

    2014-01-01

    Cell fate decisions are integral to zonation and remodeling of the adrenal cortex. Animal models exhibiting ectopic differentiation of gonadal-like cells in the adrenal cortex can shed light on the molecular mechanisms regulating steroidogenic cell fate. In one such model, prepubertal gonadectomy (GDX) of mice triggers the formation of adrenocortical neoplasms that resemble luteinized ovarian stroma. Transcriptomic analysis and genome-wide DNA methylation mapping have identified genetic and epi-genetic markers of GDX-induced adrenocortical neoplasia. Members of the GATA transcription factor family have emerged as key regulators of cell fate in this model. Expression of Gata4 is pivotal for the accumulation of gonadal-like cells in the adrenal glands of gonadectomized mice, whereas expression of Gata6 limits the spontaneous and GDX-induced differentiation of gonadal-like cells in the adrenal cortex. Additionally, Gata6 is essential for proper development of the adrenal X-zone, a layer analogous to the fetal zone of the human adrenal cortex. The relevance of these observations to developmental signaling pathways in the adrenal cortex, to other animal models of altered adrenocortical cell fate, and to human diseases is discussed. PMID:25498963

  2. Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors.

    PubMed

    Walsh, Meghaan P; Duncan, Brynn; Larabee, Shannon; Krauss, Aviva; Davis, Jessica P E; Cui, Yongzhi; Kim, Su Young; Guimond, Martin; Bachovchin, William; Fry, Terry J

    2013-01-01

    Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine. PMID:23554941

  3. Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

    PubMed Central

    Larabee, Shannon; Krauss, Aviva; Davis, Jessica P. E.; Cui, Yongzhi; Kim, Su Young; Guimond, Martin; Bachovchin, William; Fry, Terry J.

    2013-01-01

    Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine. PMID:23554941

  4. Anterior callosal section is useful for the removal of large tumors invading the dorsal part of the anterior third ventricle: operative technique and results.

    PubMed

    Shiramizu, Hideki; Hori, Tomokatsu; Matsuo, Seigo; Niimura, Kaku; Yoshimoto, Haruko; Ishida, Atsushi; Asakuno, Keizoh; Yuzawa, Miki; Moriyama, Takashi

    2013-07-01

    Large tumors invading the dorsal part of the anterior third ventricle are difficult to manage. The anterior transcallosal approach is usually used to manage these tumors. In our clinic, anterior callosal section was combined with the anterior interhemispheric (AIH) translamina terminalis approach for these tumors with excellent results. The AIH approach is useful for removing tumors in and around the anterior part of the third ventricle. However, AIH alone is insufficient for large tumors invading the dorsal part of the anterior third ventricle. In such situations, simple anterior callosal section enables the neurosurgeon to extirpate the caudal part of the tumors deeply hidden from operative field, sparing the foramen of Monro, fornix, etc. We treated four large tumors (malignant teratoma, recurrent chordoid glioma, recurrent papillary tumor of pineal region occupying the third ventricle, and paraventricular meningioma) without major complications. The malignant teratoma case exhibited no recurrence with >10 years follow-up. The chordoid glioma and papillary tumor of pineal region were totally removed. The meningioma was subtotally removed except only a small tumor around the bilateral anterior cerebral artery. This simple technique is a new way to manage difficult large lesions in and around the third ventricle. PMID:23568695

  5. Radiofrequency Ablation of Renal Tumors with an Expandable Multitined Electrode: Results, Complications, and Pilot Evaluation of Cooled Pyeloperfusion for Collecting System Protection

    SciTech Connect

    Rouviere, Olivier Badet, Lionel; Murat, Francois Joseph; Marechal, Jean Marie; Colombel, Marc; Martin, Xavier; Lyonnet, Denis; Gelet, Albert

    2008-05-15

    The objective of this study was to retrospectively evaluate the results of radiofrequency ablation (RFA) of renal tumors with an impedance-based system using an expandable multitined electrode. Twenty-two patients (30 tumors) were treated with RFA over a 7-year period, percutaneously (16 tumors) or intraoperatively (14 tumors). Follow-up imaging was performed at 1-3, 6, and 12 months and yearly thereafter. Twenty-seven of 30 tumors (19/22 patients) showed no residual tumor on the first imaging control. Two residual tumors were successfully ablated by a second RFA procedure. Our mean follow-up period was 35 months (range, 3-84 months). Two tumors that had been completely ablated based on imaging criteria recurred 11 and 48 months after RFA. One was treated by partial nephrectomy. The other one was not treated because the patient developed bone metastases. One patient had nephrectomy because of an RFA-induced ureteropelvic junction stricture. Nine patients (11 sessions) had a pyeloperfusion of cooled saline during RFA. None developed symptomatic complications, even though in three patients the ablation zone extended to the closest calyx (3-5 mm from the tumor). We conclude that RFA of renal tumors is promising, but serious complications to the collecting system must be taken into consideration. Prophylactic per-procedural cooling of the collecting system is feasible but needs further assessment.

  6. An unusual presentation of Carney complex with diffuse primary pigmented nodular adrenocortical disease on one adrenal gland and a nonpigmented adrenocortical adenoma and focal primary pigmented nodular adrenocortical disease on the other.

    PubMed

    Tung, Shih-Chen; Hwang, Daw-Yang; Yang, Joseph W; Chen, Wei-Jen; Lee, Chien-Te

    2012-01-01

    A 24-year-old female patient with cushingoid appearance was admitted in May 2000. The endocrine studies showed ACTH-independent Cushing's syndrome. A 2-day high-dose dexamethasone suppression test (HDDST) revealed paradoxical increase of 24 h urinary free cortisol (UFC). Abdominal computed tomography demonstrated a left adrenal nodule (3 x 2 cm in diameter). An adrenal scintigram with ¹³¹I-6β-iodomethyl-19-norcholesterol showed uptake of the isotope in the left adrenal gland and non-visualization in the right adrenal gland throughout the examination course. A retroperitoneoscopic left total adrenalectomy was performed in July 2000. The cut surface of the left adrenal was yellow-tan grossly. Microscopically, the left adrenal nodule contained a nonpigmented adrenocortical adenoma (NP) and another focal primary pigmented nodular adrenocortical disease (PPNAD, FP) mixed lesion. The immunohistochemical studies of CYP17 demonstrate positive in NP and FP of the left adrenal gland. Very low baseline morning plasma cortisol (0.97 μg/dL) and subnormal ACTH (8.16 pg/mL) levels were measured 1.5 months after left adrenalectomy. Right adrenal gland recovered its function 6 months after left adrenalectomy. Plasma cortisol could be suppressed to 3.47 μg/dL by overnight low-dose dexamethasone suppression test 65 months after left adrenalectomy. Cushingoid features still did not appear 122 months after left adrenalectomy. In May 2011, this patient was readmitted due to cushingoid characteristics. Paradoxical rise of 24-h UFC to 2-day HDDST was demonstrated. Ultrasonography of thyroid showed bilateral thyroid cysts. Subtotal right adrenalectomy about 80% of right adrenal was performed. Diffuse PPNAD of the right adrenal was proved pathologically. Immunohischemical stain for CYP17 is positive in the right adrenal gland but weaker positive than that in the left adrenal gland. The genetic study of the peripheral blood, left adrenocortical nodule, and right PPNAD all showed p.R16X

  7. MTHFR C677T Polymorphism is Associated with Tumor Response to Preoperative Chemoradiotherapy: A Result Based on Previous Reports

    PubMed Central

    Zhao, Yue; Li, Xingde; Kong, Xiangjun

    2015-01-01

    Background Preoperative chemoradiotherapy (pRCT) followed by surgery has been widely practiced in locally advanced rectal cancer, esophageal cancer, gastric cancer and other cancers. However, the therapy also exerts some severe adverse effects and some of the patients show poor or no response. It is very important to develop biomarkers (e.g., gene polymorphisms) to identify patients who have a higher likelihood of responding to pRCT. Recently, a series of reports have investigated the association of the genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and epidermal growth factor receptor (EGFR) genes with the tumor response to pRCT; however, the results were inconsistent and inconclusive. Material/Methods A systematic review and meta-analysis was performed by searching relevant studies about the association of MTHFR and EGFR polymorphisms with the tumor regression grade (TRG) in response to pRCT in databases of PubMed, EMBAS, Web of science, Chinese National Knowledge Infrastructure, and Wanfang database up to March 30, 2015. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the strength of the association under 5 genetic models. Results A total of 11 eligible articles were included in the present meta-analysis, of which 8 studies were performed in rectal cancer and 3 studies were performed in esophageal cancer. We finally included 8 included studies containing 839 cases for MTHFR C677T, 5 studies involving 634 cases for MTHFR A1298C, 3 studies containing 340 cases for EGFR G497A, and 4 studies containing 396 cases for EGFR CA repeat. The pooled analysis results indicated that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model (CC vs. CTTT) in overall analysis (OR=1.426(1.074–1.894), P=0.014), rectal cancer (OR=1.483(1.102–1.996), P=0.009), and TRG 1–2 vs. 3–5 group (OR=1.423(1.046–1.936), P=0.025), while other polymorphism including MTHFR

  8. A Plan to Improve Melanoma Tumor Depth Data Quality in the Surveillance, Epidemiology, and End Results Program.

    PubMed

    Lam, Clara; Dickie, Lois; Adamo, Peggy; Penberthy, Lynne

    2016-01-01

    In light of the recent assessment done for ProstateSpecific Antigen values in the Surveillance, Epidemiology, and End Results (SEER) Program, it is possible that coding procedures for melanoma tumor depth may have similar quality issues. Potential errors that have been initially identified are implied decimal errors, transcription errors, and incomplete information. Because of the SEER Program's commitment to high data quality standards, various studies are being planned to review and adjudicate incorrect lab values for several different data items in the SEER data collection. PMID:27556846

  9. KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer

    PubMed Central

    Niitsu, H; Hinoi, T; Kawaguchi, Y; Sentani, K; Yuge, R; Kitadai, Y; Sotomaru, Y; Adachi, T; Saito, Y; Miguchi, M; Kochi, M; Sada, H; Shimomura, M; Oue, N; Yasui, W; Ohdan, H

    2016-01-01

    KRAS mutations occur in 30–40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apcflox/flox; LSL-KrasG12D and CDX2P-G22Cre;Apcflox/flox mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription–PCR (qRT–PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT–PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin–nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin–NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC. PMID:27526107

  10. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    PubMed Central

    Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim

    2016-01-01

    Background Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID:27499638

  11. How parents cope with their child's diagnosis and treatment of an embryonal tumor: results of a prospective and longitudinal study.

    PubMed

    Palmer, Shawna L; Lesh, Shawn; Wallace, Dana; Bonner, Melanie J; Swain, Michelle; Chapieski, Lynn; Janzen, Laura; Mabbott, Donald; Knight, Sarah; Boyle, Robyn; Armstrong, Carol L; Gajjar, Amar

    2011-11-01

    The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor. Patients (n = 219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n = 251) completed the Coping Response Inventory at time of their child's diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates. At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T = 61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (P = .016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (P = .011 and P < .0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T = 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (P = .002). Differences in coping according to age of the patient and parent education level are also discussed. Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment. PMID:21499990

  12. Does Local Recurrence of Prostate Cancer After Radiation Therapy Occur at the Site of Primary Tumor? Results of a Longitudinal MRI and MRSI Study

    SciTech Connect

    Arrayeh, Elnasif; Westphalen, Antonio C.; Kurhanewicz, John; Roach, Mack; Jung, Adam J.; Carroll, Peter R.; Coakley, Fergus V.

    2012-04-01

    Purpose: To determine if local recurrence of prostate cancer after radiation therapy occurs at the same site as the primary tumor before treatment, using longitudinal magnetic resonance (MR) imaging and MR spectroscopic imaging to assess dominant tumor location. Methods and Materials: This retrospective study was HIPAA compliant and approved by our Committee on Human Research. We identified all patients in our institutional prostate cancer database (1996 onward) who underwent endorectal MR imaging and MR spectroscopic imaging before radiotherapy for biopsy-proven prostate cancer and again at least 2 years after radiotherapy (n = 124). Two radiologists recorded the presence, location, and size of unequivocal dominant tumor on pre- and postradiotherapy scans. Recurrent tumor was considered to be at the same location as the baseline tumor if at least 50% of the tumor location overlapped. Clinical and biopsy data were collected from all patients. Results: Nine patients had unequivocal dominant tumor on both pre- and postradiotherapy imaging, with mean pre- and postradiotherapy dominant tumor diameters of 1.8 cm (range, 1-2.2) and 1.9 cm (range, 1.4-2.6), respectively. The median follow-up interval was 7.3 years (range, 2.7-10.8). Dominant recurrent tumor was at the same location as dominant baseline tumor in 8 of 9 patients (89%). Conclusions: Local recurrence of prostate cancer after radiation usually occurs at the same site as the dominant primary tumor at baseline, suggesting supplementary focal therapy aimed at enhancing local tumor control would be a rational addition to management.

  13. Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma

    PubMed Central

    Liu-Chittenden, Yi; Jain, Meenu; Kumar, Parag; Patel, Dhaval; Aufforth, Rachel; Neychev, Vladimir; Sadowski, Samira; Gara, Sudheer K; Joshi, Bharat H; Cottle-Delisle, Candice; Merkel, Roxanne; Yang, Lily; Miettinen, Markku; Puri, Raj K; Kebebew, Electron

    2015-01-01

    Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL-13-PE is a recombinant cytotoxin consisting of human interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose-escalation trial were to assess the maximum-tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL-13-PE in patients with metastatic ACC. Eligible patients had confirmed IL-13 receptor alpha 2 (IL-13Rα2) expressions in their tumors. IL-13-PE at dose of 1–2 μg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1 μg/kg and two patients received 2 μg/kg of IL-13-PE. Dose-limiting toxicity was observed at 2 μg/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (Cmax) of IL-13-PE was 21.0 ng/mL, and the terminal half-life of IL-13-PE was 30–39 min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL-13-PE within 14–28 days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5 months before disease progression; the others progressed within 1–2 months. In conclusion, systemic IV administration of IL-13-PE is safe at 1 μg/kg. All tested patients developed high levels of neutralizing antibodies during IL-13-PE treatment. Use of strategies for immunodepletion before IL-13-PE treatment should be considered in future trials. PMID:25767039

  14. Functional results of endoscopic laser surgery in advanced head and neck tumors

    NASA Astrophysics Data System (ADS)

    Sadick, Haneen; Baker-Schreyer, Antonio; Bergler, Wolfgang; Maurer, Joachim; Hoermann, Karl

    1998-01-01

    Functional results following lasersurgery of minor laryngeal carcinomas were very encouraging. The indication for lasersurgical intervention was then extended to larger carcinomas of the larynx and hypopharynx. The purpose of this study was to assess vocal function and swallowing ability after endoscopic lasersurgery and to compare the results with conventional surgical procedures. From January 1994 to December 1996, 72 patients with advanced squamous cell carcinoma of the larynx and hypopharynx were examined prospectively. The patients underwent endoscopic lasersurgery instead of laryngopharyngectomy. The voice quality was evaluated pre- and postoperatively by subjective assessment, registration of voice parameters and sonegraphic classification. The swallowing ability was judged according to individual scores. The necessity of tracheostomy and nasogastric tube were registered and the duration of hospitalization was documented. The results showed that laryngeal phonation and swallowing ability were significantly better 12 months after lasersurgery compared to the preoperative findings whereas the recurrence rate was similar or even better after conventional pharyngolaryngectomy. Lasersurgery as an alternative surgical procedure to laryngectomy enables patients to retain a sufficient voice function and swallowing ability.

  15. Necrosis After Craniospinal Irradiation: Results From a Prospective Series of Children With Central Nervous System Embryonal Tumors

    SciTech Connect

    Murphy, Erin S.; Merchant, Thomas E.; Wu Shengjie; Xiong Xiaoping; Lukose, Renin; Wright, Karen D.; Qaddoumi, Ibrahim; Armstrong, Gregory T.; Broniscer, Alberto; Gajjar, Amar

    2012-08-01

    Purpose: Necrosis of the central nervous system (CNS) is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series. Patients and Methods: Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n = 51) received postoperative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average risk cases (n = 148) received 23.4 Gy CSI, 36 Gy to the posterior fossa, and 55.8 Gy to the primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy to the primary. All high-risk cases (n = 88) received 36-39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2 cm (pre-2003) or 1 cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis. Results: With a median follow-up of 52 months (range, 4-163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and to symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% {+-} 1.3% (n = 236) for the entire cohort and 4.4% {+-} 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis than for those without: {>=}50 Gy (92.12% {+-} 4.58% vs 72.89% {+-} 1.96%; P=.0337), {>=}52 Gy (88.95% {+-} 5.50% vs 69.16% {+-} 1.97%; P=.0275), and {>=}54 Gy (82.28% {+-} 7.06% vs 63.37% {+-} 1.96%; P=.0488), respectively. Conclusions: Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy, respectively, is predictive for necrosis.

  16. Tumor Shrinkage With Lanreotide Autogel 120 mg as Primary Therapy in Acromegaly: Results of a Prospective Multicenter Clinical Trial

    PubMed Central

    Bevan, John S.; Petersenn, Stephan; Flanagan, Daniel; Tabarin, Antoine; Prévost, Gaëtan; Maisonobe, Pascal; Clermont, Antoine

    2014-01-01

    Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation. Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas. Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study. Setting: The study was conducted at specialist endocrine centers. Patients: Treatment-naïve acromegalic patients with GH-secreting macroadenomas participated in the study. Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration). Outcome Measures: The primary endpoint was the proportion of patients with clinically significant (≥20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0) for the primary endpoint was that the proportion with TVR was ≤55%. Secondary endpoints included: TVR at other time points, GH and IGF-1, acromegalic symptoms, quality of life (QoL), and safety. Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9–75.3% in sensitivity (n = 89) and secondary analyses (n = 63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance. Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor

  17. [Results of cryosurgery for the treatment of vascular nevi and tumors (author's transl)].

    PubMed

    Scholz, A; Sebastian, G; Baerthold, W; Matthäus, W; Pässler, L

    1980-01-01

    Report on experiences of the application of cryotherapy in 187 patients with 200 vascular nevi and angiomas. The fit form of therapy for angiomas is contact-freezing because of simultaneous compression. The cryotherapy of cavernous angiomas in skin and oral mucosa, especially in difficult locations, produces excellent results. In those cases the cryotherapy is the method of choice. In founded indications capillary angiomas of infants could be successfully treated. Port-wine nevi in part are suitable for the application of low temperatures. PMID:7224821

  18. [Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991].

    PubMed

    Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G

    1998-01-01

    Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p < 0.000. Bladder tumours accounts in CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented. PMID:9807870

  19. [Melanoma research in Hungary: promising results in a previously orphan tumor].

    PubMed

    Balázs, Margit; Vízkeleti, Laura; Ecsedi, Szilvia; Ádány, Róza; Rásó, Erzsébet; Hegedûs, Balázs; Ladányi, Andrea; Tóvári, József; Tímár, József

    2015-12-01

    Melanoma research has a two decade history in Hungary and is based on three groups located at the National Institute of Oncology (NIO), the University of Debrecen (DU) and Semmelweis University (SU). Previously we have summarized the achievements of the NIO group in this Journal, now this paper summarizes the recent results of their collaborations. The research group of DU revealed several novel genetic alterations in the melanoma genome which might have clinical relevance as prognosticators or predictors in light of the novel target therapies. Data indicating unique, perhaps melanoma-specific epigenetic changes during progression might be even more important, identifying novel genes otherwise not detected as genetically altered ones. The research group in Budapest extensively used experimental human melanoma models and demonstrated the host sex as a key factor in progression due to the specific function of NK cells. Identification of functional glucocorticoid receptor in human melanoma might lead to therapeutic exploitation similar to certain leukemias. Studies on extracellular matrix revealed collagen XVII and CD44 splice variants as progression associated factors of melanoma. Since the double wild type genotype of melanoma is lacking effective therapy, data on the use of FGFR2, c-met or cannabinoid receptor as target can be important. On the other hand, experimental data on the antitumoral effects of heparin derivatives or bisphosphonate in melanoma models can also be encouraging. PMID:26665186

  20. Time-domain optical mammography Softscan: initial results on detection and characterization of breast tumors

    NASA Astrophysics Data System (ADS)

    Intes, Xavier; Djeziri, Salim; Ichalalene, Zahia; Mincu, Niculae; Wang, Yong; St.-Jean, Philippe; Lesage, Frédéric; Hall, David; Boas, David A.; Polyzos, Margaret

    2004-10-01

    Near-infrared (NIR) technology appears promising as a non-invasive clinical technique for breast cancer screening and diagnosis. The technology capitalizes on the relative transparency of human tissue in this spectral range and its sensitivity to the main components of the breast:; water, lipid and hemoglobin. In this work we present initial results obtained using the SoftScan® breast-imaging system developed by ART, Advanced Research Technologies inc., Montreal. This platform consists of a 4-wavelength time-resolved scanning system used to quantify non-invasively the local functional state of breast tissue. The different aspects of the system used to retrieve 3D optical contrast will be presented. Furthermore, preliminary data obtained from a prospective study conducted at The Royal Victoria Hospital of the McGill University Health Center in Montreal will be discussed. Analysis of the data gathered by SoftScan® demonstrated the potential of the technology in discriminating between healthy and diseased tissue.

  1. Acid Ceramidase (ASAH1) Is a Global Regulator of Steroidogenic Capacity and Adrenocortical Gene Expression

    PubMed Central

    Lucki, Natasha C.; Bandyopadhyay, Sibali; Wang, Elaine; Merrill, Alfred H.

    2012-01-01

    In H295R human adrenocortical cells, ACTH rapidly activates ceramide (Cer) and sphingosine (SPH) turnover with a concomitant increase in SPH-1-phosphate secretion. These bioactive lipids modulate adrenocortical steroidogenesis, primarily by acting as second messengers in the protein kinase A/cAMP-dependent pathway. Acid ceramidase (ASAH1) directly regulates the intracellular balance of Cer, SPH, and SPH-1-phosphate by catalyzing the hydrolysis of Cer into SPH. ACTH/cAMP signaling stimulates ASAH1 transcription and activity, supporting a role for this enzyme in glucocorticoid production. Here, the role of ASAH1 in regulating steroidogenic capacity was examined using a tetracycline-inducible ASAH1 short hairpin RNA H295R human adrenocortical stable cell line. We show that ASAH1 suppression increases the transcription of multiple steroidogenic genes, including Cytochrome P450 monooxygenase (CYP)17A1, CYP11B1/2, CYP21A2, steroidogenic acute regulatory protein, hormone-sensitive lipase, 18-kDa translocator protein, and the melanocortin-2 receptor. Induced gene expression positively correlated with enhanced histone H3 acetylation at target promoters. Repression of ASAH1 expression also induced the expression of members of the nuclear receptor nuclear receptor subfamily 4 (NR4A) family while concomitantly suppressing the expression of dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1. ASAH1 knockdown altered the expression of genes involved in sphingolipid metabolism and changed the cellular amounts of distinct sphingolipid species. Finally, ASAH1 silencing increased basal and cAMP-dependent cortisol and dehydroepiandrosterone secretion, establishing ASAH1 as a pivotal regulator of steroidogenic capacity in the human adrenal cortex. PMID:22261821

  2. Trajectories of maternal depressive symptoms over her child's life span: Relation to adrenocortical, cardiovascular, and emotional functioning in children

    PubMed Central

    Gump, Brooks B.; Reihman, Jacki; Stewart, Paul; Lonky, ED; Darvill, Tom; Granger, Douglas A.; Matthews, Karen A.

    2015-01-01

    Maternal depression has a number of adverse effects on children. In the present study, maternal depressive symptoms were assessed (using the Center for Epidemiological Studies Depression Scale) when their child was 3 months, 6 months, 1 year, 2 years, 4.25 years, 6 years, 7 years, 8 years, and 10 years of age. At 9.5 years of age, children's (94 females, 82 males) depressive symptoms as well as cardiovascular and cortisol levels during baseline and two psychologically stressful tasks were measured. Using multilevel modeling, maternal depressive symptom trajectories were considered in relation to their child's adrenocortical and cardiovascular responses to acute stress. Our goal was to determine maternal depressive symptom trajectories for children with elevated cardiovascular and cortisol reactivity to acute stress and elevated depressive symptoms. In general, those mothers with chronically elevated depressive symptoms over their child's life span had children with lower initial cortisol, higher cardiac output and stroke volume in response to acute stress, lower vascular resistance during acute stress tasks, and significantly more depressive symptoms at 9.5 years of age. These results are discussed in the context of established associations among hypothalamic–pituitary–adrenal axis dysregulation, depression, and cardiovascular disease. PMID:19144231

  3. Enucleation-induced rat adrenal gland regeneration: expression profile of selected genes involved in control of adrenocortical cell proliferation.

    PubMed

    Tyczewska, Marianna; Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Trejter, Marcin; Hochol-Molenda, Anna; Nowak, Krzysztof W; Malendowicz, Ludwik K

    2014-01-01

    Enucleation-induced adrenal regeneration is a highly controlled process; however, only some elements involved in this process have been recognized. Therefore, we performed studies on regenerating rat adrenals. Microarray RNA analysis and QPCR revealed that enucleation resulted in a rapid elevation of expression of genes involved in response to wounding, defense response, and in immunological processes. Factors encoded by these genes obscure possible priming effects of various cytokines on initiation of regeneration. In regenerating adrenals we identified over 100 up- or downregulated genes involved in adrenocortical cell proliferation. The changes were most significant at days 2-3 after enucleation and their number decreased during regeneration. For example, expression analysis revealed a notable upregulation of the growth arrest gene, Gadd45, only 24 hours after surgery while expression of cyclin B1 and Cdk1 genes was notably elevated between days 1-8 of regeneration. These changes were accompanied by changes in expression levels of numerous growth factors and immediate-early transcription factors genes. Despite notable differences in mechanisms of adrenal and liver regeneration, in regenerating adrenals we identified genes, the expression of which is well recognized in regenerating liver. Thus, it seems legitimate to suggest that, in the rat, the general model of liver and adrenal regeneration demonstrate some degree of similarity. PMID:25431590

  4. Enucleation-Induced Rat Adrenal Gland Regeneration: Expression Profile of Selected Genes Involved in Control of Adrenocortical Cell Proliferation

    PubMed Central

    Tyczewska, Marianna; Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Trejter, Marcin; Hochol-Molenda, Anna; Nowak, Krzysztof W.; Malendowicz, Ludwik K.

    2014-01-01

    Enucleation-induced adrenal regeneration is a highly controlled process; however, only some elements involved in this process have been recognized. Therefore, we performed studies on regenerating rat adrenals. Microarray RNA analysis and QPCR revealed that enucleation resulted in a rapid elevation of expression of genes involved in response to wounding, defense response, and in immunological processes. Factors encoded by these genes obscure possible priming effects of various cytokines on initiation of regeneration. In regenerating adrenals we identified over 100 up- or downregulated genes involved in adrenocortical cell proliferation. The changes were most significant at days 2-3 after enucleation and their number decreased during regeneration. For example, expression analysis revealed a notable upregulation of the growth arrest gene, Gadd45, only 24 hours after surgery while expression of cyclin B1 and Cdk1 genes was notably elevated between days 1–8 of regeneration. These changes were accompanied by changes in expression levels of numerous growth factors and immediate-early transcription factors genes. Despite notable differences in mechanisms of adrenal and liver regeneration, in regenerating adrenals we identified genes, the expression of which is well recognized in regenerating liver. Thus, it seems legitimate to suggest that, in the rat, the general model of liver and adrenal regeneration demonstrate some degree of similarity. PMID:25431590

  5. Disruption of protein kinase Ceta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis.

    PubMed

    Chida, Kazuhiro; Hara, Takeshi; Hirai, Takaaki; Konishi, Chieko; Nakamura, Kenji; Nakao, Kazuki; Aiba, Atsu; Katsuki, Motoya; Kuroki, Toshio

    2003-05-15

    We have generated a mouse strain lacking protein kinase C (PKC) eta to evaluate its significance in epithelial organization and tumor formation. The PKCeta-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. The tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKCeta suppresses tumor promotion. Epidermal hyperplasia induced by topical TPA treatment was prolonged in the mutant mice. The enhanced tumor formation may be closely associated with the prolonged hyperplasia induced by topical TPA treatment. In the mutant mice, after inflicting injury by punch biopsy, wound healing on the dorsal skin, particularly reepithelialization, was significantly delayed and impaired in structure. Impairment of epithelial regeneration in wound healing indicates a possibility that PKCeta plays a role in maintenance of epithelial architecture. Homeostasis in epithelial tissues mediated by PKCeta is important for tumor formation in vivo. We propose that PKCeta is involved in tumor formation modulated by regulation of proliferation and remodeling of epithelial cells in vivo. PMID:12750259

  6. A Novel Mutation in the type Iα Regulatory Subunit of Protein Kinase A (PRKAR1A) in a Cushing's Syndrome Patient with Primary Pigmented Nodular Adrenocortical Disease.

    PubMed

    Mineo, Ryohei; Tamba, Sachiko; Yamada, Yuya; Okita, Tomonori; Kawachi, Yusuke; Mori, Reiko; Kyo, Mitsuaki; Saisho, Kenji; Kuroda, Yohei; Yamamoto, Koji; Furuya, Akiko; Mukai, Tokuo; Maekawa, Takashi; Nakamura, Yasuhiro; Sasano, Hironobu; Matsuzawa, Yuji

    2016-01-01

    A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p.E17X (c.49G>T). This confirmed the diagnosis of PPNAD which is associated with Carney Complex. PMID:27580546

  7. [Correlation of clinical effect, pathological response of tumor cells and the end results of combined treatment of locally advanced breast cancer].

    PubMed

    Kharchenko, V P; Voznyĭ, E K; Galil-Ogly, G A; Gurov, S N; Dobrovol'skaia, N I; Alinchenko, L A; Bol'shakova, S A

    2000-01-01

    A correlation was established between the end-results of neoadjuvant chemotherapy for locally-advanced breast cancer and pathological response of tumor cells. Also, the end-results correlated with CR or PR and pathological response. Only a small proportion of patients with tumor progression were registered as stage III or IV of pathological response (0.6 and 0.8%, respectively). PMID:11219951

  8. Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma

    PubMed Central

    Shankar, Adarsh; Borin, Thaiz F; Iskander, Asm; Varma, Nadimpalli RS; Achyut, Bhagelu R; Jain, Meenu; Mikkelsen, Tom; Guo, Austin M; Chwang, Wilson B; Ewing, James R; Bagher-Ebadian, Hassan; Arbab, Ali S

    2016-01-01

    Background Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N′-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis. The aims of the studies were to determine 1) whether the addition of HET0016 can attenuate the unwanted effect of vatalanib on tumor growth and 2) whether the treatment schedule would have a crucial impact on controlling GBM. Methods U251 human glioma cells (4×105) were implanted orthotopically. Two different treatment schedules were investigated. Treatment starting on day 8 (8–21 days treatment) of the tumor implantation was to mimic treatment following detection of tumor, where tumor would have hypoxic microenvironment and well-developed neovascularization. Drug treatment starting on the same day of tumor implantation (0–21 days treatment) was to mimic cases following radiation therapy or surgery. There were four different treatment groups: vehicle, vatalanib (oral treatment 50 mg/kg/d), HET0016 (intraperitoneal treatment 10 mg/kg/d), and combined (vatalanib and HET0016). Following scheduled treatments, all animals underwent magnetic resonance imaging on day 22, followed by euthanasia. Brain specimens were equally divided for immunohistochemistry and protein array analysis. Results Our results demonstrated a trend that HET0016, alone or in combination with vatalanib, is capable of controlling the tumor growth compared with that of vatalanib alone, indicating attenuation of the unwanted effect of vatalanib. When both vatalanib and HET0016 were administered together on the day of the tumor implantation (0–21 days treatment), tumor

  9. Is Antibiotic Prophylaxis for Percutaneous Radiofrequency Ablation (RFA) of Primary Liver Tumors Necessary? Results From a Single-Center Experience

    SciTech Connect

    Bhatia, Shivank S.; Echenique, Ana Froud, Tatiana Suthar, Rekha Lawson, Ivy Dalal, Ravi; Yrizarry, Jose Narayanan, Govindarajan

    2015-08-15

    PurposeThe purpose of this study was to evaluate need for antibiotic prophylaxis for radiofrequency ablation (RFA) of liver tumors in patients with no significant co-existing risk factors for infection.Materials and MethodsFrom January 2004 to September 2013, 83 patients underwent 123 percutaneous RFA procedures for total of 152 hepatocellular carcinoma (HCC) lesions. None of the patients had pre-existing biliary enteric anastomosis (BEA) or any biliary tract abnormality predisposing to ascending biliary infection or uncontrolled diabetes mellitus. No pre- or post-procedure antibiotic prophylaxis was provided for 121 procedures. Data for potential risk factors were reviewed retrospectively and analyzed for the frequency of infectious complications, including abscess formation.ResultsOne patient (1/121 (0.8 %) RFA sessions) developed a large segment 5 liver abscess/infected biloma communicating with the gallbladder 7 weeks after the procedure, successfully treated over 10 weeks with IV and PO antibiotic therapy and percutaneous catheter drainage. This patient did not receive any antibiotics prior to RFA. During the procedure, there was inadvertent placement of RFA probe tines into the gallbladder. No other infectious complications were documented.ConclusionThese data suggest that the routine use of prophylactic antibiotics for liver RFA is not necessary in majority of the patients undergoing liver ablation for HCC and could be limited to patients with high-risk factors such as the presence of BEA or other biliary abnormalities, uncontrolled diabetes mellitus, and large centrally located tumors in close proximity to central bile ducts. Larger randomized studies are needed to confirm this hypothesis.

  10. Adrenocortical Response to Stress and Thyroid Hormone Status in Free-Living Nestling White Storks (Ciconia ciconia) Exposed to Heavy Metal and Arsenic Contamination

    PubMed Central

    Baos, Raquel; Blas, Julio; Bortolotti, Gary R.; Marchant, Tracy A.; Hiraldo, Fernando

    2006-01-01

    Background/Objective Endocrine parameters have proven useful in the detection of early or low-level responses to pollutants. Although most of the studies on endocrine modulation have been focused on processes involving gonadal steroids, contaminants may target other parts of the endocrine system as well. In this study we examined the adrenocortical stress response and thyroid hormone status in free-living nestling white storks (Ciconia ciconia) in relation to heavy metals (zinc, lead, copper, cadmium) and arsenic levels in blood. Methods Fieldwork was conducted in an area polluted by the Aznalcóllar mine accident (southwestern Spain) and in a reference site. We used a standardized capture, handling, and restraint protocol to determine both baseline and maximum plasma corticosterone. Circulating levels of thyroxine (T4) and triiodothyronine (T3) were also measured. Results No effects of metals or As were found on baseline corticosterone, but maximum levels of corticosterone were positively related to Pb in both locations. This relationship was stronger in single nestlings than in birds from multiple-chick broods, which suggests a greater impact of Pb on more stressed individuals. Metal pollution did not affect plasma T4 or T3 levels, although thyroid status differed with location. Conclusions Because a compromised hypothalamus–pituitary–adrenal (HPA) function can have far-reaching consequences in terms of altered behavioral and metabolic processes necessary for survival, our results suggest that birds exposed to sublethal Pb levels may be at risk through an altered adrenocortical stress response, and further support the idea that HPA axis-related end points might be useful indicators of metal exposure and potential toxicity in wild animals. PMID:17035132

  11. Hormonal regulation of focal adhesions in bovine adrenocortical cells: induction of paxillin dephosphorylation by adrenocorticotropic hormone.

    PubMed Central

    Vilgrain, I; Chinn, A; Gaillard, I; Chambaz, E M; Feige, J J

    1998-01-01

    A study of bovine adrenocortical cell shape on adrenocorticotropic hormone (ACTH) challenge showed that the cells round up and develop arborized processes. This effect was found to be (1) specific for ACTH because angiotensin II and basic fibroblast growth factor have no effect; (2) mediated by a cAMP-dependent pathway because forskolin reproduces the effect of the hormone; (3) inhibited by sodium orthovanadate, a phosphotyrosine phosphatase inhibitor, but unchanged by okadaic acid, a serine/threonine phosphatase inhibitor; and (4) correlated with a complete loss of focal adhesions. Biochemical studies of the focal-adhesion-associated proteins showed that pp125fak, vinculin (110 kDa) and paxillin (70 kDa) were detected in the Triton X-100-insoluble fraction from adrenocortical cells. During cell adhesion on fibronectin as substratum, two major phosphotyrosine-containing proteins of molecular masses 125 and 68 kDa were immunodetected in the same fraction. A dramatic decrease in the extent of tyrosine phosphorylation of these proteins was observed within 60 min after treatment with ACTH. No change in pp125fak tyrosine phosphorylation nor in Src activity was detected. In contrast, paxillin was found to be tyrosine-dephosphorylated in a time-dependent manner in ACTH-treated cells. Sodium orthovanadate completely prevented the effect of ACTH. These observations suggest a possible role for phosphotyrosine phosphatases in hormone-dependent cellular regulatory processes. PMID:9601084

  12. Combination of gold nanoparticle-conjugated TNF-α and radiation therapy results in a synergistic anti-tumor response in murine carcinoma models

    PubMed Central

    Koonce, Nathan A.; Quick, Matthew C.; Hardee, Matthew E.; Jamshidi-Parsian, Azemat; Dent, Judith A.; Paciotti, Giulio F.; Nedosekin, Dmitry; Dings, Ruud P.M.; Griffin, Robert J.

    2016-01-01

    Introduction Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and in combination with radiation, clinical use is hindered by systemic dose-limiting toxicities. Here, we investigated the physiological and anti-tumor effects of radiotherapy combined with the novel nanomedicine CYT-6091, a 27-nm average diameter polyethylene glycol-TNF coated gold nanoparticle which passed through Phase I trials recently. Methods Physiological and anti-tumor effects of single and fractionated radiation in combination with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. Results In the 4T1 murine breast tumor model we observed a significant reduction in tumor interstitial fluid pressure (IFP) 24h after CYT-6091 alone and combined with a radiation dose of 12 Gy (p<0.05 vs control), whereas radiation alone (12Gy) had negligible effect on IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated and there was little additional change in IFP post single dose radiation or combined therapy (p>0.05 vs control) despite extensive observed vascular damage. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared to all other groups (p<0.05). Finally, we observed a >2-fold delay in tumor growth when CYT-6091 was combined with a single 20 Gy irradiation- notably irrespective of treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied in combination with CYT-6091 treatment, a >5-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Conclusions Our results demonstrate that gold-labeled TNF nanoparticles in combination with single or fractionated high-dose radiation

  13. INFLUENCE OF CHLORDIMEFORM ON ALPHA-ADRENERGIC RECEPTOR-ASSOCIATED MECHANISMS OF HORMONAL REGULATIONS: PITUITARY AND ADRENOCORTICAL SECRETION

    EPA Science Inventory

    The acaricide chlordimeform (CDF) has been reported to have effects on the central nervous system that appear to involve an interaction with adrenergic receptor mediated mechanisms of neurotransmission. The present study examined the influence of CDF on pituitary-adrenocortical h...

  14. Epidermal Platelet-activating Factor Receptor Activation and Ultraviolet B Radiation Result in Synergistic Tumor Necrosis Factor-alpha Production

    PubMed Central

    Wolverton, Jay E.; Al-Hassani, Mohammed; Yao, Yongxue; Zhang, Qiwei; Travers, Jeffrey B.

    2010-01-01

    Ultraviolet B radiation (UVB) is a potent stimulator of epidermal cytokine production which has been implicated in photoaggravated dermatoses. In addition to cytokines such as tumor necrosis factor-α (TNF-α), UVB generates bioactive lipids including platelet-activating factor (PAF). Our previous studies have demonstrated that UVB-mediated production of keratinocyte TNF-α is in part due to PAF. The current studies use a human PAF-receptor (PAF-R) negative epithelial cell line transduced with PAF-Rs and PAF–R-deficient mice to demonstrate that activation of the epidermal PAF-R along with UVB irradiation results in a synergistic production of TNF-α. It should be noted that PAF-R effects are mimicked by the protein kinase C (PKC) agonist phorbol myristic acetate, and are inhibited by pharmacological antagonists of the PKC gamma isoenzyme. These studies suggest that concomitant PAF-R activation and UVB irradiation results in a synergistic production of the cytokine TNF-α which is mediated in part via PKC. These studies provide a novel potential mechanism for photosensitivity responses. PMID:19769579

  15. Seasonal changes in adrenocortical responses to acute stress in Eurasian tree sparrow (Passer montanus) on the Tibetan Plateau: comparison with house sparrow (P. domesticus) in North America and with the migratory P. domesticus in Qinghai Province.

    PubMed

    Li, Dongming; Wang, Gang; Wingfield, John C; Zhang, Zhi; Ding, Changqing; Lei, Fumin

    2008-08-01

    Seasonal modulation of the adrenocortical response to stress appears to be ubiquitous in arctic-breeding and temperate-zone-breeding birds, but has not been well investigated in alpine-breeding species at mid-latitude. We examined the adrenocortical response to acute stress (capture, handling and restraint) in populations of Eurasian tree sparrow (Passer montanus) among seasons and migratory house sparrow (P. domesticus bactrianus) in pre-breeding on the Qinghai-Xizang Plateau (the Tibetan Plateau). A population of house sparrow (Passer domesticus domesticus) was also sampled in lowland Phoenix, Arizona during breeding and wintering stages. In Eurasian tree sparrows, baseline corticosterone (CORT) does not differ among life history stages, but stress-induced CORT level (maximal CORT, total and corrected integrated CORT) is significantly higher in late breeding stage than those in early breeding and prebasic molt stages. In house sparrows, stress-induced CORT level does not differ between sites and life history stages, but baseline CORT is significantly lower in pre-breeding from Qinghai compared with those in breeding and wintering stages from Phoenix. Interestingly, both baseline CORT and maximal CORT do not differ between the populations of Eurasian tree sparrow and house sparrow in early/pre-breeding stage although tree sparrow is resident species whereas house sparrow is migratory in Qinghai. Our results suggest that the extreme environment of the Tibetan Plateau does not have significant effects on adrenocortical responses to acute stress in Eurasian tree sparrows and house sparrows, which may be a result of masking by human activities. These invasive human commensals may have a unique HPA axis response to different environments because they can take advantage of human food sources and shelter (i.e. buildings). PMID:18588892

  16. Efonidipine, a Ca(2+)-channel blocker, enhances the production of dehydroepiandrosterone sulfate in NCI-H295R human adrenocortical carcinoma cells.

    PubMed

    Ikeda, Keiichi; Saito, Takatoshi; Tojo, Katsuyoshi

    2011-01-01

    Steroid biosynthesis is initiated with transportation of cholesterol along with steroidogenic acute regulatory protein (StAR) into the mitchondria and is achieved with several steroidogenic enzymes. It has been reported that Ca(2+) channel blockers (CCBs), such as azelnidipine, efonidipine and nifedipine, suppress the biosynthesis of aldosterone and cortisol, but the overall effects of CCBs on steroid biosynthesis remain to be clarified. The present study was designed to evaluate the effects of CCBs on the expression of steroidogenic enzymes and the production of adrenal androgen, dehydroepiandrosterone sulfate (DHEA-S) that has anti-atherosclerotic actions. NCI-H295R human adrenocortical carcinoma cells and HepG2 human hepatoma cells were cultured for 24 hours with or without a CCB (amlodipine, efonidipine, nifedipine, azelnidipine R(-)-efonidipine, verapamil or diltiazem). HepG2 hepatoma cells were used to confirm the effects of CCBs on the expression of StAR. In fact, efonidipine and nifedipine increased the expression of StAR in HepG2 cells. Efonidipine and nifedipine, but not other examined CCBs, also increased the N(6), 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP)-induced StAR mRNA, which reflects the action of adrenocorticotropic hormone, and efonidipine and R(-)-efonidipine enhanced the dbcAMP-induced DHEA-S production in NCI-H295R adrenocortical carcinoma cells. Therefore, efonidipine and nifedipine might increase the expression of StAR and, in turn, efonidipine enhanced the dbcAMP-induced DHEA-S production, independent of Ca(2+) channel blockade. These results indicate that such effects are not associated with Ca(2+) influx. Moreover, only efonidipine enhanced the angiotensin II-induced expression of StAR mRNA (P < 0.01 vs. angiotensin II alone). In conclusion, efonidipine might exert an additional action beyond anti-hypertensive actions. PMID:21757861

  17. Chronic stress increases the opioid-mediated inhibition of the pituitary-adrenocortical response to acute stress in pigs.

    PubMed

    Janssens, C J; Helmond, F A; Loyens, L W; Schouten, W G; Wiegant, V M

    1995-04-01

    The role of endogenous opioid mechanisms in the pituitary-adrenocortical response to acute stress was investigated in a longitudinal study in cyclic female pigs before and after exposure to chronic stress (long term tethered housing). Challenge of loose-housed pigs with acute nose-sling stress for 15 min induced an activation of the hypothalamic-pituitary-adrenocortical axis, evidenced by a transient increase in plasma ACTH (peak height above basal, 98 +/- 12 pg/ml; mean +/- SEM) and cortisol (54 +/- 3 ng/ml) concentrations. Pretreatment with the opioid receptor antagonist naloxone (0.5 mg/kg BW, iv bolus) increased the challenge-induced ACTH and cortisol responses to 244 +/- 36 pg/ml and 65 +/- 5 ng/ml, respectively. This indicates that during acute nose-sling stress, endogenous opioid systems are activated that inhibit the pituitary-adrenocortical response. After exposure of the pigs to chronic stress (10-11 weeks of tethered housing), the challenge-induced ACTH response was attenuated, whereas the cortisol response remained unchanged, suggesting an increased adrenocortical sensitivity to circulating ACTH. In addition, pretreatment with naloxone induced a greater increment in the ACTH and cortisol responses in tethered pigs than in loose-housed pigs. As no such changes were found in control animals housed loose during the entire experimental period, this indicates that the impact of opioid systems had increased due to chronic stress. The increased impact of opioid systems during chronic stress may prevent excessive hypothalamic-pituitary-adrenocortical responses to acute stressors and, thus, may be of adaptive value. PMID:7895656

  18. Expression of prepro-ghrelin and related receptor genes in the rat adrenal gland and evidences that ghrelin exerts a potent stimulating effect on corticosterone secretion by cultured rat adrenocortical cells.

    PubMed

    Rucinski, Marcin; Ziolkowska, Agnieszka; Tyczewska, Marianna; Malendowicz, Ludwik K

    2009-08-01

    The orexigenic peptide ghrelin (GHREL) and obestatin (OBS) originate from the same peptide precursor, preproghrelin (ppGHREL). Apart from orexigenic effect, GHREL also regulates neuroendocrine function. We investigated GHREL and OBS effects on corticosterone secretion by freshly isolated and cultured rat adrenocortical cells. Classic RT-PCR revealed the presence of ppGHREL, GHS-R1a, GPR39v1 and GPR39v2 and GOAT4 (ghrelin O-acyl transferase) mRNAs in rat adrenals and cultured for 4 days rat adrenocortical cells. Expression of ppGHREL, GHS-R1a, and GOAT genes was notably higher in the cortex than in medulla. High expression level of GOAT gene was found in the zona glomerulosa, while expression level of both GPR39v1 and GPR39v2 genes was similar in adrenal cortical zones and in medulla. In freshly isolated cells neither GHREL nor OBS had an effect on corticosteroid output. Prolonged exposure of cultured cells to GHREL resulted in a potent, comparable to ACTH, stimulating effect of GHREL on corticosterone secretion. Prolonged exposure to OBS was ineffective. Neither GHREL nor OBS had any effect on proliferation of studied cells, while ACTH notably lowered it. GHREL down regulated GHS-R1a gene expression while both ACTH and GHREL stimulated expression level of GPR39v1 gene. Expression of CYP11A1 gene was notably stimulated and that of StAR gene remained unaffected by ACTH or GHREL. Thus, our study is the first to demonstrate direct stimulating effect of GHREL on corticosterone output by cultured rat adrenocortical cells. This stimulating action differs from that evoked by ACTH and is not dependent on the presence of functional ACTH receptor. PMID:19416745

  19. ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase

    PubMed Central

    2013-01-01

    Background Adrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro. Methods In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues. Results Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1. Conclusions Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression. PMID:24034279

  20. n-3 polyunsaturated fatty acids abrogate mTORC1/2 signaling and inhibit adrenocortical carcinoma growth in vitro and in vivo.

    PubMed

    Liu, Jun; Xu, Meinian; Zhao, Yongbin; Ao, Chunping; Wu, Yukun; Chen, Zhenguo; Wang, Bangqi; Bai, Xiaochun; Li, Ming; Hu, Weilie

    2016-06-01

    n-3 polyunsaturated fatty acids (PUFAs) are essential for human health and have been reported to reduce the risk of cancer, inhibit the growth of various types of tumors both in vitro and in vivo, and affect adrenal function. However, their effects on adrenocortical carcinoma (ACC) are not known. In the present study, we demonstrated that docosahexenoic acid (DHA) inhibited ACC cell proliferation, colony formation and cell cycle progression, and promoted apoptosis. In addition, ectopic expression of fat-1, a desaturase that converts n-6 to n-3 PUFAs endogenously, also inhibited ACC cell proliferation. Moreover, supplementing n-3 PUFAs in the diet efficiently prevented ACC cell growth in xenograft models. Notably, implanted ACC cells were unable to grow in fat-1 transgenic severe combined immune deficiency mice. Further study revealed that exogenous and endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 signaling in ACC in vitro and in vivo. Taken together, our findings provide comprehensive preclinical evidence that n-3 PUFAs efficiently prevent ACC growth by inhibiting mTORC1/2, which may have important implications in the treatment of ACC. PMID:27035283

  1. A Multi-Institutional Study of Feasibility, Implementation, and Early Clinical Results With Noninvasive Breast Brachytherapy for Tumor Bed Boost

    SciTech Connect

    Hamid, Subarna; Rocchio, Kathy; Arthur, Douglas; Vera, Robyn; Sha, Sandra; Jolly, Michele; Cavanaugh, Sean; Wooten, Eric; Benda, Rashmi; Greenfield, Brad; Prestidge, Bradley; Ackerman, Scot; Kuske, Robert; Quiet, Coral; Snyder, Margaret; Wazer, David E.

    2012-08-01

    Purpose: To evaluate the feasibility, implementation, and early results of noninvasive breast brachytherapy (NIBB) for tumor bed boost with whole breast radiation therapy (WBRT). Methods and Materials: NIBB is a commercially available (AccuBoost, Billerica, MA) mammography-based, brachytherapy system in which the treatment applicators are centered on the planning target volume (PTV) to direct {sup 192}Ir emissions along orthogonal axes. A privacy-encrypted online data registry collected information from 8 independent academic and community-based institutions. Data were from 146 consecutive women with early-stage breast cancer after lumpectomy and WBRT receiving boost with NIBB between July 2007 and March 2010. Toxicity and cosmesis were graded according to the Common Toxicity Criteria (v. 3.0) and the Harvard scale. Median follow-up was 6 months (1-39 months). Results: Grade 1-2 skin toxicity was observed in 64%, 48%, and 21% during the acute (1-3 weeks), intermediate (4-26 weeks), and late-intermediate (>26 weeks) periods. There was no Grade 4 toxicity. At 6 months, for the entire cohort, cosmesis was excellent/good in 62%/38%. The subset receiving NIBB before WBRT had cosmetic scores of 32% and 63%, whereas during WBRT, 58% and 37% were rated as excellent and good, respectively. Breast compression was scored as 'uncomfortable' in 12%, 29%, and 59% when NIBB was delivered before, during, or after WBRT. For each patient, the fraction-to-fraction variability in PTV was low. Skin flash was associated with a higher proportion of excellent cosmesis (58% vs. 42%) relative to having the applicator all within breast tissue. Conclusions: These data indicate that NIBB is feasible and can be consistently implemented in a broad array of practice settings. Preliminary evaluation suggests that NIBB is associated with acceptably mild normal tissue toxicity and favorable early cosmesis. The application of NIBB before WBRT may be associated with better patient tolerance at the

  2. Assessment of adrenocortical and gonadal hormones in male spider monkeys (Ateles geoffroyi) following capture, restraint and anesthesia.

    PubMed

    Rodas-Martínez, Alba Zulema; Canales, Domingo; Brousset, Dulce María; Swanson, William F; Romano, Marta C

    2013-01-01

    The spider monkey (SM) (Ateles geoffroyi) a New World primate species native to Mexican forests, has become endangered in the wild due to environmental perturbations. Little is known about adrenal function and its relationship to reproduction in this species. Our objectives were to assess serum glucocorticoid (GC), mineralocorticoid (MC) and testosterone concentrations in captive SM and evaluate adrenal and testicular responses to potentially stressful animal handling procedures. Seven adult males, housed in a single mixed gender group in an off-exhibit enclosure at the University Park were captured for anesthesia every 2 months over a 1-year period. Blood samples were collected from each male at three time points: (1) ∼5-10 min after ketamine injection in the outdoor enclosure; (2) ∼2 hr later following animal transport to the laboratory and immediately after tiletamine-zolazepam injection; and (3) ∼20-30 min following the second anesthetic injection. Serum samples were frozen and later analyzed for cortisol, corticosterone, aldosterone and testosterone via radioimmunoassay. Cortisol was the primary GC detected in SM serum with much higher mean concentrations than for corticosterone. Capture, restraint and anesthesia resulted in significant increases in both cortisol and corticosterone concentrations. Whereas aldosterone concentrations were unchanged by animal handling procedures, testosterone concentrations significantly declined under anesthesia over time. In summary, these results provide data for the main adrenocortical hormones in male SM and characterize their acute adrenal responses to potentially stressful handling and anesthesia procedures. Our findings also suggest an interaction between acute increases in corticosteroids and decreased concentrations of serum testosterone. PMID:24167044

  3. Adrenocortical responses of the Apollo 17 crew members

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Rambaut, P. C.; Johnson, P. C.

    1974-01-01

    Changes in adrenal activity of the three Apollo 17 crew members were studied during the 12.55-day mission and during selected post-recovery days. Aldosterone excretion was normal early and elevated later in the mission, probably causing a loss in total body exchangeable potassium. There was decreased 17-hydroxycorticosteroid excretion only during the early mission days for the two moon landers and throughout the mission for the other astronaut. Cortisol excretion was elevated on physically stressful mission days. At recovery, plasma ACTH was elevated without a similar increase in plasma cortisol. Angiotensin I activity was elevated at recovery in only one crewman. This crewman was the only one with a decreased extracellular fluid volume. These results indicate that the mission and its activities affect adrenal function of the crewmen.

  4. Effects of neuromedin-U on immature rat adrenocortical cells: in vitro and in vivo studies.

    PubMed

    Ziolkowska, Agnieszka; Macchi, Carlo; Trejter, Marcin; Rucinski, Marcin; Nowak, Magdalena; Nussdorfer, Gastone G; Malendowicz, Ludwik K

    2008-03-01

    Neuromedin U (NMU) is a brain-gut peptide, that in the peripheral organs and tissues acts via a G protein-coupled receptor, called NMUR1. Reverse transcription-polymerase chain reaction showed the expression of NMUR1 mRNA in either cortex and medulla or dispersed zona glomerulosa and zona fasciculata-reticularis cells of the immature rat adrenals. Accordingly, immunocytochemistry demonstrated the presence of NMUR1-like immunoreactivity in the cortex and medulla of immature adrenals. NMU8 administration to immature rats was found to raise aldosterone, but not corticosterone, plasma concentration, without altering adrenal growth. Conversely, the exposure to NMU8 markedly enhanced the proliferative activity of immature rat inner adrenocortical cells in primary in vitro culture, without significantly affecting their corticosterone secretion. Collectively, our findings suggest that adrenals of immature rats may be a target for circulating NMU. However, the physiological significance and relevance of the adrenal effects of NMU remain to be ascertained. PMID:18288377

  5. Interparental Aggression and Infant Patterns of Adrenocortical and Behavioral Stress Responses

    PubMed Central

    Towe-Goodman, Nissa R.; Stifter, Cynthia A.; Mills-Koonce, W. Roger; Granger, Douglas A.

    2011-01-01

    Drawing on emotional security theory, this study examined linkages between interparental aggression, infant self-regulatory behaviors, and patterns of physiological and behavioral stress responses in a diverse sample of 735 infants residing in predominately low-income, nonmetropolitan communities. Latent profile analysis revealed four classes of adrenocortical and behavioral stress response patterns at 7-months of age, using assessments of behavioral and cortisol reactivity to an emotion eliciting challenge, as well as global ratings of the child’s negative affect and basal cortisol levels. The addition of covariates within the latent profile model suggested that children with more violence in the home and who used less caregiver-oriented regulation strategies were more likely to exhibit a pattern of high cortisol reactivity with moderate signs of distress rather than the average stress response, suggesting possible patterns of adaptation in violent households. PMID:22127795

  6. Androgen secreting giant adrenocortical carcinoma with no metastases: A case report and review of the literature

    PubMed Central

    Uruc, Fatih; Urkmez, Ahmet; Yuksel, Ozgur Haki; Sahin, Aytac; Verit, Ayhan

    2015-01-01

    Functional adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Over half (60%) of ACCs bigger than 6 cm synthesize hormones; hormone-secreting ACCs generally include virilization, feminization or Cushing syndrome. Besides, 82% of ACCs are metastatic at the time of diagnosis. While a 48-year-old female patient was examined for abdominal pain and flushing, we detected a non-metastasizing mass (23 × 18 × 16 cm) in the adrenal lodge. The mass was extracted en bloc during open exploration and its histopathology was reported as ACC. We review the literature and report the largest androgen-producing, clinically silent ACC mass cited in the literature so far. PMID:26425231

  7. Simultaneous adrenocortical carcinoma and ganglioneuroblastoma in a child with Turner syndrome and germline p53 mutation.

    PubMed Central

    Pivnick, E K; Furman, W L; Velagaleti, G V; Jenkins, J J; Chase, N A; Ribeiro, R C

    1998-01-01

    The predisposition to malignancy that is dominantly inherited in Li-Fraumeni syndrome is associated with germline mutations of the tumour suppressor gene p53. Although second malignant neoplasms have been described in children with p53 mutations, the synchronous occurrence of two embryologically different tumours in these children has not been reported. A 20 month old girl with failure to thrive and congenital heart defects was found to have unilateral adrenal masses which, at surgical removal, proved to be an adrenocortical carcinoma and a ganglioneuroblastoma. Further investigation showed a germline p53 mutation and Turner syndrome. It remains to be determined what effect the 45,X chromosomal complement may have on the expression of neoplasms seen in patients with p53 germline mutations. Images PMID:9598730

  8. Cortisol Stimulates Secretion of Dehydroepiandrosterone in Human Adrenocortical Cells Through Inhibition of 3βHSD2

    PubMed Central

    Topor, Lisa Swartz; Asai, Masato; Dunn, James; Majzoub, Joseph A.

    2011-01-01

    Context: Initiating factors leading to production of adrenal androgens are poorly defined. Cortisol is present in high concentrations within the adrenal gland, and its production rises with growth during childhood. Objective: Our aim was to characterize the effect of cortisol and other glucocorticoids on androgen secretion from a human adrenocortical cell line and from nonadrenal cells transfected with CYP17A1 or HSD3B2. Design/Setting: This study was performed in cultured cells, at an academic medical center. Methods: The effects of cortisol upon steroid production in human adrenal NCI-H295R cells were measured by immunoassay, tandem mass spectrometry, and thin-layer chromatography. The effects of cortisol upon the activities of 17, 20 lyase and 3βHSD2 were measured in NCI-H295R cells and in transfected COS-7 cells. Results: Cortisol markedly and rapidly stimulated dehydroepiandrosterone (DHEA) in a dose-dependent manner at cortisol concentrations ≥50 μm. Cortisone and 11-deoxycortisol were also potent stimulators of DHEA secretion, whereas prednisolone and dexamethasone were not. Treatment with cortisol did not affect expression of CYP17A1 or HSD3B2 mRNAs. Stimulation of DHEA secretion by cortisol was associated with competitive inhibition of 3βHSD2 activity. Conclusions: Cortisol inhibits 3βHSD2 activity in adrenal cells and in COS-7 cells transfected with HSD3B2. Thus, it is possible that intraadrenal cortisol may participate in the regulation of adrenal DHEA secretion through inhibition of 3βHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3βHSD2 activity and contribute to the initiation of adrenarche. PMID:20943790

  9. High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells.

    PubMed

    Karmaus, Agnes L; Toole, Colleen M; Filer, Dayne L; Lewis, Kenneth C; Martin, Matthew T

    2016-04-01

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ≥ 70% viability) per sample. The second stage quantified changes in hormone levels at the MTC whereas the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were prestimulated with 10 µM forskolin for 48 h to induce steroidogenesis followed by chemical treatment for 48 h. Of the 2060 chemical samples evaluated, 524 samples were selected for 6-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 17β-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into 5 distinct profiles generally representing putative mechanisms of action, including CYP17A1 and HSD3B inhibition. A distinct pattern was observed between imidazole and triazole fungicides suggesting potentially distinct mechanisms of action. From a chemical testing and prioritization perspective, this assay platform provides a robust model for high-throughput screening of chemicals for effects on steroidogenesis. PMID:26781511

  10. High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells

    PubMed Central

    Toole, Colleen M.; Filer, Dayne L.; Lewis, Kenneth C.; Martin, Matthew T.

    2016-01-01

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ≥ 70% viability) per sample. The second stage quantified changes in hormone levels at the MTC whereas the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were prestimulated with 10 µM forskolin for 48 h to induce steroidogenesis followed by chemical treatment for 48 h. Of the 2060 chemical samples evaluated, 524 samples were selected for 6-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 17β-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into 5 distinct profiles generally representing putative mechanisms of action, including CYP17A1 and HSD3B inhibition. A distinct pattern was observed between imidazole and triazole fungicides suggesting potentially distinct mechanisms of action. From a chemical testing and prioritization perspective, this assay platform provides a robust model for high-throughput screening of chemicals for effects on steroidogenesis. PMID:26781511

  11. Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats.

    PubMed

    Grayson, Bernadette E; Hakala-Finch, Andrew P; Kekulawala, Melani; Laub, Holly; Egan, Ann E; Ressler, Ilana B; Woods, Stephen C; Herman, James P; Seeley, Randy J; Benoit, Stephen C; Ulrich-Lai, Yvonne M

    2014-12-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  12. Real-Time US-CT/MRI Image Fusion for Guidance of Thermal Ablation of Liver Tumors Undetectable with US: Results in 295 Cases

    SciTech Connect

    Mauri, Giovanni Cova, Luca; Beni, Stefano De; Ierace, Tiziana Tondolo, Tania Cerri, Anna; Goldberg, S. Nahum; Solbiati, Luigi

    2015-02-15

    PurposeThis study was designed to assess feasibility of US-CT/MRI fusion-guided ablation in liver tumors undetectable with US.MethodsFrom 2002 to 2012, 295 tumors (162 HCCs and 133 metastases; mean diameter 1.3 ± 0.6 cm, range 0.5–2.5 cm) detectable on contrast-enhanced CT/MRI, but completely undetectable with unenhanced US and either totally undetectable or incompletely conspicuous with contrast-enhanced US (CEUS), were treated in 215 sessions using either internally cooled radiofrequency or microwave with standard ablation protocols, guided by an image fusion system (Virtual Navigation System, Esaote S.p.A., Genova, Italy) that combines US with CT/ MRI images. Correct targeting and successful ablation of tumor were verified after 24 hours with CT or MRI.ResultsA total of 282 of 295 (95.6 %) tumors were correctly targeted with successful ablation achieved in 266 of 295 (90.2 %). Sixteen of 295 (5.4 %) tumors were correctly targeted, but unsuccessfully ablated, and 13 of 295 (4.4 %) tumors were unsuccessfully ablated due to inaccurate targeting. There were no perioperative deaths. Major complications were observed in 2 of the 215 treatments sessions (0.9 %).ConclusionsReal-time virtual navigation system with US-CT/MRI fusion imaging is precise for targeting and achieving successful ablation of target tumors undetectable with US alone. Therefore, a larger population could benefit from ultrasound guided ablation procedures.

  13. Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

    PubMed Central

    2014-01-01

    Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated

  14. Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758)

    PubMed Central

    Ferreira, João C. P.; Fujihara, Caroline J.; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C.; Teixeira, Carlos R.; Pantoja, José C. F.; Schmidt, Elizabeth M. S.; Palme, Rupert

    2015-01-01

    Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots’ physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3–9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural

  15. Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758).

    PubMed

    Ferreira, João C P; Fujihara, Caroline J; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C; Teixeira, Carlos R; Pantoja, José C F; Schmidt, Elizabeth M S; Palme, Rupert

    2015-01-01

    Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots' physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3-9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural

  16. The adrenocortical response of tufted puffin chicks to nutritional deficits

    USGS Publications Warehouse

    Kitaysky, A.S.; Romano, Marc D.; Piatt, J.F.; Wingfield, J.C.; Kikuchi, M.

    2005-01-01

    In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus-pituitary-adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation. 

  17. The adrenocortical response of tufted puffin chicks to nutritional deficits.

    PubMed

    Kitaysky, Alexander S; Romano, Marc D; Piatt, John F; Wingfield, John C; Kikuchi, Motoshi

    2005-05-01

    In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus-pituitary-adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation. PMID:15811363

  18. Evaluation of adrenocortical function in Florida manatees (Trichechus manatus latirostris)

    USGS Publications Warehouse

    Tripp, K.M.; Verstegen, J.P.; Deutsch, C.; Bonde, Robert K.; de Wit, M.; Manire, C.A.; Gaspard, J.; Harr, K.E.

    2011-01-01

    The study objectives were to determine the predominant manatee glucocorticoid; validate assays to measure this glucocorticoid and adrenocorticotropic hormone (ACTH); determine diagnostic thresholds to distinguish physiological vs. pathological concentrations; identify differences associated with sex, age class, female reproductive status, capture time, and lactate; and determine the best methods for manatee biologists and clinicians to diagnose stress. Cortisol is the predominant manatee glucocorticoid. IMMULITE 1000 assays for cortisol and ACTH were validated. Precision yielded intra- and inter-assay coefficients of variation for serum cortisol: ≤23.5 and ≤16.7%; and ACTH: ≤6.9 and ≤8.5%. Accuracy resulted in a mean adjusted R(2)≥0.87 for serum cortisol and ≥0.96 for ACTH. Assay analytical sensitivities for cortisol (0.1 µg/dl) and ACTH (10.0 pg/ml) were verified. Methods were highly correlated with another IMMULITE 1000 for serum cortisol (r=0.97) and ACTH (r=0.98). There was no significant variation in cortisol or ACTH with sex or age class and no correlation with female progesterone concentrations. Cortisol concentrations were highest in unhealthy manatees, chronically stressed by disease or injury. ACTH was greatest in healthy free-ranging or short-term rehabilitating individuals, peracutely stressed by capture and handling. Cortisol concentrations ≥1.0 µg/dl were diagnostic of chronic stress; ACTH concentrations ≥87.5 pg/ml were diagnostic of peracute stress. In healthy long-term captive manatees, cortisol (0.4±0.2 µg/dl) and ACTH (47.7±15.9 pg/ml) concentrations were lower than healthy free-ranging, short-term rehabilitated or unhealthy manatees. Capture time was not significantly correlated with cortisol; ACTH correlation was borderline significant. Cortisol and ACTH were positively correlated with lactate.

  19. Evaluation of adrenocortical function in Florida manatees (Trichechus manatus latirostris)

    USGS Publications Warehouse

    Tripp, K.M.; Verstegen, J.P.; Deutsch, C.J.; Bonde, R.K.; Wit, M.D.; Manire, C.A.; Gaspard, J.; Harr, K.E.

    2011-01-01

    The study objectives were to determine the predominant manatee glucocorticoid; validate assays to measure this glucocorticoid and adrenocorticotropic hormone (ACTH); determine diagnostic thresholds to distinguish physiological vs. pathological concentrations; identify differences associated with sex, age class, female reproductive status, capture time, and lactate; and determine the best methods for manatee biologists and clinicians to diagnose stress. Cortisol is the predominant manatee glucocorticoid. IMMULITE 1000 assays for cortisol and ACTH were validated. Precision yielded intra- and inter-assay coefficients of variation for serum cortisol: ???23.5 and ???16.7%; and ACTH: ???6.9 and ???8.5%. Accuracy resulted in a mean adjusted R2???0.87 for serum cortisol and ???0.96 for ACTH. Assay analytical sensitivities for cortisol (0.1??g/dl) and ACTH (10.0pg/ml) were verified. Methods were highly correlated with another IMMULITE 1000 for serum cortisol (r=0.97) and ACTH (r=0.98). There was no significant variation in cortisol or ACTH with sex or age class and no correlation with female progesterone concentrations. Cortisol concentrations were highest in unhealthy manatees, chronically stressed by disease or injury. ACTH was greatest in healthy free-ranging or short-term rehabilitating individuals, peracutely stressed by capture and handling. Cortisol concentrations ???1.0??g/dl were diagnostic of chronic stress; ACTH concentrations ???87.5pg/ml were diagnostic of peracute stress. In healthy long-term captive manatees, cortisol (0.4??0.2??g/dl) and ACTH (47.7??15.9pg/ml) concentrations were lower than healthy free-ranging, short-term rehabilitated or unhealthy manatees. Capture time was not significantly correlated with cortisol; ACTH correlation was borderline significant. Cortisol and ACTH were positively correlated with lactate. ?? 2010 Wiley-Liss, Inc.

  20. Evaluation of adrenocortical function in Florida manatees (Trichechus manatus latirostris).

    PubMed

    Tripp, Kathleen M; Verstegen, John P; Deutsch, Charles J; Bonde, Robert K; de Wit, Martine; Manire, Charles A; Gaspard, Joseph; Harr, Kendal E

    2011-01-01

    The study objectives were to determine the predominant manatee glucocorticoid; validate assays to measure this glucocorticoid and adrenocorticotropic hormone (ACTH); determine diagnostic thresholds to distinguish physiological vs. pathological concentrations; identify differences associated with sex, age class, female reproductive status, capture time, and lactate; and determine the best methods for manatee biologists and clinicians to diagnose stress. Cortisol is the predominant manatee glucocorticoid. IMMULITE 1000 assays for cortisol and ACTH were validated. Precision yielded intra- and inter-assay coefficients of variation for serum cortisol: ≤23.5 and ≤16.7%; and ACTH: ≤6.9 and ≤8.5%. Accuracy resulted in a mean adjusted R(2)≥0.87 for serum cortisol and ≥0.96 for ACTH. Assay analytical sensitivities for cortisol (0.1 µg/dl) and ACTH (10.0 pg/ml) were verified. Methods were highly correlated with another IMMULITE 1000 for serum cortisol (r=0.97) and ACTH (r=0.98). There was no significant variation in cortisol or ACTH with sex or age class and no correlation with female progesterone concentrations. Cortisol concentrations were highest in unhealthy manatees, chronically stressed by disease or injury. ACTH was greatest in healthy free-ranging or short-term rehabilitating individuals, peracutely stressed by capture and handling. Cortisol concentrations ≥1.0 µg/dl were diagnostic of chronic stress; ACTH concentrations ≥87.5 pg/ml were diagnostic of peracute stress. In healthy long-term captive manatees, cortisol (0.4±0.2 µg/dl) and ACTH (47.7±15.9 pg/ml) concentrations were lower than healthy free-ranging, short-term rehabilitated or unhealthy manatees. Capture time was not significantly correlated with cortisol; ACTH correlation was borderline significant. Cortisol and ACTH were positively correlated with lactate. PMID:20187090

  1. SU-C-210-06: Quantitative Evaluation of Dosimetric Effects Resulting From Positional Variations of Pancreatic Tumor Volumes

    SciTech Connect

    Yu, S; Sehgal, V; Wei, R; Lawrenson, L; Kuo, J; Hanna, N; Ramsinghani, N; Daroui, P; Al-Ghazi, M

    2015-06-15

    Purpose: The aim of this study is to quantify dosimetric effects resulting from variation in pancreatic tumor position assessed by bony anatomy and implanted fiducial markers Methods: Twelve pancreatic cancer patients were retrospectively analyzed for this study. All patients received modulated arc therapy (VMAT) treatment using fiducial-based Image Guided Radiation Therapy (IGRT) to the intact pancreas. Using daily orthogonal kV and/or Cone beam CT images, the shift needed to co-register the daily pre-treatment images to reference CT from fiducial to bone (Fid-Bone) were recorded as Left-Right (LR), Anterior-Posterior (AP) and Superior-Inferior (SI). The original VMAT plan iso-center was shifted based on KV bone matching positions at 5 evenly spaced fractions. Dose coverage of the planning target volumes (PTVs) (V100%), mean dose to liver, kidney and stomach/duodenum were assessed in the modified plans. Results: A total of 306 fractions were analyzed. The absolute fiducial-bone positional shifts were greatest in the SI direction, (AP = 2.7 ± 3.0, LR = 2.8 ± 2.8, and SI 6.3 ± 7.9 mm, mean ± SD). The V100% was significantly reduced by 13.5%, (Fid-Bone = 95.3 ± 2.0 vs. 82.3 ± 11.8%, p=0.02). This varied widely among patients (Fid-Bone V100% Range = 2–60%), where 33% of patients had a reduction in V100% of more than 10%. The impact on OARs was greatest to the liver (Fid-Bone= 14.6 vs. 16.1 Gy, 10%), and stomach, (Fid-Bone = 23.9 vx. 25.5 Gy, 7%), however was not statistically significant (p=0.10 both). Conclusion: Compared to matching by fiducial markers, matching by bony anatomy would have substantially reduced the PTV coverage by 13.5%. This reinforces the importance of online position verification based on fiducial markers. Hence, implantation of fiducial markers is strongly recommended for pancreatic cancer patients undergoing intensity modulated radiation therapy treatments.

  2. Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis

    PubMed Central

    Powell, Anne E.; Vlacich, Gregory; Zhao, Zhen-Yang; McKinley, Eliot T.; Washington, M. Kay; Manning, H. Charles

    2014-01-01

    Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1+) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1+ cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging. PMID:24833705

  3. GATA-4 and FOG-2 Expression in Pediatric Ovarian Sex Cord-Stromal Tumors Replicates Embryonal Gonadal Phenotype: Results from the TREP Project

    PubMed Central

    Virgone, Calogero; Cecchetto, Giovanni; Ferrari, Andrea; Bisogno, Gianni; Donofrio, Vittoria; Boldrini, Renata; Collini, Paola; Dall’Igna, Patrizia; Alaggio, Rita

    2012-01-01

    Aim GATA proteins are a family of zinc finger transcription factors regulating gene expression, differentiation and proliferation in various tissues. The expression of GATA-4 and FOG-2, one of its modulators, was studied in pediatric Sex Cord-Stromal tumors of the ovary, in order to evaluate their potential role as diagnostic markers and prognostic factors. Materials and Methods Clinical and histological data of 15 patients, enrolled into the TREP Project since 2000 were evaluated. When available, immunostaines for FOG-2, GATA-4, α-Inhibin, Vimentin and Pancytokeratin were also analyzed. Results In our series there were 6 Juvenile Granulosa Cell Tumors (JGCT), 6 Sertoli-Leydig Cell Tumors (SLCT), 1 Cellular Fibroma, 1 Theca Cell Tumor and 1 Stromal Sclerosing Tumor (SST). Thirteen patients obtained a complete remission (CR), 1 reached a second CR after the removal of a metachronous tumor and 1 died of disease. Inhibin was detectable in 11/15, Vimentin in 13/15, Pancytokeratin in 6/15, GATA-4 in 5/13 and FOG-2 in 11/15. FOG-2 was highly expressed in 5/6 JGCT, while GATA-4 was weakly detectable only in 1 of the cases. SLCT expressed diffusely FOG-2 (4/6) and GATA-4 (3/5). GATA-4 and FOG-2 were detected in fibroma and thecoma but not in the SST. Conclusions Pediatric granulosa tumors appear to express a FOG-2/GATA-4 phenotype in keeping with primordial ovarian follicles. High expression of GATA-4 does not correlate with aggressive behaviour as seen in adults, but it is probably involved in cell proliferation its absence can be associated with the better outcome of JGCT. SLCTs replicate the phenotype of Sertoli cells during embryogenesis in normal testis. In this group, the lack of expression of FOG-2 in tumors in advanced stages might reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway. In fibroma/thecoma group GATA-4 and FOG-2 point out the abnormal activation of GATA pathway and might be involved in the onset of these tumors. PMID:23029311

  4. Adrenocortical carcinoma

    MedlinePlus

    ... increased aldosterone are the same as symptoms of low potassium, and include: Muscle cramps Weakness ... will be high. Cortisol level will be high. Potassium level will be low. Male or female hormones may be abnormally high. ...

  5. Loss of tumor suppressor Merlin results in aberrant activation of Wnt/β-catenin signaling in cancer

    PubMed Central

    Meng, Erhong; Menezes, Mitchell E.; Bailey, Sarah K.; Metge, Brandon J.; Buchsbaum, Donald J.; Samant, Rajeev S.; Shevde, Lalita A.

    2016-01-01

    The expression of the tumor suppressor Merlin is compromised in nervous system malignancies due to genomic aberrations. We demonstrated for the first time, that in breast cancer, Merlin protein expression is lost due to proteasome-mediated elimination. Immunohistochemical analysis of tumor tissues from patients with metastatic breast cancer revealed characteristically reduced Merlin expression. Importantly, we identified a functional role for Merlin in impeding breast tumor xenograft growth and reducing invasive characteristics. We sought to determine a possible mechanism by which Merlin accomplishes this reduction in malignant activity. We observed that breast and pancreatic cancer cells with loss of Merlin show an aberrant increase in the activity of β-catenin concomitant with nuclear localization of β-catenin. We discovered that Merlin physically interacts with β-catenin, alters the sub-cellular localization of β-catenin, and significantly reduces the protein levels of β-catenin by targeting it for degradation through the upregulation of Axin1. Consequently, restoration of Merlin inhibited β-catenin-mediated transcriptional activity in breast and pancreatic cancer cells. We also present evidence that loss of Merlin sensitizes tumor cells to inhibition by compounds that target β-catenin-mediated activity. Thus, this study provides compelling evidence that Merlin reduces the malignant activity of pancreatic and breast cancer, in part by suppressing the Wnt/β-catenin pathway. Given the potent role of Wnt/β-catenin signaling in breast and pancreatic cancer and the flurry of activity to test β-catenin inhibitors in the clinic, our findings are opportune and provide evidence for Merlin in restraining aberrant activation of Wnt/β-catenin signaling. PMID:26908451

  6. Radiotherapy in Ewing tumors of the vertebrae: Treatment results and local relapse analysis of the Chess 81/86 and EICESS 92 trials

    SciTech Connect

    Schuck, Andreas . E-mail: schuck@uni-muenster.de; Ahrens, Susanne; Schorlemer, Ines von; Kuhlen, Michaela; Paulussen, Michael; Hunold, Andrea; Gosheger, Georg; Winkelmann, Winfried; Dunst, Juergen; Willich, Normann; Juergens, Heribert

    2005-12-01

    Purpose: Treatment results in patients with Ewing tumors of the vertebrae enrolled in the Cooperative Ewing's Sarcoma Study (CESS) 81, 86, and the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92 trials were analyzed with special emphasis on radiation-associated factors. Patients and Methods: A retrospective analysis was performed on 116 patients with primary tumors of the cervical, thoracic, or lumbar vertebrae treated between 1981 and 1999. Furthermore, a relapse analysis was done on those patients who underwent radiotherapy and subsequently had a local recurrence. Results: A total of 64.6% of the patients received definitive radiotherapy; 27.5% of patients had surgery and radiotherapy. Only 4 patients (3.4%) underwent definitive surgery. Twenty-seven patients presented with metastases at diagnosis. 22.4% of the total group developed a local relapse. Among the subgroup with definitive radiotherapy, local recurrence was seen in 17 of 75 patients (22.6%). Event-free survival and survival at 5 years were 47% and 58%, respectively. Of the 14 evaluable patients with a local relapse after radiotherapy, 13 were in-field. No correlation between radiation dose and local control could be found. Conclusion: Surgery with wide resection margins is rarely possible. The results after definitive radiotherapy in vertebral tumors are comparable to those of other tumor sites when definitive radiotherapy is given. Nearly all local relapses after radiotherapy are in-field.

  7. Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus

    PubMed Central

    Wood, Michelle A.; Acharya, Asha; Finco, Isabella; Swonger, Jessica M.; Elston, Marlee J.; Tallquist, Michelle D.; Hammer, Gary D.

    2013-01-01

    The lineage relationships of fetal adrenal cells and adrenal capsular cells to the differentiated adrenal cortex are not fully understood. Existing data support a role for each cell type as a progenitor for cells of the adult cortex. This report reveals that subsets of capsular cells are descendants of fetal adrenocortical cells that once expressed Nr5a1. These fetal adrenocortical cell descendants within the adrenal capsule express Gli1, a known marker of progenitors of steroidogenic adrenal cells. The capsule is also populated by cells that express Tcf21, a known inhibitor of Nr5a1 gene expression. We demonstrate that Tcf21-expressing cells give rise to Nr5a1-expressing cells but only before capsular formation. After the capsule has formed, capsular Tcf21-expressing cells give rise only to non-steroidogenic stromal adrenocortical cells, which also express collagen 1a1, desmin and platelet-derived growth factor (alpha polypeptide) but not Nr5a1. These observations integrate prior observations that define two separate origins of adult adrenocortical steroidogenic cells (fetal adrenal cortex and/or the adrenal capsule). Thus, these observations predict a unique temporal and/or spatial role of adult cortical cells that arise directly from either fetal cortical cells or from fetal cortex-derived capsular cells. Last, the data uncover the mechanism by which two populations of fetal cells (fetal cortex derived Gli1-expressing cells and mesenchymal Tcf21-expressing mesenchymal cells) participate in the establishment of the homeostatic capsular progenitor cell niche of the adult cortex. PMID:24131628

  8. Metabolic Tumor Volume as a Prognostic Imaging-Based Biomarker for Head and Neck Cancer—Pilot Results from RTOG 0522

    PubMed Central

    Schwartz, David L.; Harris, Jonathan; Yao, Min; Rosenthal, David I.; Opanowski, Adam; Levering, Anthony; (R)(CT)(MR), RT; Ang, K. Kian; Trotti, Andy M.; Garden, Adam S.; Jones, Christopher U.; Harari, Paul; Foote, Robert; Holland, John; Zhang, Qiang; Le, Quynh-Thu

    2014-01-01

    Purpose To evaluate candidate FDG-PET/CT imaging biomarkers for head and neck chemoradiotherapy outcomes in the cooperative group trial setting. Methods RTOG 0522 patients consenting to a secondary FDG-PET/CT sub-study were serially imaged at baseline and 8 weeks following radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1 cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes. Results Out of 940 patients entered onto RTOG 0522, 74 were analyzable for this sub-study. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse LRC (HR 4.01, 95% CI [1.28, 12.52], p = 0.02) and PFS (HR 2.34, 95% CI [1.02, 5.37], p = 0.05). Although MTV and T stage appeared to correlate (mean MTV 6.4, 13.2, 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for PFS in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited. Conclusion High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials. PMID:25752384

  9. Metabolic Tumor Volume as a Prognostic Imaging-Based Biomarker for Head-and-Neck Cancer: Pilot Results From Radiation Therapy Oncology Group Protocol 0522

    SciTech Connect

    Schwartz, David L.; Harris, Jonathan; Yao, Min; Rosenthal, David I.; Opanowski, Adam; Levering, Anthony; Ang, K. Kian; Trotti, Andy M.; Garden, Adam S.; Jones, Christopher U.; Harari, Paul; Foote, Robert; Holland, John; Zhang, Qiang; Le, Quynh-Thu

    2015-03-15

    Purpose: To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting. Methods and Materials: Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes. Results: Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited. Conclusion: High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

  10. The Adrenocortical Response of Greater Sage Grouse (Centrocercus urophasianus) to Capture, ACTH Injection, and Confinement, as Measured in Fecal Samples

    PubMed Central

    Jankowski, M. D.; Wittwer, D. J.; Heisey, D. M.; Franson, J. C.; Hofmeister, E. K.

    2009-01-01

    Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4°C for up to 16 h contained similar levels of ICM as those frozen (−20°C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. PMID:19199814

  11. The adrenocortical response of greater sage grouse (Centrocercus urophasianus) to capture, ACTH injection, and confinement, as measured in fecal samples

    USGS Publications Warehouse

    Jankowski, M.D.; Wittwer, D.J.; Heisey, D.M.; Franson, J.C.; Hofmeister, E.K.

    2009-01-01

    Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4??C for up to 16 h contained similar levels of ICM as those frozen (-20??C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. ?? 2009 by The University of Chicago. All rights reserved.

  12. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

    SciTech Connect

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Masuelli, Laura; Marchese, Rodolfo; Misiti, Silvia; De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo; Stigliano, Antonio

    2011-06-10

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  13. The adrenocortical response of greater sage grouse (Centrocercus urophasianus) to capture, ACTH injection, and confinement, as measured in fecal samples.

    PubMed

    Jankowski, M D; Wittwer, D J; Heisey, D M; Franson, J C; Hofmeister, E K

    2009-01-01

    Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assessments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4 degrees C for up to 16 h contained similar levels of ICM as those frozen (-20 degrees C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. PMID:19199814

  14. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.

    PubMed

    Zhang, Hong; Neely, Laura; Lundgren, Karen; Yang, Yong-Ching; Lough, Rachel; Timple, Noel; Burrows, Francis

    2010-03-01

    17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis. PMID:19676042

  15. Early perfusion changes in patients with recurrent high-grade brain tumor treated with Bevacizumab: preliminary results by a quantitative evaluation

    PubMed Central

    2012-01-01

    Background To determine whether early monitoring of the effects of bevacizumab in patients with recurrent high-grade gliomas, by a Perfusion Computed Tomography (PCT), may be a predictor of the response to treatment assessed through conventional MRI follow-up. Methods Sixteen patients were enrolled in the present study. For each patient, two PCT examinations, before and after the first dose of bevacizumab, were acquired. Areas of abnormal Cerebral Blood Volume (CBV) were manually defined on the CBV maps, using co-registered T1- weighted images, acquired before treatment, as a guide to the tumor location. Different perfusion metrics were derived from the histogram analysis of the normalized CBV (nCBV) maps; both hyper and hypo-perfused sub-volumes were quantified in the lesion, including tumor necrosis. A two-tailed Wilcoxon test was used to establish the significance of changes in the different perfusion metrics, observed at baseline and during treatment. The relationships between changes in perfusion and morphological MRI modifications at first follow-up were investigated. Results Significant reductions in mean and median nCBV were detected throughout the entire patient population, after only a single dose of bevacizumab. The nCBV histogram modifications indicated the normalization effect of bevacizumab on the tumor abnormal vasculature. An improvement in hypoxia after a single dose of bevacizumab was predictive of a greater reduction in T1-weighted contrast-enhanced volumes at first follow-up. Conclusions These preliminary results show that a quantification of changes in necrotic intra-tumoral regions could be proposed as a potential imaging biomarker of tumor response to anti-VEGF therapies. PMID:22494770

  16. Imaging Tumor Perfusion and Oxidative Metabolism in Patients With Head-and-Neck Cancer Using 1- [{sup 11}C]-Acetate PET During Radiotherapy: Preliminary Results

    SciTech Connect

    Sun Aijun; Johansson, Silvia; Turesson, Ingela; Dasu, Alexandru; Soerensen, Jens

    2012-02-01

    Background: A growing body of in vitro evidence links alterations of the intermediary metabolism in cancer to treatment outcome. This study aimed to characterize tumor oxidative metabolism and perfusion in vivo using dynamic positron emission tomography (PET) with 1- [{sup 11}C]-acetate (ACE) during radiotherapy. Methods and Materials: Nine patients with head-and-neck cancer were studied. Oxidative metabolic rate (k{sub mono}) and perfusion (rF) of the primary tumors were assessed by dynamic ACE-PET at baseline and after 15, 30, and 55 Gy was delivered. Tumor glucose uptake (Tglu) was evaluated with [{sup 18}F]-fluorodeoxyglucose PET at baseline. Patients were grouped into complete (CR, n = 6) and partial responders (PR, n = 3) to radiotherapy. Results: The 3 PR patients died within a median follow-up period of 33 months. Baseline k{sub mono} was almost twice as high in CR as in PR (p = 0.02) and Tglu was lower in CR than in PR (p = 0.04). k{sub mono} increased during radiotherapy in PR (p = 0.004) but remained unchanged in CR. There were no differences in rF between CR and PR at any dosage. k{sub mono} and rF were coupled in CR (p = 0.001), but not in PR. Conclusions: This study shows that radiosensitive tumors might rely predominantly on oxidative metabolism for their bioenergetic needs. The impairment of oxidative metabolism in radioresistant tumors is potentially reversible, suggesting that therapies targeting the intermediary metabolism might improve treatment outcome.

  17. Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines

    SciTech Connect

    Mill, Christopher P.; Gettinger, Kathleen L.; Riese, David J.

    2011-02-15

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. Indeed, it has been estimated that 37,000 Americans will die from this disease in 2010. Late diagnosis, chemoresistance, and radioresistance of these tumors are major reasons for poor patient outcome, spurring the search for pancreatic cancer early diagnostic and therapeutic targets. ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases (RTKs), a family that also includes the Epidermal Growth Factor Receptor (EGFR/ErbB1/HER1), Neu/ErbB2/HER2, and ErbB3/HER3. These RTKs play central roles in many human malignancies by regulating cell proliferation, survival, differentiation, invasiveness, motility, and apoptosis. In this report we demonstrate that human pancreatic tumor cell lines exhibit minimal ErbB4 expression; in contrast, these cell lines exhibit varied and in some cases abundant expression and basal tyrosine phosphorylation of EGFR, ErbB2, and ErbB3. Expression of a constitutively-dimerized and -active ErbB4 mutant inhibits clonogenic proliferation of CaPan-1, HPAC, MIA PaCa-2, and PANC-1 pancreatic tumor cell lines. In contrast, expression of wild-type ErbB4 in pancreatic tumor cell lines potentiates stimulation of anchorage-independent colony formation by the ErbB4 ligand Neuregulin 1{beta}. These results illustrate the multiple roles that ErbB4 may be playing in pancreatic tumorigenesis and tumor progression.

  18. Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: results from a single center over a 10 year period.

    PubMed

    Smith, Timothy R; Nanney, Allan D; Lall, Rishi R; Graham, Randall B; McClendon, Jamal; Lall, Rohan R; Adel, Joseph G; Zakarija, Anaadriana; Cote, David J; Chandler, James P

    2015-03-01

    Patients who undergo craniotomy for brain neoplasms have a high risk of developing venous thromboembolism (VTE), including deep vein thromboses (DVT) and pulmonary emboli (PE). The reasons for this correlation are not fully understood. This retrospective, single-center review aimed to determine the risk factors for VTE in patients who underwent neurosurgical resection of brain tumors at Northwestern University from 1999 to 2010. Our cohort included 1148 patients, 158 (13.7%) of whom were diagnosed with DVT and 38 (3.3%) of whom were diagnosed with PE. A variety of clinical factors were studied to determine predictors of VTE, including sex, ethnicity, medical co-morbidities, surgical positioning, length of hospital stay, tumor location, and tumor histology. Use of post-operative anticoagulants and hemorrhagic complications were also investigated. A prior history of VTE was found to be highly predictive of post-operative DVT (odds ratio [OR]=7.6, p=0.01), as was the patient's sex (OR=14.2, p<0.001), ethnicity (OR=0.5, p=0.04), post-operative intensive care unit days (OR=0.2, p=0.003), and tumor histology (OR=-0.16, p=0.01). Contrary to reports in the literature, the data collected did not indicate that the administration of post-operative medical prophylaxis for VTE was significant in preventing their formation (OR=-0.14, p=0.76). Hemorrhagic complications were low (2.2%) and resultant neurologic deficit was lower still (0.7%). The study indicates that patients with high-grade primary brain tumors and metastatic lesions should receive aggressive preventative measures in the post-operative period. PMID:25533212

  19. The effect of mitotane on viability, steroidogenesis and gene expression in NCI‑H295R adrenocortical cells.

    PubMed

    Lehmann, Tomasz P; Wrzesiński, Tomasz; Jagodziński, Paweł P

    2013-03-01

    Mitotane, also known as o,p'‑DDD or (RS)‑1‑chl-oro‑2‑[2,2‑dichloro‑1‑(4‑chlorophenyl)‑ethyl]‑benzene, is an adrenal cortex-specific cytotoxic drug used in the therapy of adrenocortical carcinoma (ACC). The drug also inhibits steroidogenesis, however, the mechanisms of its anticancer and antisteroidogenic effects remain unknown. At present, data on the impact of mitotane on cell viability and the regulation of genes encoding proteins associated with steroids synthesis in the adrenal cortex, including cortisol and dehydroepiandrosterone sulfate (DHEAS), are limited and contradictory. In the present study, the effect of 24‑h mitotane treatment on viability of the ACC cell line, NCI‑H295R, was analyzed, identifying a decrease in cell viability and an increase in caspase‑3 and ‑7 activities. Mitotane treatment also led to decreased cortisol and DHEAS concentration in the culture media. Concomitantly, mitotane resulted in decreased mRNA levels of two cytochromes P450 (CYP11A1 and CYP17A1), mRNAs encoding proteins involved in the synthesis of cortisol and DHEAS. Mitotane did not affect mRNA levels of cyclin dependent kinase inhibitor 1A (encoding p21) and MYC (encoding cMyc). cMyc and p21 are key transcription factors associated with cell cycle regulation. However, mitotane inhibited expression of transforming growth factor β1 gene, encoding a potent inhibitor of cell proliferation and steroidogenesis. PRKAR1A, a protein kinase A regulatory subunit, is involved in the activation of steroidogenesis. PRKAR1A mRNA levels were reduced following 24‑h treatment with mitotane. Results indicate that mitotane markedly inhibited expression of genes involved in steroidogenesis, secretion of cortisol and DHEAS. Reduced expression of TGFB1 cannot account fully for the effect of mitotane on CYP11A1 and CYP17A1. We hypothesized that reduced viability of NCI‑H295R cells in the presence of mitotane may be a result of apoptosis triggered by increased

  20. Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation

    SciTech Connect

    Greer, S.; Schwade, J.; Marion, H.S.

    1995-07-15

    The purpose of this investigation was to extend our findings in previous radiation and biochemical studies with five rodent tumors, in which we used one and occasionally two or three irradiations. The extent of control of the EMT-6 mammary adenocarcinoma was determined using fractionated radiation (12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2{prime}-deoxycytidine (CldC) and biomodulators of its metabolism. Drug and radiation treatments overlapped for 3 weeks. Fifty to 80% cures (usually 70%) were obtained with no apparent morbidity and the same moderate weight loss that occurs with radiation alone. An apparent threefold dose increase effect was obtained with the end point: {open_quotes}days to reach 4 times initial tumor volume.{close_quotes} Increasing the radiation dose threefold (without drugs) resulted in four out of five deaths; increasing the dose twofold (without drugs) resulted in extensive weight loss and hair loss in the entire ventral area and no cures. Increasing the dose of drugs or radiation 1.5-fold, in the complete protocol, did not result in increased morbidity. Comparative studies with Iododeoxyuridine demonstrate the heightened efficacy of CldC. One cannot achieve the same results obtained with CldC and the modulators by merely increasing the dose of radiation. There is a significant window of safety in this approach. The evidence we have obtained with EMT-6, the fifth rodent tumor we have studied with CldC, as well as the demonstrated and proposed reasons for its superior efficacy over 5-Iododeoxyuridine (and 5-Bromodeoxyuridine), drugs in current use, indicate that CldC will allow more aggressive treatment of human tumors with radiation than is now feasible. 50 refs., 2 figs., 4 tabs.

  1. Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells.

    PubMed

    Sbiera, Silviu; Leich, Ellen; Liebisch, Gerhard; Sbiera, Iuliu; Schirbel, Andreas; Wiemer, Laura; Matysik, Silke; Eckhardt, Carolin; Gardill, Felix; Gehl, Annemarie; Kendl, Sabine; Weigand, Isabel; Bala, Margarita; Ronchi, Cristina L; Deutschbein, Timo; Schmitz, Gerd; Rosenwald, Andreas; Allolio, Bruno; Fassnacht, Martin; Kroiss, Matthias

    2015-11-01

    Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer. PMID:26305886

  2. Non-invasive monitoring of adrenocortical activity in captive African Penguin (Spheniscus demersus) by measuring faecal glucocorticoid metabolites.

    PubMed

    Ozella, L; Anfossi, L; Di Nardo, F; Pessani, D

    2015-12-01

    Measurement of faecal glucocorticoid metabolites (FGMs) has become a useful and widely-accepted method for the non-invasive evaluation of stress in vertebrates. In this study we assessed the adrenocortical activity of five captive African Penguins (Spheniscus demersus) by means of FGM evaluation following a biological stressor, i.e. capture and immobilization. In addition, we detected individual differences in secretion of FGMs during a stage of the normal biological cycle of penguins, namely the breeding period, without any external or induced causes of stress. Our results showed that FGM concentrations peaked 5.5-8h after the induced stress in all birds, and significantly decreased within 30 h. As predictable, the highest peak of FGMs (6591 ng/g) was reached by the youngest penguin, which was at its first experience with the stressor. This peak was 1.8-2.7-fold higher compared to those of the other animals habituated to the stimulus. For the breeding period, our results revealed that the increase in FGMs compared to ordinary levels, and the peaks of FGMs, varied widely depending on the age and mainly on the reproductive state of the animal. The bird which showed the lowest peak (2518 ng/g) was an old male that was not in a reproductive state at the time of the study. Higher FGM increases and peaks were reached by the two birds which were brooding (male: 5552%, 96,631 ng/g; female: 1438%, 22,846 ng/g) and by the youngest bird (1582%, 39,700 ng/g). The impact of the reproductive state on FGM levels was unexpected compared to that produced by the induced stress. The EIA used in this study to measure FGM levels proved to be a reliable tool for assessing individual and biologically-relevant changes in FGM concentrations in African Penguin. Moreover, this method allowed detection of physiological stress during the breeding period, and identification of individual differences in relation to the reproductive status. The increase in FGM levels as a response to capture and

  3. The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity.

    PubMed

    Szalóki, Gábor; Krasznai, Zoárd T; Tóth, Ágnes; Vízkeleti, Laura; Szöllősi, Attila G; Trencsényi, György; Lajtos, Imre; Juhász, István; Krasznai, Zoltán; Márián, Teréz; Balázs, Margit; Szabó, Gábor; Goda, Katalin

    2014-01-01

    P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10-40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC). PMID:25238617

  4. [From the history of endocrinology: reminiscence of the discovery of adrenocortical hormones].

    PubMed

    Pura, M; Kreze, A

    2005-01-01

    In the article authors describe the milestones in history of discoveries of the adrenocortical hormones. Preparation of the adrenal extract cortine was the first experimental contribution. Cortine prolonged life of animals whose adrenals have been removed and had beneficial effects in patients with Addison disease (AD). It was mixture of compounds comprising carbon, hydrogen and oxygen that belong to the steroids. From those deoxycorticosterone had impact on mineral metabolism, substances that Kendall termed as compounds A, B, E, and F influenced metabolism of saccharides and proteins. In 1929 Dr. Hench had observed that the painful symptoms of rheumatoid arthritis (RA) were relieved in a patient who developed jaundice and in 1931 he remarked favourable effects of pregnancy to the course of RA. He suggested that some agent (substance X) was present during jaundice and in pregnancy through that the symptoms of RA were relieved. In 1941 interest concerned to the compound A, however, this was almost ineffective in patients with AD. In 1948 compound E was successfully administered to patients with AD and RA for the first time. Concerning the relation between vitamin E Kendall and Hench gave compound E distinctive name cortisone. Consequently it was confirmed that compound F (hydrocortisone) is the final product of the adrenal cortex. Appreciating the work of the most significant groups was awarding the Nobel Prize to Edward Kendall, Tadeusz Reichstein and Philip Hench in 1950. PMID:16193947

  5. The Social Buffering of the Hypothalamic-Pituitary-Adrenocortical Axis in Humans: Developmental and Experiential Determinants

    PubMed Central

    Gunnar, Megan R.; Hostinar, Camelia E.

    2015-01-01

    Social buffering, a subset of social support, is the process through which the availability of a conspecific reduces the activity of stress-mediating neurobiological systems. While its role in coping and resilience is significant, we know little about its developmental history in humans. This brief review presents an integrative developmental account of the social buffering of hypothalamic-pituitary-adrenocortical (HPA) stress reactivity in humans, from infancy to adulthood. During infancy, parents are powerful stress-regulators for children, but child temperament also plays a role and interacts with parenting quality to predict the magnitude of stress responses to fear or pain stimuli. Recent work indicates that parental support remains a potent stress buffer into late childhood, but that it loses its effectiveness as a buffer of the HPA axis by adolescence. Puberty may be the switch that alters the potency of parental buffering. In Beginning in middle childhood, friends may serve as stress buffers, particularly when other peers are the source of stress. By adulthood romantic partners assume this protective role, though studies often reveal sex differences that are currently not well understood. Translational research across species will be critical for developing a mechanistic understanding of social buffering and the processes involved in developmental changes noted in this review. PMID:26230646

  6. GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

    PubMed Central

    Zolea, Fabiana; Rizza, Pietro; Avena, Paola; Malivindi, Rocco; De Luca, Arianna; Campana, Carmela; Martire, Emilia; Domanico, Francesco; Fallo, Francesco; Carpinelli, Giulia; Cerquetti, Lidia; Amendola, Donatella; Stigliano, Antonio; Pezzi, Vincenzo

    2015-01-01

    We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC. PMID:26131713

  7. GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo.

    PubMed

    Chimento, Adele; Sirianni, Rosa; Casaburi, Ivan; Zolea, Fabiana; Rizza, Pietro; Avena, Paola; Malivindi, Rocco; De Luca, Arianna; Campana, Carmela; Martire, Emilia; Domanico, Francesco; Fallo, Francesco; Carpinelli, Giulia; Cerquetti, Lidia; Amendola, Donatella; Stigliano, Antonio; Pezzi, Vincenzo

    2015-08-01

    We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC. PMID:26131713

  8. A comparison between the equine and bovine hypothalamus-pituitary-adrenocortical axis.

    PubMed

    van der Kolk, J H; Fouché, N; Gross, J J; Gerber, V; Bruckmaier, R M

    2016-07-01

    In this review, we address the function of the hypothalamus-pituitary-adrenocortical (HPA) axis with special emphasis on the comparison between the bovine and equine species. The pars intermedia of the pituitary gland is particularly well developed in horses and cattle. However, its function is not well appreciated in cattle yet. The Wulzen's cone of the adenohypophysis is a special feature of ruminants. Total basal cortisol concentration is much higher in horses than that in cows with similar free cortisol fractions. Corticotropin-releasing factor (CRF) concentrations in equine pituitary venous blood are lower compared with other species, whereas plasma ACTH concentrations in cows are higher than those in horses. A CRF challenge test induced a more pronounced cortisol response in horses compared with cattle, whereas regarding ACTH challenge testing, the opposite seems true. Based on data from literature, the bovine species is characterized by relatively high basal blood CRF and ACTH and low cortisol and glucose concentrations. Obviously, further lowering of blood cortisol in cattle is easily prevented by the high sensitivity to ACTH, and as a consequence, subsequent increased gluconeogenesis prevents imminent hypoglycemia. Hypoglycemia is less likely in horses given their high muscle glycogen content and their relatively high cortisol concentration. When assessing HPA axis reactivity, response patterns to exogenous ACTH or CRH might be used as a reliable indicator of animal welfare status in cows and horses, respectively, although it is emphasized that considerable caution should be exercised in using measures of HPA activity solely to assess animal welfare. PMID:27345307

  9. Microwave tumor ablation: cooperative academic-industry development of a high-power gas-cooled system with early clinical results

    NASA Astrophysics Data System (ADS)

    Brace, Christopher L.; Ziemlewicz, Timothy J.; Schefelker, Rick; Hinshaw, J. L.; Lubner, Meghan G.; Lee, Fred T.

    2013-02-01

    Microwave tumor ablation continues to evolve into a viable treatment option for many cancers. Current systems are poised to supplant radiofrequency ablation as the dominant percutaneous thermal therapy. Here is provided an overview of technical details and early clinical results with a high-powered, gas-cooled microwave ablation system. The system was developed with academic-industry collaboration using federal and private funding. The generator comprises three synchronous channels that each produce up to 140W at 2.45GHz. A mountable power distribution module facilitates CT imaging guidance and monitoring and reduces clutter in the sterile field. Cryogenic carbon-dioxide cools the coaxial applicator, permitting a thin applicator profile (~1.5 mm diameter) and high power delivery. A total of 106 liver tumors were treated (96 malignant, 10 benign) from December 2010 to June 2012 at a single academic institution. Mean tumor size +/- standard deviation was 2.5+/-1.3cm (range 0.5-13.9cm). Treatment time was 5.4+/-3.3min (range 1-20min). Median follow-up was 6 months (range 1-16 months). Technical success was reported in 100% of cases. Local tumor progression was noted in 4/96 (4.3%) of malignancies. The only major complication was a pleural effusion that was treated with thoracentesis. Microwave ablation with this system is an effective treatment for liver cancer. Compared to previous data from the same institution, these results suggest an increased efficacy and equivalent safety to RF ablation. Additional data from the lung and kidney support this conclusion.

  10. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation

    PubMed Central

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

  11. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.

    PubMed

    Fokas, E; Prevo, R; Pollard, J R; Reaper, P M; Charlton, P A; Cornelissen, B; Vallis, K A; Hammond, E M; Olcina, M M; Gillies McKenna, W; Muschel, R J; Brunner, T B

    2012-01-01

    Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC. PMID:23222511

  12. Alternative splicing of Wilms tumor suppressor 1 (Wt1) exon 4 results in protein isoforms with different functions.

    PubMed

    Schnerwitzki, Danny; Perner, Birgit; Hoppe, Beate; Pietsch, Stefan; Mehringer, Rebecca; Hänel, Frank; Englert, Christoph

    2014-09-01

    The Wilms tumor suppressor gene Wt1 encodes a zinc finger transcription factor that is essential for development of multiple organs including kidneys, gonads, spleen and heart. In mammals Wt1 comprises 10 exons with two characteristic splicing events: inclusion or skipping of exon 5 and alternative usage of two splice donor sites between exons 9 and 10. Most fish including zebrafish and medaka possess two wt1 paralogs, wt1a and wt1b, both lacking exon 5. Here we have characterized wt1 in guppy, platyfish and the short-lived African killifish Nothobranchius furzeri. All fish except zebrafish show alternative splicing of exon 4 of wt1a but not of wt1b with the wt1a(-exon 4) isoform being the predominant splice variant. With regard to function, Wt1a(+exon 4) showed less dimerization but stimulated transcription more effectively than the Wt1a(-exon 4) isoform. A specific knockdown of wt1a exon 4 in zebrafish was associated with anomalies in kidney development demonstrating a physiological function for Wt1a exon 4. Interestingly, alternative splicing of exon 4 seems to be an early evolutionary event as it is observed in the single wt1 gene of the sturgeon, a species that has not gone through teleost-specific genome duplication. PMID:25014653

  13. Use of Contrast-Enhanced Ultrasound in the Differential Diagnosis of Adrenal Tumors in Dogs.

    PubMed

    Bargellini, Paolo; Orlandi, Riccardo; Dentini, Alfredo; Paloni, Chiara; Rubini, Giuseppe; Fonti, Paolo; Diana, Alessia; Peterson, Mark E; Boiti, Cristiano

    2016-01-01

    We evaluated the diagnostic accuracy of the contrast-enhanced ultrasonography (CEUS), using a second-generation microbubble contrast agent, in differentiating the different types of adrenal mass lesions in 24 dogs. At B-mode ultrasound, 9 lesions involved the right adrenal gland, 14 the left, and 1 was bilateral. Each dog received a bolus of the contrast agent into the cephalic vein, immediately followed by a 5-mL saline flush. The first contrast enhancement of each adrenal lesion was evaluated qualitatively to assess the degree of enhancement and its distribution during the wash-in and wash-out phases, as well as the presence of non-vascularized areas and specific vascular patterns. Pathological diagnoses were determined in all dogs by histopathology or by cytology. Combining enhancement degree and vascularity resulted in the best predictive model, allowing CEUS to differentiate adrenocortical adenoma (n=10), adenocarcinoma (n=7), and pheochromocytoma (n=7) with an accuracy of 91.7% (P < 0.001). Combining enhancement degree and vascularity, CEUS can discriminate malignant versus benign adrenal lesions with a sensitivity of 100.0%, a specificity of 80.0%, and an accuracy of 91.7% (P < 0.001). In conclusion, results of this study confirm that CEUS is useful for differentiating between the different types of adrenal tumors in dogs. PMID:27008325

  14. AB058. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Hu, Hailong; Tian, Dawei; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan-Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  15. Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

    PubMed Central

    Zhang, Yu; Xie, Linguo; Chen, Tao; Xie, Wanqin; Wu, Zhouliang; Xu, Hao; Xing, Chen; Sha, Nan; Shen, Zhonghua; Qie, Yunkai; Liu, Xiaoteng; Hu, Hailong; Wu, Changli

    2016-01-01

    Objective The management of stage 1 and grade 3 (T1G3) bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after TURBT (P<0.001). The progression rate was 10.6% for patients who underwent intravesical chemotherapy alone and 2.3% for patients who underwent the combined chemotherapies (P=0.003). Kaplan–Meier curves showed significant differences in recurrence-free survival and progression-free survival between the two treatment strategies, with a log-rank P-value of <0.001 and 0.003, respectively. Multivariable analyses revealed that intravenous chemotherapy was the independent prognostic factor for tumor recurrence and

  16. Diagnosis of adrenal tumors with radionuclide imaging

    SciTech Connect

    Beierwaltes, W.H.; Sisson, J.C.; Shapiro, B.

    1984-01-01

    The development of radiolabeled cholesterols in 1969 as precursors of adrenocortical steroid production allowed the first noninvasive imaging of the adrenal cortices. FDA-NDA approval in 1984 should allow routine use of these agents in most hospitals. NP-59 is most commonly used in the diagnosis and management of Cushing syndrome; the second most common use is in the diagnosis of primary aldosteronism. It is also helpful in the differential diagnosis of adrenal and ovarian hyperandrogenism and hirsutism, and is the only noninvasive method of detecting unilateral adrenocortical hypofunction. The newest and most popular use is in the differential diagnosis of asymptomatic masses in the region of the adrenal gland discovered incidentally with CT scan (incidentalomas). In this situation, the NP-59 scan can define whether the tumor is in the adrenal gland and if it is functional or nonfunctional. The authors believe that, in the future, radiolabeled enzyme inhibitors might offer better diagnostic imaging of the adrenal cortex, although these agents will probably not be available for routine use for some time. The development of a radioiodinated guanethidine analog, /sup 131/I-MIBG, has allowed differentiation of normal adrenal medullary function from bilateral adrenal medullary hyperplasia before the development of hypertension or tachycardia, diagnostic increases in plasma or urinary catecholamines, or abnormal CT scans. The search for a pheochromocytoma should begin with /sup 131/I-MIBG scintigraphy. While over 90% of primary pheochromocytomas occur in the abdomen, neither a survey of the abdomen nor the finding of a single tumor should conclude the search.

  17. Results.

    ERIC Educational Resources Information Center

    Zemsky, Robert; Shaman, Susan; Shapiro, Daniel B.

    2001-01-01

    Describes the Collegiate Results Instrument (CRI), which measures a range of collegiate outcomes for alumni 6 years after graduation. The CRI was designed to target alumni from institutions across market segments and assess their values, abilities, work skills, occupations, and pursuit of lifelong learning. (EV)

  18. Production of platelet-activating factor is a component of the angiotensin II-protein kinase C activation pathway in bovine adrenocortical cells.

    PubMed

    Pelosin, J M; Keramidas, M; Chambaz, E M

    1991-08-15

    Lyso-platelet-activating factor (lyso-PAF): acetyl-CoA acetyltransferase (EC 2.3.1.67) enzyme activity was characterized for the first time in bovine adrenocortical tissue. It was found to be associated with the microsomal membrane fraction, in which it exhibited a specific activity of 0.4 nmol/min per mg of protein and catalytic properties similar to those described in other cell types. The adrenocortical acetyltransferase activity was increased by 2-3-fold on incubation of the preparation with purified protein kinase C (PKC) under phosphorylating condition. This activation was optimal after 5 min of incubation and paralleled an increase in PKC-catalysed 32P incorporation into microsomal proteins. Both acetyltransferase activation and protein phosphorylation were dependent on the presence of Ca2+ and phospholipids, and were blocked in the presence of the potent PKC inhibitor H-7. In the intact adrenocortical cell, angiotensin II and a potent phorbol ester (phorbol 12-myristate 13-acetate) were able to rapidly induce an increase in the biosynthesis of PAF, which was mostly released into the extracellular medium. These data suggest that bovine adrenocortical lyso-PAF acetyltransferase may be regulated by a PKC-dependent activation pathway, whereas no evidence for an additional adrenocorticotropin/cyclic AMP-dependent stimulation process was obtained in this cell type. Bovine adrenocortical cell membrane preparations were shown to possess high-affinity PAF-binding sites (Kd approximately 0.5 nM). Altogether, these observations suggest that PAF production and release may play a role in the autocrine or paracrine control of adrenocortical cell activation. PMID:1883337

  19. Development of a single vial kit formulation of [99mTc]-labeled doxorubicin for tumor imaging and treatment response assessment-preclinical evaluation and preliminary human results.

    PubMed

    Kumar, Pardeep; Singh, Baljinder; Ghai, Anchal; Hazari, Puja P; Mittal, B R; Mishra, Anil K

    2015-05-30

    The present study describes the successful radiolabeling of [99mTcO(-) 4 ] with doxorubicin, and the resultant product was formulated in to a ready-to-label lyophilized single vial kit preparation for convenient use in a routine clinical setting. The radiolabeled preparation of [99mTc]-doxorubicin exhibited a high radiolabeling efficiency of more than 95.0%, serum stability for up to 24 h, and shelf-life of lyophilized cold kits was more than 6 months. Animal imaging data in tumor-bearing mice demonstrated that [99mTc]-doxorubicin accumulated in the tumor site with high target (tumor) to non-target (contra-lateral thigh) ratio (3.2 ± 0.5). The ratio decreased to 1.2 ± 0.6 indicating a good response on follow up imaging performed after 2 weeks of doxorubicin treatment. [99mTc]-doxorubicin scintigraphic data in human volunteers supported the hepato-renal excretion of the radiotracer as reflected by the increased accumulation of the radiotracer as a function of time in intestine, kidneys, and urinary bladder. Further, imaging in patients (very limited number) indicated that the technique may be useful in the detection of active sarcoma and post treatment (surgery/chemotherapy) remission or absence of the disease. The technique, however, needs validation through further preclinical evaluation and imaging in a larger number of patients. PMID:25968484

  20. Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial

    PubMed Central

    Schneider, Bryan P.; Gray, Robert J.; Radovich, Milan; Shen, Fei; Vance, Gail; Li, Lang; Jiang, Guanglong; Miller, Kathy D.; Gralow, Julie R.; Dickler, Maura N.; Cobleigh, Melody A.; Perez, Edith A.; Shenkier, Tamara N.; Nielsen, Kirsten Vang; Müller, Sven; Thor, Ann; Sledge, George W.; Sparano, Joseph A.; Davidson, Nancy E.; Badve, Sunil S.

    2013-01-01

    Purpose Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. Patients and Methods E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed. Results ER+ or PR+ tumors were less likely to have VEGFA amplification compared with ER/PR-tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. Conclusion VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab. PMID:23340303

  1. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction.

    PubMed

    Uherek, Christoph; Tonn, Torsten; Uherek, Barbara; Becker, Sven; Schnierle, Barbara; Klingemann, Hans-Georg; Wels, Winfried

    2002-08-15

    The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 zeta chain. Transduced NK-92-scFv(FRP5)-zeta cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-zeta cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-zeta cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies. PMID:12149207

  2. Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor (GIST): ACOSOG Z9000 (Alliance) intergroup phase 2 trial

    PubMed Central

    DeMatteo, Ronald P.; Ballman, Karla V.; Antonescu, Cristina R.; Corless, Christopher; Kolesnikova, Violetta; von Mehren, Margaret; McCarter, Martin D.; Norton, Jeffrey; Maki, Robert G.; Pisters, Peter W.T.; Demetri, George D.; Brennan, Murray F.; Owzar, Kouros

    2014-01-01

    Objective To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). Summary Background Data GIST is the most common sarcoma. While surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT proto-oncogene or, less frequently, platelet-derived growth factor receptor alpha (PDGFRA) is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. Methods This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group (ACOSOG), registered at ClinicalTrials.gov as NCT00025246. From 09/2001 to 09/2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg/day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). Results After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rate was 99, 97, and 83%, which compared favorably with a historical 5 year OS rate of 35%. The 1-, 3-, and 5-year RFS rate was 96, 60, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. Conclusion Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared to that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246) PMID:23860199

  3. Assessment of adrenocortical activity and behavior of the collared anteater (Tamandua tetradactyla) in response to food-based environmental enrichment.

    PubMed

    Eguizábal, Gabina V; Palme, Rupert; Villarreal, Daniel; Dal Borgo, Carla; Di Rienzo, Julio A; Busso, Juan M

    2013-01-01

    One of the current standard approaches to the study of animal welfare is measuring hypothalamic-pituitary-adrenal activity, frequently in association with behavioral assessment. We studied the effects of food-based environmental enrichment on adrenocortical activity and behavior in zoo-housed collared anteaters (Tamandua tetradactyla; n = 5). We successfully validated measurements of fecal cortisol metabolites (FCMs) using an 11-oxoetiocholanolone enzyme immunoassay by stimulating (ACTH injection) and suppressing (dexamethasone administration) adrenocortical activity. Three months later, we subjected animals to an ABA-type experiment (three 6-week periods): pre-enrichment (routine diet: A), enrichment (modified diet: B), and post-enrichment (routine diet: A) periods. We assessed adrenocortical activity by collecting individual feces three times a week (total number of samples: 228), and evaluated behavior by performing 3 days of behavioral observations per period (with a total of 3,600 behavioral data points for the individuals studied). Statistical analysis revealed changes in FCM concentrations (µg/g) over the periods (3.04 ± 0.68, 2.98 ± 0.66, and 4.04 ± 0.90, respectively). Additionally, it showed that the number of FCM peaks was highly reduced during enrichment; meanwhile active natural behaviors were significantly increased. We consider that these changes in response to food-based environmental enrichment improved the welfare of individual zoo-housed collared anteaters. This research might contribute to in situ and ex situ studies on the physiology and behavior of this endemic South American species. PMID:24307059

  4. Adrenocortical response in rats subjected to a stress of restraint by immobilization whether accompanied by hypothermia or not

    NASA Technical Reports Server (NTRS)

    Buchel, L.; Prioux-Guyonneau, M.; Libian, L.

    1980-01-01

    The restraint associated with hypothermia which increases the adrenal activity in rats was investigated. In rats with nomothermia or light hypothermia, the plasma and adrenal corticosterone levels increase at least threefold whatever the duration of restraint. Their return to normal values depends on the duration of the restraint. Exposure to cold produces in free rats a light hypothermia with an increase of the plasma and adrenal corticosterone levels, and in restraint animals an important hypothermia which does not potentiate the stimulation of adrenocortical activity induced by the restraint alone.

  5. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

    PubMed

    Schijns, Virgil E J C; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence M; Chen, Thomas C; Mespouille, Pascal; Hantos, Peter; Glorieux, Philippe; Bota, Daniela A; Stathopoulos, Apostolos

    2015-05-28

    Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330). PMID:25865468

  6. Whole-Body MR Imaging for Staging of Malignant Tumors in Pediatric Patients: Results of the American College of Radiology Imaging Network 6660 Trial

    PubMed Central

    Acharyya, Suddhasatta; Hoffer, Frederic A.; Wyly, J. Brad; Friedmann, Alison M.; Snyder, Bradley S.; Babyn, Paul S.; Khanna, Geetika; Siegel, Barry A.

    2013-01-01

    Purpose: To compare whole-body magnetic resonance (MR) imaging with conventional imaging for detection of distant metastases in pediatric patients with common malignant tumors. Materials and Methods: This institutional review board–approved, HIPAA-compliant, multicenter prospective cohort study included 188 patients (109 male, 79 female; mean age, 10.2 years; range, < 1 to 21 years) with newly diagnosed lymphoma, neuroblastoma, or soft-tissue sarcoma. Informed consent was obtained and all patients underwent noncontrast material–enhanced whole-body MR imaging and standard-practice conventional imaging. All images were reviewed centrally by 10 pairs of readers. An independent panel verified the presence or absence of distant metastases. Detection of metastasis with whole-body MR and conventional imaging was quantified by using the area under the receiver operating characteristic curve (AUC). The effects of tumor subtype, patient age, and distant skeletal and pulmonary disease on diagnostic accuracy were also analyzed. Results: Of the 134 eligible patients, 66 (33 positive and 33 negative for metastasis) were selected for image review and analysis. Whole-body MR imaging did not meet the noninferiority criterion for accuracy when compared with conventional imaging for detection of metastasis (difference between average AUCs was −0.03 [95% confidence interval: −0.10, 0.04]); however, the average AUC for solid tumors was significantly higher than that for lymphomas (P = .006). More skeletal metastases were detected by using whole-body MR imaging than by using conventional imaging (P = .03), but fewer lung metastases were detected (P < .001). Patient age did not affect accuracy. Conclusion: The noninferior accuracy for diagnosis of distant metastasis in patients with common pediatric tumors was not established for the use of whole-body MR imaging compared with conventional methods. However, improved accuracy was seen with whole-body MR imaging in patients with

  7. Sinus Tumors

    MedlinePlus

    ... Tumors Nasal Deformities Choanal Atresia Epiphora (Excessive Tearing) Disclosure Statement Printer Friendly Sinus Tumors Abtin Tabaee, MD Introduction Tumors of the nose and paranasal sinuses are rare, accounting for fewer than 1% of all tumors. These ...

  8. Bone tumor

    MedlinePlus

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  9. Differential regulation of glucocorticoid synthesis in murine intestinal epithelial versus adrenocortical cell lines.

    PubMed

    Mueller, Matthias; Atanasov, Atanas; Cima, Igor; Corazza, Nadia; Schoonjans, Kristina; Brunner, Thomas

    2007-03-01

    Glucocorticoids are steroid hormones with important functions in development, immune regulation, and glucose metabolism. The adrenal glands are the predominant source of glucocorticoids; however, there is increasing evidence for extraadrenal glucocorticoid synthesis in thymus, brain, skin, and vascular endothelium. We recently identified intestinal epithelial cells as an important source of glucocorticoids, which regulate the activation of local intestinal immune cells. The molecular regulation of intestinal glucocorticoid synthesis is currently unexplored. In this study we investigated the transcriptional regulation of the steroidogenic enzymes P450 side-chain cleavage enzyme and 11beta-hydroxylase, and the production of corticosterone in the murine intestinal epithelial cell line mICcl2 and compared it with that in the adrenocortical cell line Y1. Surprisingly, we observed a reciprocal stimulation pattern in these two cell lines. Elevation of intracellular cAMP induced the expression of steroidogenic enzymes in Y1 cells, whereas it inhibited steroidogenesis in mICcl2 cells. In contrast, phorbol ester induced steroidogenic enzymes in intestinal epithelial cells, which was synergistically enhanced upon transfection of cells with the nuclear receptors steroidogenic factor-1 (NR5A1) and liver receptor homolog-1 (NR5A2). Finally, we observed that basal and liver receptor homolog-1/phorbol ester-induced expression of steroidogenic enzymes in mICcl2 cells was inhibited by the antagonistic nuclear receptor small heterodimer partner. We conclude that the molecular basis of glucocorticoid synthesis in intestinal epithelial cells is distinct from that in adrenal cells, most likely representing an adaptation to the local environment and different requirements. PMID:17170096

  10. Loner or socializer? Ravens' adrenocortical response to individual separation depends on social integration.

    PubMed

    Stocker, Martina; Munteanu, Alexandru; Stöwe, Mareike; Schwab, Christine; Palme, Rupert; Bugnyar, Thomas

    2016-02-01

    Non-breeding common ravens (Corvus corax) live in complex social groups with a high degree of fission-fusion dynamics. They form valuable relationships and alliances with some conspecifics, while taking coordinated action against others. In ravens, affiliates reconcile their conflicts, console each other after conflicts with a third party, and provide each other with social support - all behaviors that presumably reduce corticosterone levels and alleviate stress. However, how well an individual is socially integrated in a (sub)group might vary substantially. This raises the question whether the social integration of a raven affects its stress responses to fission-fusion dynamics. The present study aims to investigate this effect experimentally by separating single ravens (n=16) individually from their group for four days and subsequently reintroducing them. To determine stress response patterns in the separated individuals we measured the amounts of immunoreactive corticosterone metabolites (CM) in droppings. We compared two enzyme immunoassays, which we validated by conducting an ACTH challenge, and finally decided to apply an 11-oxoetiocholanolone enzyme immunoassay. Additionally, we determined levels of social integration using focal observations. Our findings suggest that a strong social integration is related to low CM levels when the individuals are within the group and high levels during separations, implying that separation leads to stress in these birds. In contrast, poorly socially integrated ravens seem to exhibit the opposite pattern, indicating that to them group living is more stressful than being temporarily separated. We, therefore, conclude that the birds' adrenocortical activity is modulated by their social integration. PMID:26631484

  11. Minireview: Hair Cortisol: A Novel Biomarker of Hypothalamic-Pituitary-Adrenocortical Activity

    PubMed Central

    Novak, Melinda A.

    2012-01-01

    Activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is commonly assessed by measuring glucocorticoids such as cortisol (CORT). For many years, CORT was obtained primarily from blood plasma or urine, whereas later approaches added saliva and feces for noninvasive monitoring of HPA functioning. Despite the value of all these sample matrices for answering many research questions, they remain limited in the temporal range of assessment. Plasma and saliva are point samples that vary as a function of circadian rhythmicity and are susceptible to confounding by environmental disturbances. Even urine and feces generally assess HPA activity over a period of only 24 h or less. We and others have recently developed and validated methods for measuring the concentration of CORT in the body hair of animals (e.g. rhesus monkeys) and scalp hair of humans. CORT is constantly deposited in the growing hair shaft, as a consequence of which such deposition can serve as a biomarker of integrated HPA activity over weeks and months instead of minutes or hours. Since the advent of this methodological advance, hair CORT has already been used as an index of chronic HPA activity and stress in human clinical and nonclinical populations, in a variety of laboratory-housed and wild-living animal species, and in archival specimens that are many decades or even centuries old. Moreover, because human hair is known to grow at an average rate of about 1 cm/month, several studies suggest that CORT levels in hair segments that differ in proximity to the scalp can, under certain conditions, be used as a retrospective calendar of HPA activity during specific time periods preceding sample collection. PMID:22778226

  12. Cloacal gland, endocrine testicular, and adrenocortical photoresponsiveness in male Japanese quail exposed to short days.

    PubMed

    Busso, J M; Dominchin, M F; Marin, R H; Palme, R

    2013-04-01

    Photoperiod is the most important "noise-free" seasonal environmental cue for synchronizing physiological states (such as reproductive activity) in birds. However, in photoperiodic birds such as Japanese quail, the effect of photoperiod on adrenocortical activity remains unclear, particularly in males with differences in cloacal gland photoresponsiveness. At 8 wk of age, birds (n = 55) were either assigned to a short photoperiod (8L:16D; SD) or maintained under long photoperiod (16L:8D; LD; control). After 5 wk of SD exposure, males were classified as nonresponsive (SD-NR; with foam production) or responsive (SD-R; with no foam production) to short days, depending on the cloacal gland volume was above or below 1,000 mm(3). At 14 wk of age, droppings were collected during 3 consecutive days to determine corticosterone (CMs) and androgen metabolites (AMs) by enzyme immunoassays. Male Japanese quail under LD showed significantly higher concentrations of CMs (300 ± 10 ng/g) and AMs (1,257 ± 115 ng/g) than birds kept under SD. Under short days, SD-NR and SD-R showed differences (P < 0.0001), both in CM (153 ± 8 ng/g and 98 ± 6 ng/g, respectively) and AM concentrations (1,294 ± 309 ng/g and 275 ± 53 ng/g, respectively). Interestingly, although SD-NR males exhibited no cloacal gland arrest (according to cloacal gland volume and foam production) and similar testicular activity (AM values) to LD males, they showed lower concentrations of CMs compared with males that remained on LD (P < 0.05). Our findings suggest length of photoperiod affected hypothalamic-pituitary-adrenal activity; however, that was not the only factor involved, because birds subjected to shorter days but whose hypothalamic-pituitary-gonadal axis failed to respond had intermediate CM values. Further research is required to elucidate the underlying mechanisms of this interesting finding. PMID:23411012

  13. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

    PubMed

    Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial. PMID:15299189

  14. Loner or socializer? Ravens’ adrenocortical response to individual separation depends on social integration

    PubMed Central

    Stocker, Martina; Munteanu, Alexandru; Stöwe, Mareike; Schwab, Christine; Palme, Rupert; Bugnyar, Thomas

    2016-01-01

    Non-breeding common ravens (Corvus corax) live in complex social groups with a high degree of fission–fusion dynamics. They form valuable relationships and alliances with some conspecifics, while taking coordinated action against others. In ravens, affiliates reconcile their conflicts, console each other after conflicts with a third party, and provide each other with social support — all behaviors that presumably reduce corticosterone levels and alleviate stress. However, how well an individual is socially integrated in a (sub)group might vary substantially. This raises the question whether the social integration of a raven affects its stress responses to fission–fusion dynamics. The present study aims to investigate this effect experimentally by separating single ravens (n = 16) individually from their group for four days and subsequently reintroducing them. To determine stress response patterns in the separated individuals we measured the amounts of immunoreactive corticosterone metabolites (CM) in droppings. We compared two enzyme immunoassays, which we validated by conducting an ACTH challenge, and finally decided to apply an 11-oxoetiocholanolone enzyme immunoassay. Additionally, we determined levels of social integration using focal observations. Our findings suggest that a strong social integration is related to low CM levels when the individuals are within the group and high levels during separations, implying that separation leads to stress in these birds. In contrast, poorly socially integrated ravens seem to exhibit the opposite pattern, indicating that to them group living is more stressful than being temporarily separated. We, therefore, conclude that the birds’ adrenocortical activity is modulated by their social integration. PMID:26631484

  15. [Craniosinusonasal tumors].

    PubMed

    Blagoveshchenskaia, N S; Egorova, V K

    1997-01-01

    Tumors extending into the nasal cavity, cranium, and paranasal sinuses have a number of distinctive features to take into consideration. Among them are the communication with an open air, high incidence of associated intracranial infections, specific complications (i.e. suppurative sinusitis, polyps, mucocele, pneumocephalus, nasal CSF leak). The features mentioned make these lesions unique. 50 consecutive patients underwent treatment in Burdenko Neurosurgical Institute. The diagnosis was confirmed either by CT, MRI, or at operation. Rhinological and otoneurological signs were also subjected to analysis. Most frequently these tumors (the majority of which were meningiomas (n = 34) extended into the nasal cavity (40 patients) and paranasal sinuses (n = 50). It was noted that the clinical signs vary depending on the histological type of tumor, its location and direction of growth (i.e. medial or lateral). Medially growing tumors usually involved 2-4 sinuses, while laterally growing tumors involved only one sinus. Among the symptoms, disturbances of smell, conductive hearing impairment, deformation of both the soft and hard palate, slowing of the experimental nystagmus due to disturbed extraocular movements. Some light is shed on the differential diagnosis, indications for various surgical approaches (transcranial, transnasal, and facial). The results of surgical treatment and postoperative complications are presented in the paper. The diagnosis and treatment of such patients require an interdisciplinary approach while would involve a team of a neurosurgeon, neuroradiologist, otoneurologist, and a neuro-ophthalmologist. PMID:9424946

  16. Atypical teratoid rhabdoid tumors: a population-based clinical outcomes study involving 174 patients from the Surveillance, Epidemiology, and End Results database (1973–2010)

    PubMed Central

    Lau, Christine SM; Mahendraraj, Krishnaraj; Chamberlain, Ronald S

    2015-01-01

    Introduction Atypical teratoid rhabdoid tumors (ATRTs) are rare, highly malignant embryonal tumors of the central nervous system (CNS) accounting for 20% of CNS tumors in children under the age of 3. This study examines a large cohort of ATRT patients to determine demographic, clinical, and pathologic factors which impact prognosis and survival. Methods Demographic and clinical data were abstracted on 174 ATRT patients (171 pediatric patients age <20 and 3 adult patients age ≥20) from the Surveillance, Epidemiology, and End Results database (1973–2010). Standard statistical methodology was used. Results A total of 174 ATRT cases (mean age of 2.84 years) were identified. ATRT had a higher incidence in males (56.3%), Caucasians (59.1%), and children <3 years of age (80.5%), P<0.001. The most common primary sites were the cerebellum (17.8%), ventricles (16.1%), and frontal lobe (12.6%). Mean overall survival was 3.2±0.4 years, while overall and cancer-specific mortality were 63.2% and 56.3%, respectively, P=0.005. Most ATRT cases were treated with surgery alone (58.0%), followed by a combination of surgery and radiation (34.3%), no treatment (6.5%), and radiation alone (1.2%). The use of combination therapy has increased significantly (16.1%) since 2005 (P<0.001), while primary surgical resection and radiation therapy rates remain relatively unchanged. The longest survival was observed among ATRT patients receiving combination therapy (5.9±0.7 years), followed by radiation alone (2.8±1.2 years), and surgery alone (1.9±0.4 years), P<0.001. Multivariable analysis identified only distant metastases (OR =4.6) as independently associated with increased mortality, whereas combination therapy (OR =0.4) was associated with reduced mortality, P<0.005. Conclusion ATRT is a rare and highly aggressive embryonal malignancy of the CNS that presents more often as locoregional tumors >4 cm in male Caucasian children of age <3 years, involving the cerebellum, ventricles, or

  17. [Thymic tumors].

    PubMed

    Le Péchoux, C; Mahé, M; Bretel, J-J; Roberti, E; Ruffié, P

    2005-11-01

    Thymomas and thymic carcinomas are rare and slow-growing tumors, which develop within the anterior mediastinum. Thymomas are often associated with autoimmune disorders and most particularly myasthenia gravis. The treatment of choice remains a complete surgical resection. Postoperative radiotherapy is often combined in case of invasive thymoma invading into adjacent organs. Postoperative radiotherapy in stage II with invasion into capsule has been more controversial lately. In inoperable locally advanced, or metastatic thymic tumors, neoadjuvant cisplatin-based followed by surgery and radiotherapy has given interesting results in the past years. PMID:16168694

  18. PROFILING GENE EXPRESSION IN HUMAN H295R ADRENOCORTICAL CARCINOMA CELLS AND RAT TESTES TO IDENTIFY PATHWAYS OF TOXICITY FOR CONAZOLE FUNGICIDES

    EPA Science Inventory

    Profiling Gene Expression in Human H295R Adrenocortical Carcinoma Cells and Rat Testes to Identify Pathways of Toxicity for Conazole Fungicides
    Ren1, H., Schmid1, J., Retief2, J., Turpaz2, Y.,Zhang3, X.,Jones3, P., Newsted3, J.,Giesy3, J., Wolf1, D.,Wood1, C., Bao1, W., Dix1, ...

  19. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

    ERIC Educational Resources Information Center

    Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which…

  20. Quantitative Sodium MR Imaging at 7 T: Initial Results and Comparison with Diffusion-weighted Imaging in Patients with Breast Tumors.

    PubMed

    Zaric, Olgica; Pinker, Katja; Zbyn, Stefan; Strasser, Bernhard; Robinson, Simon; Minarikova, Lenka; Gruber, Stephan; Farr, Alex; Singer, Christian; Helbich, Thomas H; Trattnig, Siegfried; Bogner, Wolfgang

    2016-07-01

    Purpose To investigate the clinical feasibility of a quantitative sodium 23 ((23)Na) magnetic resonance (MR) imaging protocol developed for breast tumor assessment and to compare it with 7-T diffusion-weighted imaging (DWI). Materials and Methods Written informed consent in this institutional review board-approved study was obtained from eight healthy volunteers and 17 patients with 20 breast tumors (five benign, 15 malignant). To achieve the best image quality and reproducibility, the (23)Na sequence was optimized and tested on phantoms and healthy volunteers. For in vivo quantification of absolute tissue sodium concentration (TSC), an external phantom was used. Static magnetic field, or B0, and combined transmit and receive radiofrequency field, or B1, maps were acquired, and image quality, measurement reproducibility, and accuracy testing were performed. Bilateral (23)Na and DWI sequences were performed before contrast material-enhanced MR imaging in patients with breast tumors. TSC and apparent diffusion coefficient (ADC) were calculated and correlated for healthy glandular tissue and benign and malignant lesions. Results The (23)Na MR imaging protocol is feasible, with 1.5-mm in-plane resolution and 16-minute imaging time. Good image quality was achieved, with high reproducibility (mean TSC values ± standard deviation for the test, 36 mmol per kilogram of wet weight ± 2 [range, 34-37 mmol/kg]; for the retest, 37 mmol/kg ± 1 [range, 35-39 mmol/kg]; P = .610) and accuracy (r = 0.998, P < .001). TSC values in normal glandular and adipose breast tissue were 35 mmol/kg ± 3 and 18 mmol/kg ± 3, respectively. In malignant lesions (mean size, 31 mm ± 24; range, 6-92 mm), the TSC of 69 mmol/kg ± 10 was, on average, 49% higher than that in benign lesions (mean size, 14 mm ± 12; range, 6-35 mm), with a TSC of 47 mmol/kg ± 8 (P = .002). There were similar ADC differences between benign ([1.78 ± 0.23] × 10(-3) mm(2)/sec) and malignant ([1.03 ± 0.23] × 10(-3) mm

  1. Protein kinase A alterations in endocrine tumors.

    PubMed

    Yu, B; Ragazzon, B; Rizk-Rabin, M; Bertherat, J

    2012-09-01

    Various molecular and cellular alterations of the cyclic adenosine monophosphate (cAMP) pathway have been observed in endocrine tumors. Since protein kinase A (PKA) is a central key component of the cAMP pathway, studies of the alterations of PKA subunits in endocrine tumors reveal new aspects of the mechanisms of cAMP pathway alterations in human diseases. So far, most alterations have been observed for the regulatory subunits, mainly PRKAR1A and to a lower extent, PRKAR2B. One of the best examples of such alteration today is the multiple neoplasia syndrome Carney complex (CNC). The most common endocrine gland manifestations of CNC are pituitary GH-secreting adenomas, thyroid tumors, testicular tumors, and ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) are observed in about two-third of CNC patients, and also in patients with isolated PPNAD. PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic endocrine tumors. More than 120 different PRKAR1A mutations have been found today. Most of them lead to an unstable mutant mRNA, which will be degraded by nonsense mediated mRNA decay. In vitro and in vivo functional studies are in progress to understand the mechanisms of endocrine tumor development due to PKA regulatory subunits inactivation. PRKAR1A mutations stimulate in most models PKA activity, mimicking in some way cAMP pathway constitutive activation. Cross-talks with other signaling pathways summarized in this review have been described and might participate in endocrine tumorigenesis. PMID:22752956

  2. The S229L Colon Tumor-associated Variant of DNA Polymerase β Induces Cellular Transformation as a Result of Decreased Polymerization Efficiency*

    PubMed Central

    Nemec, Antonia A.; Murphy, Drew L.; Donigan, Katherine A.; Sweasy, Joann B.

    2014-01-01

    DNA polymerase β (Pol β) plays a key role in base excision repair (BER) by filling in small gaps that are generated after base adducts are excised from the DNA. Pol β is mutated in a large number of colorectal tumors, and these mutations may drive carcinogenesis. In the present study, we wished to determine whether the S229L somatic Pol β variant identified in a stage 3 colorectal tumor is a driver of carcinogenesis. We show that S229L does not possess any defects in binding to either DNA or nucleotides compared with the WT enzyme, but exhibits a significant loss of polymerization efficiency, largely due to an 8-fold decrease in the polymerization rate. S229L participates in BER, but due to its lower catalytic rate, does so more slowly than WT. Expression of S229L in mammalian cells induces the accumulation of BER intermediate substrates, chromosomal aberrations, and cellular transformation. Our results are consistent with the interpretation that S229L is a driver of carcinogenesis, likely as a consequence of its slow polymerization activity during BER in vivo. PMID:24668809

  3. Premature termination of SMARCB1 translation may be followed by reinitiation in schwannomatosis-associated schwannomas, but results in absence of SMARCB1 expression in rhabdoid tumors.

    PubMed

    Hulsebos, Theo J M; Kenter, Susan; Verhagen, Wim I M; Baas, Frank; Flucke, Uta; Wesseling, Pieter

    2014-09-01

    In schwannomatosis, germline SMARCB1 mutations predispose to the development of multiple schwannomas, but not vestibular schwannomas. Many of these are missense or splice-site mutations or in-frame deletions, which are presumed to result in the synthesis of altered SMARCB1 proteins. However, also nonsense and frameshift mutations, which are characteristic for rhabdoid tumors and are predicted to result in the absence of SMARCB1 protein via nonsense-mediated mRNA decay, have been reported in schwannomatosis patients. We investigated the consequences of four of the latter mutations, i.e. c.30delC, c.34C>T, c.38delA, and c.46A>T, all in SMARCB1-exon 1. We could demonstrate for the c.30delC and c.34C>T mutations that the respective mRNAs were still present in the schwannomas of the patients. We hypothesized that these were prevented from degradation by translation reinitiation at the AUG codon encoding methionine at position 27 of the SMARCB1 protein. To test this, we expressed the mutations in MON cells, rhabdoid cells without endogenous SMARCB1 protein, and found that all four resulted in synthesis of the N-terminally truncated protein. Mutation of the reinitiation methionine codon into a valine codon prevented synthesis of the truncated protein, thereby confirming its identity. Immunohistochemistry with a SMARCB1 antibody revealed a mosaic staining pattern in schwannomas of the patients with the c.30delC and c.34C>T mutations. Our findings support the concept that, in contrast to the complete absence of SMARCB1 expression in rhabdoid tumors, altered SMARCB1 proteins with modified activity and reduced (mosaic) expression are formed in the schwannomas of schwannomatosis patients with a germline SMARCB1 mutation. PMID:24740647

  4. Predicting tumor sizes of ductal carcinoma in situ from immunohistochemical images using a novel approach of mathematical pathology: preliminary results, potentials and challenges ahead

    NASA Astrophysics Data System (ADS)

    Chuang, Yao-Li; Edgerton, Mary; Macklin, Paul; Yang, Wei; Bearer, Elaine; Cristini, Vittorio

    2012-02-01

    Differential equation models have recently drawn increasing attentions as a useful tool to help advance the knowledge in cancer research. However, challenges remain for applying such models to clinical practices on a patient-specific basis to assist surgical decisions. Clinical diagnoses essentially at a single time point are often insufficient to fully constrain the time-dependent differential equations. Here we present a novel mathematical pathology approach, identifying robust indicators for time-invariant predictions of the model that can be used for surgical planning. We demonstrate this approach by predicting the sizes of ductal carcinoma in situ by calibrating model parameters from immunohistochemical images. Our preliminary studies of 17 excised tumor cases resulted in a better agreement with the actual measured sizes than the other estimates available to us, showing the potential of our approach for patient-specific cancer diagnosis. Conversely, our studies also revealed challenges to overcome before we can take this approach to the next level.

  5. Rare inactivating PDE11A variants associated with testicular germ cell tumors.

    PubMed

    Pathak, Anand; Stewart, Douglas R; Faucz, Fabio R; Xekouki, Paraskevi; Bass, Sara; Vogt, Aurelie; Zhang, Xijun; Boland, Joseph; Yeager, Meredith; Loud, Jennifer T; Nathanson, Katherine L; McGlynn, Katherine A; Stratakis, Constantine A; Greene, Mark H; Mirabello, Lisa

    2015-12-01

    Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk. PMID:26459559

  6. Spinal tumor

    MedlinePlus

    Tumor - spinal cord ... spinal tumors occur in the nerves of the spinal cord itself. Most often these are ependymomas and other ... gene mutations. Spinal tumors can occur: Inside the spinal cord (intramedullary) In the membranes (meninges) covering the spinal ...

  7. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

    PubMed

    Sorace, Anna G; Quarles, C Chad; Whisenant, Jennifer G; Hanker, Ariella B; McIntyre, J Oliver; Sanchez, Violeta M; Yankeelov, Thomas E

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically

  8. Tumor angiogenesis--characteristics of tumor endothelial cells.

    PubMed

    Hida, Kyoko; Maishi, Nako; Torii, Chisaho; Hida, Yasuhiro

    2016-04-01

    Tumor blood vessels provide nutrition and oxygen to the tumor, resulting in tumor progression. They also act as gatekeepers, inducing tumor metastasis. Thus, targeting tumor blood vessels is an important strategy in cancer therapy. Tumor endothelial cells (TECs), which line the inner layer of blood vessels of the tumor stromal tissue, are the main targets of anti-angiogenic therapy. Because new tumor blood vessels generally sprout from pre-existing vasculature, they have been considered to be the same as normal blood vessels. However, tumor blood vessels demonstrate a markedly abnormal phenotype that includes several important morphological changes. The degree of angiogenesis is determined by the balance between the angiogenic stimulators and inhibitors released by the tumor and host cells. Recent studies have revealed that TECs also exhibit altered characteristics which depend on the tumor microenvironment. Here, we review recent studies on TEC abnormalities and heterogeneity with respect to tumor progression and consider their therapeutic implications. PMID:26879652

  9. Evidence suggesting that ghrelin O-acyl transferase inhibitor acts at the hypothalamus to inhibit hypothalamo-pituitary-adrenocortical axis function in the rat.

    PubMed

    Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Hochol, Anna; Malendowicz, Ludwik K

    2012-06-01

    Production of n-octanoyl-modified ghrelin (GHREL), an active form of the peptide requires prohormone processing protease and GHREL O-acyltransferase (GOAT), as well as n-octanoic acid. Recently a selective GOAT antagonist (GO-CoA-Tat) was invented and this tool was used to study the possible role of endogenous GHREL in regulating HPA axis function in the rat. Administration of GOAT inhibitor (GOATi) resulted in a notable decrease in plasma ACTH, aldosterone and corticosterone concentrations at min 60 of experiment. Octanoic acid (OA) administration had no effect on levels of studied hormones. Plasma levels of unacylated and acylated GHREL remained unchanged for 60min after either GOATi or OA administration. Under experimental conditions applied, no significant changes were observed in the levels of GOAT mRNA in hypothalamus, pituitary, adrenal and stomach fundus. After GOATi injection hypothalamic CRH mRNA levels were elevated at 30 min and pituitary POMC mRNA levels at 60 min. Both GOATi and OA lowered basal, but not K(+)-stimulated CRH release by hypothalamic explants and had no effect on basal or CRH-stimulated ACTH release by pituitary slices. Neither GOATi nor OA affected corticosterone secretion by freshly isolated or cultured rat adrenocortical cells. Thus, results of our study suggest that in the rat endogenous GHREL exerts tonic stimulating effect on hypothalamic CRH release. This effect could be demonstrated by administering rats with selected inhibitor of ghrelin O-acyltransferase, the enzyme responsible for GHREL acylation, a process which is absolutely required for both GHSR-1a binding and its central endocrine activities. PMID:22543218

  10. Adiponectin and adiponectin receptor system in the rat adrenal gland: ontogenetic and physiologic regulation, and its involvement in regulating adrenocortical growth and steroidogenesis.

    PubMed

    Paschke, Lukasz; Zemleduch, Tomasz; Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Malendowicz, Ludwik K

    2010-09-01

    Adiponectin (ADN) is a regulatory peptide secreted mostly by adipose tissue and acting via two receptors: AdipoR1 and AdipoR2. Our aim was to investigate expression of adiponectin system genes in the rat adrenal gland as well as its ontogenetic and physiological control. Furthermore, we examined the effects of acute and prolonged activation of HPA axis on ADN system in adipose tissue. By means of QPCR, ADN and AdipoR1 expression was demonstrated in rat adrenal cortex both at mRNA and protein levels, while AdipoR2 could only be detected at mRNA levels. ADN expression level was significantly upregulated in a developing and regenerating adrenal cortex. Globular domain of adiponectin at 10(-9) M stimulated corticosterone output and BrdU incorporation by cultured rat adrenocortical cells. Moreover, both acute (ACTH and ether stress) and prolonged (ACTH) adrenal stimulation resulted in lowered ADN levels, while expression of AdipoR1 and AdipoR2 was upregulated by the acute treatment. Depending on its site of origin, visceral (VAT) or subcutaneous (SAT) adipose tissue responded differently to alterations in HPA axis. VAT expression of ADN and its receptors remained almost unchanged by experimental manipulations. In SAT, on the other hand, expression of ADN and AdipoR2 was markedly increased by ACTH treatment and stress, while dexamethasone suppressed ADN and AdipoR1 mRNA levels. The results of this study provide new evidence for direct and indirect interactions between adipokines and HPA axis. PMID:20600433

  11. Structural fragility of blood vessels and peritoneum in calponin h1-deficient mice, resulting in an increase in hematogenous metastasis and peritoneal dissemination of malignant tumor cells.

    PubMed

    Taniguchi, S; Takeoka, M; Ehara, T; Hashimoto, S; Shibuki, H; Yoshimura, N; Shigematsu, H; Takahashi, K; Katsuki, M

    2001-10-15

    We have observed weak expression of calponin h1, which stabilizes the actin filament system, in blood vessels within human malignant tumors. This observation suggested that because of a deficiency in stabilization by calponin h1, the structure of blood vessels in malignant tumors is fragile compared with blood vessels in normal tissues. We therefore generated calponin h1-deficient (CN(-/-)) mice to examine the effect of calponin h1 on the integrity of the barrier system in blood vessels against cancer metastasis. The CN(-/-) mice exhibited morphological fragility of the tissues, including the uterus and blood vessels. In particular, we frequently observed bleeding into the surrounding tissue from blood vessels of the ocular fundus in CN(-/-) mice. In addition, mesothelial cells, which usually express calponin h1 in normal (CN(+/+)) mice, were retracted in the CN(-/-) mice. When fluorescein was injected i.v. into mice, the CN(-/-) mice exhibited a greater and more rapid leakage of fluorescein from the blood vessels of the ocular fundus compared with the CN(+/+) mice. In the CN(-/-) mice receiving i.v. inoculations of B16 melanoma cells, significantly more metastatic nodules were formed in the lung than in the CN(+/+) mice. When B16 melanoma cells were injected i.p., the severity of peritonitis carcinomatosa was greater in CN(-/-) than in CN(+/+) mice. These results indicate that calponin h1 plays an important role in the regulation of the integrity of the blood vessels and peritoneum, which in turn is an important factor influencing the frequency of cancer metastasis. The CN(-/-) mice, which exhibit fragile blood vessels and peritoneum, could serve as sensitive and useful host models to investigate cancer metastasis. PMID:11606404

  12. THE TUMOR MACROENVIRONMENT: CANCER-PROMOTING NETWORKS BEYOND TUMOR BEDS

    PubMed Central

    Rutkowski, Melanie R.; Svoronos, Nikolaos; Puchalt, Alfredo Perales; Conejo-Garcia, Jose R.

    2015-01-01

    During tumor progression, alterations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion to distal organs, and eventual metastatic disease. Distally produced hormones, commensal microbiota residing within mucosal surfaces, and myeloid cells and even the bone marrow impact the systemic immune system, tumor growth, and metastatic spread. Understanding the reciprocal interactions between the cells and soluble factors within the macroenvironment and the primary tumor will enable the design of specific therapies that have the potential to prevent dissemination and metastatic spread. This chapter will summarize recent findings detailing how the primary tumor and systemic tumor macroenvironment coordinate malignant progression. PMID:26216635

  13. Somatic mutation of GRIN2A in malignant melanoma results in loss of tumor suppressor activity via aberrant NMDAR complex formation.

    PubMed

    Prickett, Todd D; Zerlanko, Brad J; Hill, Victoria K; Gartner, Jared J; Qutob, Nouar; Jiang, Jiji; Simaan, May; Wunderlich, John; Gutkind, J Silvio; Rosenberg, Steven A; Samuels, Yardena

    2014-09-01

    The ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca(2+)) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2A mutants demonstrated a loss of NMDAR complex formation between GRIN1 and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma. Depletion of endogenous GRIN2A in melanoma cells expressing WT GRIN2A resulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2A in mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2A results in increased survival, and we demonstrate the functional importance of GRIN2A mutations in melanoma and the significance that ionotropic glutamate receptor signaling has in malignant melanoma. PMID:24739903

  14. RGD peptide conjugation results in enhanced antitumor activity of PD0325901 against glioblastoma by both tumor-targeting delivery and combination therapy.

    PubMed

    Hou, Jianjun; Diao, Yiping; Li, Wei; Yang, Zhenjun; Zhang, Lihe; Chen, Zili; Wu, Yun

    2016-05-30

    Glioblastoma (GBM) is the most aggressive tumor type in the central nervous system. Both tumor-targeting drug delivery and combination therapy of multiple therapeutic agents with distinct mechanisms are important for GBM treatment. We combined these two strategies and developed a new platform of peptide-drug conjugate (RGD-PEG-Suc-PD0325901, W22) for tumor-targeting delivery using a combination of PD0325901 (a MEK1/2 inhibitor) and RGD peptide. In the present study, the combination of PD0325901 and RGD peptide strongly inhibited U87MG model in vitro and in vivo. This inhibition contributed to synergistic suppression of cell proliferation by blocking ERK pathway activity and cell migration. Modified by conjugation strategy, their conjugate W22 enhanced PD0325901 delivery to GBM cells by receptor mediated cellular internalization. W22 showed great superiority in targeting to U87MG xenografted tumors and strong anti-tumor efficacy based on ERK pathway inhibition and tumor-targeted delivery in vitro and in vivo. Moreover, W22 was stable in serum and able to release PD0325901 in the enzymatic environment. These data indicated that the RGD-PEG-Suc-PD0325901 conjugate provided a strategy for effective delivery of PD0325901 and RGD peptide into the GBM cells and inhibition of tumor growth in a synergistic manner. PMID:27085642

  15. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer1

    PubMed Central

    Caruso, Denise A.; Orme, Lisa M.; Neale, Alana M.; Radcliff, Fiona J.; Amor, Gerlinda M.; Maixner, Wirginia; Downie, Peter; Hassall, Timothy E.; Tang, Mimi L.K.; Ashley, David M.

    2004-01-01

    We conducted a phase 1 study of 9 pediatric patients with recurrent brain tumors using monocyte-derived dendritic cells pulsed with tumor RNA to produce antitumor vaccine (DCRNA) preparations. The objectives of this study included (1) establishing safety and feasibility and (2) measuring changes in general, antigen-specific, and tumor-specific immune responses after DCRNA. Dendritic cells were derived from freshly isolated monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony–stimulating factor, pulsed with autologous tumor RNA, and then cryopreserved. Patients received at least 3 vaccines, each consisting of an intravenous and an intra-dermal administration at biweekly intervals. The study showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric brain tumor population. Immune function at the time of enrollment into the study was impaired in all patients tested. While humoral responses to recall antigens (diphtheria and tetanus) were intact in all patients, cellular responses to mitogen and recall antigens were below normal. Following DCRNA vaccine, 2 of 7 patients showed stable clinical disease and 1 of 7 showed a partial response. Two of 7 patients who were tested showed a tumor-specific immune response to DCRNA. This study showed that DCRNA vaccines are both safe and feasible in children with tumors of the central nervous system with a single leukapheresis. PMID:15279716

  16. Beyond biology: the impact of marital status on survival of patients with adrenocortical carcinoma

    PubMed Central

    Klaassen, Zachary; Reinstatler, Lael; Terris, Martha K.; Underwood, Willie; Moses, Kelvin A.

    2015-01-01

    ABSTRACT Purpose: To analyze the association of marital status and survival of patients with ACC using a population-based database. Material and Methods: Patients with ACC were abstracted from the Surveillance Epidemiology and End Results (SEER) database from 1988-2010 (n=1271). Variables included marital status (married vs single/divorced/widowed (SDW)), gender, age, race, tumor (T) and node (N) classification, receipt of surgery, and SEER stage. Statistical analysis was performed using Cox proportional hazard models to generate hazard ratios and 95% confidence intervals. Results: There were 728 (57.3%) females and median age was 56 years (IQR 44-66). Patients who were alive were more frequently married (65.6% vs 61.6%, p=0.008), female (61.1% vs 58.0%, p=0.001), younger (median 51 vs 57 years, p=0.0001), submitted to adrenalectomy (88.6% vs 63.8%, p<0.0001), and more favorable SEER stage (localized-64.9% vs 29.9%; regional–25.1% vs 30.1%; distant 4.8% vs 31.5%, p<0.0001) compared to patients dead of disease (DOD). On multivariable analysis, factors significantly associated with all-cause mortality were SDW status (HR 1.28, 95% CI 1.091.51), age, non-operative management, and N+ disease. Risk factors for disease-specific mortality included SDW status (HR 1.30, 95% CI 1.07-1.56), age, non-operative management, T-classification, and N+ disease. Conclusions: Marital status is significantly associated with survival in patients with ACC. Our results suggest that the decreased survival seen among SDW individuals highlights an area for further research and needed intervention to reduce disparity. PMID:26742968

  17. Neuroimaging of Spinal Tumors.

    PubMed

    Merhemic, Zulejha; Stosic-Opincal, Tatjana; Thurnher, Majda M

    2016-08-01

    Intradural tumors are relatively rare neoplasms; however, when unrecognized in a timely manner, they can result in serious deficits and disability. These tumors lack obvious clinical symptoms until compression of the cord or neurologic deficits occur. The most common intramedullary lesions are ependymomas, astrocytomas, and hemangioblastomas. Meningiomas and nerve sheath tumors (schwannomas and neurofibromas) comprise most intradural-extramedullary tumors. Less common tumors are hemangiopericytoma, paraganglioma, melanocytoma, melanoma, metastases, and lymphoma. MR imaging is the imaging method of choice, helpful for localization and characterization of these lesions before treatment and for follow-up after treatment. PMID:27417401

  18. Non-surgical organ preservation strategies for locally advanced laryngeal tumors: what is the Italian attitude? Results of a national survey on behalf of AIRO and AIOM.

    PubMed

    Alterio, D; Franco, P; Numico, G; Licitra, L; Cossu Rocca, M; Ferrari, A; Pinto, C; Russi, E G; Ricardi, U; Jereczek Fossa, B A

    2016-07-01

    Chemoradiotherapy is the treatment mostly used as organ preservation (OP) strategy worldwide in advanced laryngo-hypopharyngeal cancer. Due to the not homogeneous results of the literature data regarding the pre-treatment assessment and treatment schedule in this setting of patients, the Italian societies of radiation oncology and medical oncology surveyed (by an online survey) their memberships regarding the Italian attitude on larynx preservation in clinical practice. The survey outline addressed different items such as: demographics (11 items), pre-treatment evaluation (12 items), treatment schedules (10 items) and outcomes (3 items). The survey was filled in by 116 clinical oncologists (64 % radiation and 36 % medical oncologists). Results highlighted that pretreatment evaluation was not homogeneous among the respondents. The treatment of choice for the OP program resulted the concurrent chemoradiotherapy (66 %). Induction chemotherapy was proposed mostly in case of aggressive tumors such as advanced stage (T4 or N3) and/or unfavorable primary sites (hypopharynx). Moreover, after induction chemotherapy, for responders patients most participants (46 %) proposed concurrent chemoradiotherapy, while 18 and 19 % proposed radiotherapy alone or radiotherapy and cetuximab, respectively. For patients with stable disease after induction chemotherapy, the respondents declared to suggest surgery, radiotherapy and cetuximab or radiotherapy alone in 38, 32 and 15 % of cases, respectively. Results of the present survey highlighted the variability of therapeutic approaches offered in clinical practice for patients candidate to a larynx OP program. Analysis of abovementioned results may give the chance to modify some clinical attitudes and create the background for future clinical investigation in this field. PMID:27290695

  19. Lack of Proinflammatory Cytokine Interleukin-6 or Tumor Necrosis Factor Receptor-1 Results in a Failure of the Innate Immune Response after Bacterial Meningitis

    PubMed Central

    Albrecht, Lea-Jessica; Tauber, Simone C.; Merres, Julika; Kress, Eugenia; Stope, Matthias B.; Jansen, Sandra; Pufe, Thomas; Brandenburg, Lars-Ove

    2016-01-01

    The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6−/−, TNFR1−/−, and TNFR1-IL-6−/− KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1−/−, IL-6−/−, and TNFR1-IL-6−/− mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1−/− and TNFR1-IL-6−/− mice in contrast to IL-6−/− and wild type mice. Furthermore, the increased mortality of TNFR1−/− and TNFR1-IL-6−/− mice correlated with decreased glial cell activation compared to IL-6−/− or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone. PMID:27057100

  20. 10 rare tumors that warrant a genetics referral.

    PubMed

    Banks, Kimberly C; Moline, Jessica J; Marvin, Monica L; Newlin, Anna C; Vogel, Kristen J

    2013-03-01

    The number of described cancer susceptibility syndromes continues to grow, as does our knowledge on how to manage these syndromes with the aim of early detection and cancer prevention. Oncologists now have greater responsibility to recognize patterns of cancer that warrant referral for a genetics consultation. While some patterns of common cancers are easy to recognize as related to hereditary cancer syndromes, there are a number of rare tumors that are highly associated with cancer syndromes yet are often overlooked given their infrequency. We present a review of ten rare tumors that are strongly associated with hereditary cancer predisposition syndromes: adrenocortical carcinoma, carcinoid tumors, diffuse gastric cancer, fallopian tube/primary peritoneal cancer, leiomyosarcoma, medullary thyroid cancer, paraganglioma/pheochromocytoma, renal cell carcinoma of chromophobe, hybrid oncocytoic, or oncocytoma histology, sebaceous carcinoma, and sex cord tumors with annular tubules. This review will serve as a guide for oncologists to assist in the recognition of rare tumors that warrant referral for a genetic consultation. PMID:23377869

  1. Tumors associated with p53 germline mutations: a synopsis of 91 families.

    PubMed Central

    Kleihues, P.; Schäuble, B.; zur Hausen, A.; Estève, J.; Ohgaki, H.

    1997-01-01

    Although inherited p53 mutations are present in all somatic cells, malignant transformation is limited to certain organs and target cells. The analysis of 475 tumors in 91 families with p53 germline mutations reported since 1990 shows that breast carcinomas are most frequent (24.0%), followed by bone sarcomas (12.6%), brain tumors (12.0%), and soft tissue sarcomas (11.6%). The sporadic counterparts of these tumors also carry a high incidence of p53 mutations, suggesting that in these tissues p53 mutations are capable of initiating the process of malignant transformation. Hematological neoplasms (acute lymphoblastic leukemia and Hodgkin's lymphoma) and adrenocortical carcinomas occurred at a frequency of 4.2 and 3.6%, respectively. One-half of the families fulfilled the diagnostic criteria of the Li-Fraumeni syndrome. There were marked organ-specific differences in the mean age at which carriers of p53 germline mutations present with neoplastic disease: 5 years for adrenocortical carcinomas, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancer, and almost 50 years for lung cancer. Analysis of the mutational spectrum showed a predominance of G:C-->A:T transitions at CpG sites, suggesting an endogenous formation, eg, by deamination of 5-methylcytosine, rather than a causation by environmental mutagenic carcinogens. The location of mutations within the p53 gene was found to be similar to that of somatic mutations in sporadic tumors. There is no evidence of an organ or target cell specificity of p53 germline mutations; the occasional familial clustering of certain tumor types is more likely to reflect the genetic background of the respective kindred or the additional influence of environmental and nongenetic host factors. Images Figure 4 PMID:9006316

  2. Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-α receptor II following a trial of hypnosis: Results of a randomized controlled pilot study

    PubMed Central

    Goodin, Burel R.; Quinn, Noel B.; Kronfli, Tarek; King, Christopher D.; Page, Gayle G.; Haythornthwaite, Jennifer A.; Edwards, Robert R.; Stapleton, Laura M.; McGuire, Lynanne

    2011-01-01

    Objective Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. Design Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble receptor of tumor necrosis factor-α (sTNFαRII). Results Compared to the no-intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFαRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. Conclusions Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID:22233394

  3. Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases

    NASA Astrophysics Data System (ADS)

    Sauter, Bernhard V.; Martinet, Olivier; Zhang, Wei-Jian; Mandeli, John; Woo, Savio L. C.

    2000-04-01

    Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.

  4. Adrenocortical Carcinoma: Impact of Surgical Margin Status on Long-Term Outcomes

    PubMed Central

    Margonis, Georgios Antonios; Kim, Yuhree; Prescott, Jason D.; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Evans, Douglas B.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Poultsides, George A.; Pawlik, Timothy M.

    2016-01-01

    Background The influence of surgical margin status on long-term outcomes of patients undergoing adrenal resection for ACC remains not well defined. We studied the impact of surgical tumor margin status on recurrence-free survival (RFS) and overall survival (OS) of patients undergoing resection for ACC. Methods A total of 165 patients who underwent adrenal resection for ACC and met inclusion criteria were identified form a multi-institutional database. Clinicopathological data, pathologic margin status, and long-term outcomes were assessed. Patients were stratified into two groups based on margin status: R0 (margin >1 mm) versus R1. Results R0 resection was achieved in 126 patients (76.4 %), whereas 39 patients (23.6 %) had an R1 resection. Median and 5-year OS for patients undergoing R0 resection were 96.3 months and 64.8 % versus 25.1 months and 33.8 % for patients undergoing an R1 resection (both p < 0.001). On multivariable analysis, surgical margin status was an independent predictor of worse OS (hazard ratio [HR] 2.22, 95 % confidence interval [CI] 1.03–4.77; p = 0.04). The incidence of recurrence also differed between the two groups; 5-year RFS was 30.3 % among patients with an R0 resection versus 13.8 % among patients who had an R1 resection (p = 0.03). Lymph node metastasis (N1) was an independent predictor of RFS (HR 2.70, 95 % CI 1.04–6.99; p = 0.04). Conclusions A positive margin after ACC resection was associated with worse long-term survival. Patient selection and an emphasis on surgical technique to achieve R0 margins are pivotal to optimizing the best chance for long-term outcome among patients with ACC. PMID:26286195

  5. Brain tumors.

    PubMed Central

    Black, K. L.; Mazziotta, J. C.; Becker, D. P.

    1991-01-01

    Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors, which are sparse in normal brain, is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors, the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors. Images PMID:1848735

  6. YPEL4 modulates HAC15 adrenal cell proliferation and is associated with tumor diameter.

    PubMed

    Oki, Kenji; Plonczynski, Maria W; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E

    2016-10-15

    Yippee-like (YPEL) proteins are thought to be related to cell proliferation because of their structure and location in the cell. The aim of this study was to clarify the effects of YPEL4 on aldosterone production and cell proliferation in the human adrenocortical cell line (HAC15) and aldosterone producing adenoma (APA). Basal aldosterone levels in HAC15 cells over-expressing YPEL4 was higher than those of control HAC15 cells. The positive effects of YPEL4 on cell proliferation were detected by XTT assay and crystal violet staining. YPEL4 levels in 39 human APA were 2.4-fold higher compared to those in 12 non-functional adrenocortical adenomas, and there was a positive relationship between YPEL4 levels and APA diameter (r = 0.316, P < 0.05). In summary, we have demonstrated that YPEL4 stimulates human adrenal cortical cell proliferation, increasing aldosterone production as a consequence. These results in human adrenocortical cells are consistent with the clinical observations with APA in humans. PMID:27333825

  7. Tumors of the spine

    PubMed Central

    Ciftdemir, Mert; Kaya, Murat; Selcuk, Esref; Yalniz, Erol

    2016-01-01

    Spine tumors comprise a small percentage of reasons for back pain and other symptoms originating in the spine. The majority of the tumors involving the spinal column are metastases of visceral organ cancers which are mostly seen in older patients. Primary musculoskeletal system sarcomas involving the spinal column are rare. Benign tumors and tumor-like lesions of the musculoskeletal system are mostly seen in young patients and often cause instability and canal compromise. Optimal diagnosis and treatment of spine tumors require a multidisciplinary approach and thorough knowledge of both spine surgery and musculoskeletal tumor surgery. Either primary or metastatic tumors involving the spine are demanding problems in terms of diagnosis and