Anthony P Heaney

University of California, Los Angeles, Los Angeles, California, United States

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Publications (73)435.52 Total impact

  • Marvin Bergsneider, Anthony P Heaney, John Y K Lee
    Journal of Neuro-Oncology 04/2014; · 3.12 Impact Factor
  • Anthony Heaney
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    ABSTRACT: Pituitary tumors are benign but not uncommonly invade locally into adjacent tissues such as the cavernous sinus and dura. Some of these invasive tumors exhibit varying degrees of resistance to standard therapy and tend to recur. Early prediction of which pituitary tumors will recur and/or exhibit an invasive phenotype remains difficult despite introduction of several tissue-based molecular markers. Management of these recurrent invasive pituitary tumors usually comprises combination medical, surgical and radiation therapy but in some instances is suboptimal. Earlier diagnosis of invasive/recurrent pituitary tumor and application of aggressive multi-modal therapy at presentation may be advantageous in some cases. Clinical trials to develop additional therapeutic options are needed for this subgroup of pituitary tumors. Although it is not yet possible to diagnose at presentation, the subset of pituitary tumors that will become invasive and/or recurrent pituitary tumors, broader use of molecular markers and standardization of histopathological criteria for "atypical" pituitary tumor features have assisted earlier diagnosis. Aggressive therapy early in disease may be warranted and exploration of recently available targeted therapies may improve disease management.
    Journal of Neuro-Oncology 03/2014; · 3.12 Impact Factor
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    ABSTRACT: Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both "stalk effect" hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the "stalk effect" pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.
    Journal of Neuro-Oncology 02/2014; · 3.12 Impact Factor
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    ABSTRACT: Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.
    Proceedings of the National Academy of Sciences 05/2013; · 9.81 Impact Factor
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    ABSTRACT: Disease heterogeneity and multisystem complications represent challenges to the diagnosis and management of neuroendocrine tumours (NET), with the disease often remaining undiagnosed for years after initial presentation. The purpose of this review is to assess the limitations of traditional care models and review the potential benefits of the multidisciplinary team approach in cancer treatment and to explore the potential usefulness of the multidisciplinary team approach for patients with NET. This article outlines important considerations for the multidisciplinary management of NET, offers a model for team structure and function and identifies skill sets of members that may augment patient care. We believe a multidisciplinary team should include three to four clinicians with extensive NET experience. A coordinating physician plays a crucial role by facilitating team cohesiveness and maintaining constant patient contact throughout the course of treatment. Our model emphasizes collaboration between members of the core team and can be extended to include interactions with community healthcare professionals and others. A multidisciplinary approach offers the best prospect for improving clinical outcomes and understanding the natural history of NET.
    Current opinion in endocrinology, diabetes, and obesity 08/2012; 19(4):306-13. · 3.77 Impact Factor
  • Li Du, Anthony P Heaney
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    ABSTRACT: Adipose tissue is an important metabolic organ that is crucial for whole-body insulin sensitivity and energy homeostasis. Highly refined fructose intake increases visceral adiposity although the mechanism(s) remain unclear. Differentiation of preadipocytes to mature adipocytes is a highly regulated process that is associated with characteristic sequential changes in adipocyte gene expression. We demonstrate that fructose treatment of murine 3T3-L1 cells incubated in standard differentiation medium increases adipogenesis and adipocyte-related gene expression. We further show that the key fructose transporter, GluT5, is expressed in early-stage adipocyte differentiation but is not expressed in mature adipocytes. GluT5 overexpression or knockdown increased and decreased adipocyte differentiation, respectively, and treatment of 3T3-L1 cells with a specific GluT5 inhibitor decreased adipocyte differentiation. Epidymal white adipose tissue was reduced in GluT5-/- mice compared with wild-type mice, and mouse embryonic fibroblasts derived from GluT5-/- mice exhibited impaired adipocyte differentiation. Taken together, these results demonstrate that fructose and GluT5 play an important role in regulating adipose differentiation.
    Molecular Endocrinology 07/2012; 26(10):1773-82. · 4.75 Impact Factor
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    ABSTRACT: Introduction: Little is known about pituitary function in patients with normal pressure hydrocephalus (NPH). This study evaluated pituitary function in a large series of patients awaiting neurosurgical correction for NPH. We also sought to ascertain whether surgical correction of hydrocephalus would result in improvement of any noted pituitary dysfunction. Methods: Patients with NPH referred for neurosurgical evaluation between February 2010 and January 2011 were eligible for recruitment. Pituitary endocrine evaluation including serum prolactin, free thyroid hormone, TSH, IGF-I, FSH, LH, estradiol, testosterone, cortisol, and ACTH was preformed at baseline and 1 and 3 months after surgery. Results: Of the 63 patients referred for possible NPH, 32 met study criteria, 20 could provide informed consent, and laboratory evaluation was obtainable in 16. The mean age of these patients was 62 ± 14 yr, and 75% were men. The overall incidence of NPH-associated pituitary dysfunction was 31% (five of 16 patients) at baseline laboratory assessment. Hypogonadism was the most common type of pituitary dysfunction detected. Conclusion: NPH is associated with pituitary dysfunction, observed in a significant proportion (31%) of patients. As such, we recommend that pituitary screening should be considered in all NPH patients. In two patients with hypogonadism, surgical correction of NPH was associated with improved testosterone levels. Therefore, not all patients with NPH-associated pituitary dysfunction will require hormone replacement therapy because surgical correction may correct pituitary deficiencies in some instances.
    The Journal of clinical endocrinology and metabolism 07/2012; 97(10):3545-9. · 6.50 Impact Factor
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    ABSTRACT: To discuss the role of bilateral adrenalectomy in Cushing syndrome, as illustrated in a case of severe hypercortisolism that was unresponsive to combination agent medical therapy. We report the clinical, laboratory, imaging, and pathologic findings in a patient with ectopic Cushing syndrome attributable to an adrenocorticotropic hormone (ACTH)-secreting neuroblastoma. In addition, we provide a literature review regarding olfactory neuroblastoma and discuss current and emerging therapeutic options for Cushing syndrome. A 59-year-old man presented with nasal congestion and neck swelling and was noted to have hypokalemia, hypertension, and hyperglycemia. A nasal biopsy demonstrated a poorly differentiated carcinoma with neuroendocrine features. He was subsequently diagnosed as having ACTH-dependent Cushing syndrome, but despite high-dose combination medical therapy, his condition rapidly deteriorated. Urgent bilateral adrenalectomy provided rapid control of the hypercortisolism, and the patient was later able to undergo an uncomplicated total macroscopic resection of his locally metastatic primary tumor. This report describes the challenges in the diagnosis and management of ACTH-dependent Cushing syndrome and highlights the important role that bilateral adrenalectomy can still have in patients with severe hypercortisolism causing life-threatening complications.
    Endocrine Practice 02/2012; 18(4):e85-90. · 2.49 Impact Factor
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    ABSTRACT: Pituitary adenomas rarely originate outside the sella turcica. Ectopic locations include the suprasellar region, sphenoid sinus, cavernous sinus and clivus. We describe a 50-year-old female who presented with clinical signs and biochemical evidence of acromegaly. Pituitary MRI demonstrated a 2 mm hypointense lesion on the right side of the pituitary gland. However upon drilling of the upper clival bone to expose the sella during endoscopic transsphenoidal surgery, soft tumor-like tissue was encountered within the clivus. Exploration of the sella, including the area of hypointensity noted on preoperative imaging, did not identify any other abnormality. Immunohistochemical examination of the fully resected tumor demonstrated growth hormone immunoreactivity. Failed preoperative diagnosis of this rare ectopic GH-producing tumor was compounded by the presence of a misleading pituitary abnormality consistent with a microadenoma. The epidemiology and pertinent literature of this uncommon condition is discussed.
    Pituitary 09/2011; · 2.67 Impact Factor
  • Anthony P Heaney
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    ABSTRACT: Although pituitary tumors are common, pituitary carcinoma is very rare and is only diagnosed when pituitary tumor noncontiguous with the sellar region is demonstrated. Diagnosis is difficult, resulting in delays that may adversely effect outcome that is traditionally poor. Barriers to earlier diagnosis and management strategies for pituitary carcinoma are discussed. PubMed was employed to identify relevant studies, a review of the literature was conducted, and data were summarized and integrated from the author's perspective. The available data highlight the difficulties in diagnosis and management and practical challenges in conducting clinical trials in this rare condition. They suggest that earlier diagnosis with aggressive multimodal therapy may be advantageous in some cases. Although pituitary carcinoma remains difficult to diagnose and treat, recent developments have led to improved outcomes in selected cases. With broader use of molecular markers, efforts to modify current histopathological criteria for pituitary carcinoma diagnosis may now be possible. This would assist earlier diagnosis and, in combination with targeted therapies, potentially improve long-term survival.
    The Journal of clinical endocrinology and metabolism 09/2011; 96(12):3649-60. · 6.50 Impact Factor
  • Haibo Liu, Anthony P Heaney
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    ABSTRACT: INTRODUCTION: Caloric excess, including increased refined carbohydrate intake, is associated with higher cancer risk emphasizing the importance of improved understanding of cancer cell metabolism in tumor survival and metastasis. AREAS COVERED: This article reviews the relationship between increased dietary refined sugar and cancer risk, with specific emphasis on the monosaccharide fructose. Cancer cell metabolism is reviewed, and the potential mechanisms by which dietary sugars contribute to the tumor microenvironment are discussed. Recent observations indicate that cancer cells readily utilize fructose to support proliferation and preferentially use fructose for nucleic acid synthesis. This review discusses the potential role of how dietary fructose can promote cancer growth by a variety of mechanisms, including altered cellular metabolism, increased reactive oxygen species, DNA damage and inflammation. Preliminary insights into potential therapeutic strategies by which fructose-mediated cancer effects may be abrogated are presented. EXPERT OPINION: Other sugars (particularly fructose, given its abundance in the modern diet) must be considered with reference to cancer cell metabolism. Cancer cells utilize similar sugars in distinct ways, which may present important new therapeutic avenues of targeting cancer.
    Expert Opinion on Therapeutic Targets 05/2011; 15(9):1049-59. · 4.90 Impact Factor
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    ABSTRACT: Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.
    Lipids in Health and Disease 01/2011; 10:20. · 2.31 Impact Factor
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    ABSTRACT: Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth.
    Cancer Research 08/2010; 70(15):6368-76. · 9.28 Impact Factor
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    ABSTRACT: We sought to develop an assay to measure circulating fructose concentrations in pancreatic cancer patients. Using fructose dehydrogenase-catalyzed conversion of d-fructose to 5-ketofructose, followed by quantitation of MTT [3-(4,5-dimethylthiaze-syl)-2,5-diphenyltetrazolium bromide] formazan production by direct spectrophotometry, an assay to measure serum fructose concentration was developed, and assay sensitivity and specificity were tested. Validity of the assay was confirmed by gas chromatography-mass spectroscopy, and the assay was tested in healthy subjects and pancreatic cancer patients. The assay was highly specific, exhibiting no cross-reactivity with other sugars. Mean serum fructose concentration in fasting healthy volunteers was 1.9+/-0.4 mM and after ingestion of a fructose and glucose-containing drink rose to 16.3+/-1.2 mM at 15 minutes and peaked at 30 minutes when serum fructose was 17.2+/-1.1 mM. Mean fasting serum fructose level was significantly higher at 5.7+/-2.5 mM in patients with pancreatic cancer than those with no pancreatic cancer. The fructose dehydrogenase-based enzymatic assay correlated highly with gas chromatography-mass spectroscopic analysis of serum fructose with a correlation coefficient of 0.94. This spectrophotometric assay for fructose is easy to perform and well suited to determination of serum fructose. Measurement of serum fructose concentration may provide insight into the relationship between refined fructose intake and diseases including pancreatic cancer.
    Pancreas 07/2009; 38(6):706-12. · 2.95 Impact Factor
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    Stephanie Smooke Praw, Anthony P Heaney
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    ABSTRACT: Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure <1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.
    International Journal of General Medicine 01/2009; 2:209-17.
  • Run Yu, Nicholas N Nissen, Deepti Dhall, Anthony P Heaney
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    ABSTRACT: We report a rare case of nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas. The patient's clinical presentation, diagnosis, treatment, pancreas pathology, and follow-up are reviewed. A 60-year-old patient was incidentally found to harbor a pancreatic mass with markedly elevated glucagon levels but without glucagonoma syndrome. She was initially diagnosed with glucagonoma, and the tumor was resected. Pathological examination demonstrated that the tumor was a nonfunctioning islet cell tumor and revealed nesidioblastosis and hyperplasia of alpha cells and microglucagonoma in the apparently normal surgical margin. The patient still had high postoperative glucagons levels which were suppressed by somatostatin analog treatment. No pancreatic tumors recurred 36 months after surgery. This is the third case of alpha-cell nesidioblastosis reported in the English literature. Nesidioblastosis and hyperplasia of alpha cells should be considered in the differential diagnosis of hyperglucagonemia. Somatostatin analog may be used to suppress glucagon secretion in alpha-cell hyperplasia.
    Pancreas 06/2008; 36(4):428-31. · 2.95 Impact Factor
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    Hongxiang Hui, Manory A Fernando, Anthony P Heaney
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    ABSTRACT: The selective alpha(1)-adrenergic receptor antagonist doxazosin (dox) has been reported to inhibit prostate cancer proliferation. We now demonstrate that dox-treatment inhibits proliferation and induces apoptosis in breast cancer cells in vitro by mechanisms that do not wholly involve the alpha1-adrenergic receptor. Intriguingly, dox-treatment reduced phosphorylated EGFR expression, decreased pERK1/2 levels and decreased NF-kappaB, AP-1, SRE, E2F and CRE-mediated transcriptional activity. EGF- and TNFalpha treatment alone failed to block dox-mediated breast cancer apoptotic effects, but combination of EGF and TNFalpha treatments completely abrogated dox-induced breast cancer cell apoptosis, indicating doxazosin inhibits both EGFR and NF-kappaB signalling pathways to induce breast cancer cell apoptosis. Doxazosin is proposed as a possible novel medical therapy for breast cancer.
    European Journal of Cancer 02/2008; 44(1):160-6. · 5.06 Impact Factor
  • Anthony P Heaney
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    ABSTRACT: BACKGROUND: Pituitary tumors are common and usually grow insidiously over many years. Rarely fatal, treatment still requires multiple cytoreductive surgeries and/or radiation therapy with its attendant side effects. As a disease process of regulatory pathways, pituitary tumors offer numerous potential therapeutic targets, and many, such as the membranal dopamine(2) and somatostatin receptors, have been successfully exploited for many years. Nuclear receptors, such as the estrogen receptor, peroxisome proliferator-activating receptor and retinoic acid receptor, are abundantly expressed in pituitary tumors, and a variety of increasingly potent and specific ligands are emerging. Subcellular therapies aimed at the pituitary tumor transforming gene may also have some utility in pituitary tumor management, though obstacles to targeting nuclear proteins using gene therapy still exist. Other novel agents such as doxazosin, an alpha-adrenoceptor blocker that appears to inhibit nuclear signaling mediated by nuclear factor kappa-B (NFkappaB), and epidermal growth factor receptor may also represent new and safe medical therapies for these benign but problematic tumors. CONCLUSIONS: Increased understanding regarding the etiopathogenesis of pituitary tumors has identified new proteins and pathways that may lead to novel therapies. Empiric exploration of novel targeted therapies developed for other tumor types, guided by pharmacogenomic profiling studies, will likely reveal the utility of many of these novel targeted agents in the treatment of pituitary tumors.
    Hormone Research 02/2007; 68 Suppl 5:132-6. · 2.48 Impact Factor
  • The Lancet Oncology 07/2006; 7(6):518-20. · 25.12 Impact Factor
  • Manory A Fernando, Anthony P Heaney
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    ABSTRACT: Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective alpha(1)-adrenergic receptor antagonist, used to treat hypertension, also inhibits prostate cancer cell proliferation. We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G(0)-G(1) cell cycle arrest, and reduced phosphorylated retinoblastoma levels. In addition, increased annexin-fluorescein isothiocyanate immunoreactivity and cleaved caspase-3 levels, in keeping with dox-mediated apoptosis, were observed in the human and murine pituitary tumor cells, and dox administration to mice, harboring corticotroph tumors, decreased tumor growth and reduced plasma ACTH levels. dox-mediated antiproliferative and proapoptotic actions were not confined to alpha-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the alpha-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory kappaB (IkappaB)-alpha expression, and nuclear factor-kappaB transcription and decreased basal and TNFalpha-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective alpha(1)-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its alpha-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-kappaB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.
    Molecular Endocrinology 01/2006; 19(12):3085-96. · 4.75 Impact Factor

Publication Stats

2k Citations
435.52 Total Impact Points

Institutions

  • 2002–2013
    • University of California, Los Angeles
      • • Department of Medicine
      • • Division of Endocrinology
      Los Angeles, California, United States
  • 1999–2008
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Department of Medicine
      • • Division of Endocrinology
      • • Division of Hematology and Oncology
      Los Angeles, CA, United States
  • 2003
    • University of Birmingham
      • Group of Medical Science and Education
      Birmingham, ENG, United Kingdom
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 2000
    • Children's Hospital Los Angeles
      Los Angeles, California, United States
  • 1996–2000
    • Royal Victoria Eye and Ear Hospital
      Dublin, Leinster, Ireland